bluuebunny/crossref_metadata_2025 huggingface dataset:
RTL1/PEG11 imprinted in human and mouse brain mediates anxiety-like and social behaviors and regulates neuronal excitability in the locus coeruleus
Authors: Chou Ming-Yi , Hu Meng-Chuen , Chen Pin-Yu , Hsu Chi-Lin , Lin Ting-Yu , Tan Mao-Jia , Lee Chih-Yu , Kuo Meng-Fai , Huang Pei-Hsin , Wu Vin-Cent , Yang Shih-Hung , Fan Pi-Chuan , Huang Hsin-Yi , Akbarian Schahram , Loo Tsui-Han , Stewart Colin L , Huang Hsiang-Po , Gau Susan Shur-Fen , Huang Hsien-Sung
Published: May 2022

RTL1/PEG11, which has been associated with anxiety disorders, is a retrotransposon-derived imprinted gene in the placenta. However, imprinting patterns and functions of RTL1 in the brain have not been well-investigated. We found Rtl1 was paternally, but not maternally, expressed in brain stem, thalamus, and hypothalamus of mice, and imprinting status of RTL1 was maintained in human brain. Paternal Rtl1 knockout (Rtl1m+/p-) mice had higher neonatal death rates due to impaired suckling, and low body weights beginning on embryonic day 16.5. High paternal expression of Rtl1 was detected in the locus coeruleus (LC) and Rtl1m+/p- mice showed an increased delay in time of onset for action potentials and inward currents with decreased neuronal excitability of LC neurons. Importantly, Rtl1m+/p- mice exhibited behaviors associated with anxiety, depression, fear-related learning and memory, social dominance, and low locomotor activity. Taken together, our findings demonstrate RTL1 is imprinted in brain, mediates emotional and social behaviors, and regulates excitability in LC neurons.
Feminist constitutionalism: Mapping a discourse in contestation
Authors: Atrey Shreya
Published: May 2022

This article explores what we call feminist constitutionalism and what should be called feminist constitutionalism. It argues that feminist constitutionalism, properly understood, is a discourse in contestation and the competing substantive arguments that define such contestation. A study in feminist constitutionalism would revolve around unraveling this discourse rather than categorizing or labeling particular constitutional texts or judicial outcomes as feminist. The article thus interrogates the current impulse to brand a recent spate of good outcomes by the Supreme Court of India as conclusively feminist, against a long trajectory of gender jurisprudence which brings out a rich and complicated history which can neither be simply cast aside nor celebrated. The only way to make sense of the practice of feminist constitutionalism is thus to study the discourse itself. The article shows the kind of discourse analysis which may lend itself to feminist constitutionalism.
The gatekeepers: Executive lawyers and the executive power in comparative constitutional law
Authors: Casey Conor , Kenny David
Published: May 2022

The growth in the power of the executive branch of government has been accompanied by a related growth—heretofore unexplored in the literature on comparative constitutional law—of the role and importance of executive legal advisors. These influential but often secretive advisors can be the first—and sometimes the only—group to review the actions of the executive or legislative proposals before enactment, for compliance with the constitution. In this article, we compare this practice in four similar but somewhat distinct jurisdictions—the United Kingdom, Canada, the United States, and Ireland—to assess its impact on constitutionalism and the executive power. We conclude that the practice of constitutional review by executive lawyers is highly variable, changing between places and over time along four key axes that can either empower or constrain the executive to varying degrees. It can restrain executive action by holding it within constitutional boundaries; it can bolster the executive power by giving legalistic credibility to its actions while providing little restraint in practice; or it can create policy distortion by overly tightly binding executive and legislative action. Constitutional advice from executive legal advisors, then, does not operate as an exogenous constraint on executive power, but can be structured and manipulated by the executive to have various different effects. As such, we argue that this institution requires much more attention from both comparative constitutional lawyers and constitutional designers to map its effects on the constitutional order and to see what structures, processes, and cultural factors might shape it. Finally, we argue for increased transparency in the provision of executive constitutional advice, as without this, even understanding its effects is extremely difficult.
Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults
Authors: Chen Lu , van Rhee Koen P , Wasmann Roeland E , Krekels Elke H J , Wiezer Marinus J , van Dongen Eric P A , Verweij Paul E , van der Linden Paul D , Brüggemann Roger J , Knibbe Catherijne A J
Published: May 2022

Background

Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the pharmacokinetics and therapeutic efficacy of a drug. In this study, we aim to assess the impact of obesity on fluconazole pharmacokinetics given orally or IV to guide dose adjustments for the obese population.

Methods

We performed a prospective pharmacokinetic study with intensive sampling in obese subjects undergoing bariatric surgery (n = 17, BMI ≥ 35 kg/m2) and non-obese healthy controls (n = 8, 18.5 ≤ BMI < 30.0 kg/m2). Participants received a semi-simultaneous oral dose of 400 mg fluconazole capsules, followed after 2 h by 400 mg IV. Population pharmacokinetic modelling and simulation were performed using NONMEM 7.3.

Results

A total of 421 fluconazole concentrations in 25 participants (total bodyweight 61.0–174 kg) until 48 h after dosing were obtained. An estimated bioavailability of 87.5% was found for both obese and non-obese subjects, with a 95% distribution interval of 43.9%–98.4%. With increasing total bodyweight, both higher CL and Vd were found. Sex also significantly impacted Vd, being 27% larger in male compared with female participants.

Conclusions

In our population of obese but otherwise healthy individuals, obesity clearly alters the pharmacokinetics of fluconazole, which puts severely obese adults, particularly if male, at risk of suboptimal exposure, for which adjusted doses are proposed.
Comparative genomic analysis of ESBL-producing Escherichia coli from faecal carriage and febrile urinary tract infection in children: a prospective multicentre study
Authors: Bidet Philippe , Birgy André , Ouldali Naim , Béchet Stéphane , Levy Corinne , Madhi Fouad , Sobral Elsa , Cohen Robert , Bonacorsi Stéphane
Published: May 2022

Background

The reliability of ESBL-producing Escherichia coli (ESBL-Ec) faecal carriage monitoring to guide probabilistic treatment of febrile urinary tract infection (FUTI) in children remains unclear.

Objectives

To compare the genomic characteristics of ESBL-Ec isolates from faecal carriage and FUTI to assess their correlation and identify a FUTI-associated virulence profile.

Methods

We conducted a prospective multicentre hospital and ambulatory-based study. We analysed the genotypes and virulence factors of both faecal and FUTI ESBL-Ec by whole genome sequencing. Correlations were assessed by non-parametric Spearman coefficient and virulence factors were assessed by chi-squared tests with Bonferroni correction.

Results

We included 218 ESBL-Ec causing FUTI and 154 ESBL-Ec faecal carriage isolates. The most frequent ST was ST131 (44%) in both collections. We found high correlation between carriage and ESBL-Ec FUTI regarding genes/alleles (rho = 0.88, P < 0.0001) and combinations of virulence genes, MLST and serotypes (rho = 0.90, P < 0.0001, rho = 0.99, P = 0.0003, rho = 0.97, P = 0.005 respectively). Beside this strong correlation, we found five genes that were significantly associated with FUTI (papC, papGII, hlyC, hek and traJ). The strongest association with FUTI was found with adhesin gene allele papGII (54% in FUTI versus 16% in carriage) and for papGII and gene traJ alone or in combination (63% versus 24%).

Conclusions

The genomic profile of ESBL-Ec causing FUTI in children strongly correlates with faecal carriage isolates except for a few genes. The presence of papGII and/or traJ in a previously identified carriage strain could be used as a marker of uropathogenicity and may guide the empirical antimicrobial choice in subsequent FUTI.
In vitro activity of mecillinam, temocillin and nitroxoline against MDR Enterobacterales
Authors: Plambeck Lars , Fuchs Frieder , Sattler Janko , Hamprecht Axel
Published: May 2022

Background

With increasing resistance to common antibiotics the treatment of urinary tract infections has become challenging and alternative therapeutic options are needed. In the present study, we evaluate the activity of three older and less frequently used antibiotics against MDR Enterobacterales.

Methods

Susceptibility of mecillinam, temocillin and nitroxoline was assessed in Enterobacterales isolated from urinary specimens with elevated MICs of third-generation cephalosporins. Susceptibility was determined by the recommended reference MIC methods and additionally by disc diffusion. All isolates were characterized for common β-lactamases by phenotypic and molecular assays.

Results

In total 394 Enterobacterales were included. The most common resistance mechanisms were ESBLs (n = 273), AmpC (n = 132), carbapenemases [n = 12, including OXA-48-like (n = 8), VIM (n = 2), KPC (n = 1) and NDM (n = 1)] or others (n = 2). Resistance was observed in 59% of isolates to ceftazidime, in 41% to piperacillin/tazobactam and in 54% to ciprofloxacin. In comparison, resistance was less frequent against mecillinam (15%), temocillin (13%) or nitroxoline (2%). Mecillinam showed higher activity in Enterobacter spp., Escherichia coli and in OXA-48-like-producing isolates compared with temocillin, which was more active in Proteus mirabilis and in ESBL-producing isolates. Activity of nitroxoline was high against all isolates, including carbapenemase-producing isolates. Correlation between disc diffusion and MIC methods was good for mecillinam and moderate for temocillin and nitroxoline.

Conclusions

Mecillinam, temocillin and nitroxoline show good to excellent in vitro activity in MDR Enterobacterales. The activity of mecillinam and temocillin was higher in certain species and restricted depending on β-lactamase production while nitroxoline showed universally high activity irrespective of species or β-lactamase present.
Investigation of Fentanyl Usage in the Seattle Area
Authors: Reinhart Alexandria A , Simpson Celia , Yarid Nicole , Haruff Richard , Baird Geoffrey S
Published: May 2022

Background

Fentanyl was developed in the 1960s as an alternative to morphine, but quickly became a drug of abuse due to its potency, inexpensiveness, and ease of synthesis. One source of exposure is mixing fentanyl into other drugs of abuse (e.g., heroin), but users also actively seek out this potent opioid. While monitoring for pain medication compliance and office-based opioid treatment, we noticed increasing fentanyl use. We sought to investigate this increase in the local population, and see if this reflected the regional health, morbidity, and mortality statistics.

Methods

This data review was determined not to involve “human subjects” as defined by federal regulations by the University of Washington (UW) Human Subjects Division (STUDY00014988). Local data were extracted from the laboratory information system and analyzed. Data from the King County Medical Examiner’s Office derives from cases sent to the Washington State Toxicology Laboratory. The Addictions, Drug, and Alcohol Institute (ADAI) at the UW compiled data from the Washington State Department of Health, the Forensic Laboratory Services Bureau, Washington State Patrol, and the state Office of Financial Management.

Results

We found a significant increase in fentanyl positivity in clinical LC-MS/MS assays, an increase in deaths due to fentanyl, and an increase in the fentanyl usage documented by the public health laboratory.

Conclusions

Clinical data from community toxicology testing performed at academic medical centers can reflect trends in society at large, and as such, there may be a compelling reason to publish and use these data to inform public health approaches.
Realisations, Arrangements, and Ecstasies—Narratives of Religious Experience in the Hare Kṛṣṇa Movement
Authors: Čargonja Hrvoje
Published: May 2022

In Gauḍīya Vaiṣṇava emotional-aesthetic theology and practice, religious experience is understood as realisation or actualisation of the personal relationship with Kṛṣṇa, the original and the supreme form of God. Within such devotional framework, there are two distinct but not exclusive types of accounts of this realisation: ecstasies and arrangements. These two types of stories reflect one of the temporal ambiguities involved in the notion of experience: immediacy/reflection exemplified by the two words for experience in German Erlebnis and Erfahrung. Except for the differences in their temporality, these two types of stories differ in their intersubjectivity. Arrangements are more readily imparted in the public discourse, whereas ecstasy narratives are shared predominantly in private and confidential settings. The difference reflects Gauḍīya orthodoxy’s caution towards deviant ritual behaviour. Although ecstasies with their immediate and extraordinary affectivity are hoped for and cherished, Hare Kṛṣṇa devotees generally stress historical, reflected dimension of experience. Developing a devotional and moral character is valued over transient eudaimonian episodes. In this way, the article shows how temporal ambiguity of experience is culturally elaborated through distinct concepts and narrative types, enabling the intersubjective management of religious affections and articulations of personal religious identities.
Delphinidin induces autophagic flux blockage and apoptosis by inhibiting both multidrug resistance gene 1 and DEAD-box helicase 17 expressions in liver cancer cells
Authors: Sun Shenghui , Xu Kun , Yan Mingjing , Cui Ju , Zhu Kaiyi , Yang Yao , Zhang Xiaoyi , Tang Weiqing , Huang Xiuqing , Dou Lin , Chen Beidong , Lin Yajun , Zhang Xiyue , Man Yong , Li Jian , Shen Tao
Published: May 2022

Objectives

To investigate the function and regulatory mechanisms of delphinidin in the treatment of hepatocellular carcinoma.

Methods

HepG2 and HuH-7 cells were treated with different concentrations of delphinidin. Cell viability was analysed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The cell autophagy and autophagic flux were analysed by LC3b-green fluorescent protein (GFP)-Adv and LC3b-GFP-monomeric red fluorescent protein-Adv transfected HepG2 and HuH-7 cells, respectively. Cell apoptosis was analysed by Hoechst33342 staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and DNA laddering. Cell autophagy, apoptosis and survival related protein expressions were detected by Western blotting.

Key findings

After treatment with different concentrations of delphinidin, the cell survival rate was significantly decreased. Delphinidin could block the autophagic flux, resulting in a significant increase in autophagosomes, and led to an increase in cell apoptosis. The combined application of delphinidin and cisplatin could promote the antitumour effect and reduce the dose of cisplatin in tumour cells. Further mechanism studies reveal that delphinidin could inhibit the multidrug resistance gene 1 (MDR1) and the tumour-promoting transcription cofactor DEAD-box helicase 17 (DDX17) expression in tumour cells. Overexpression of DDX17 could reverse delphinidin’s antitumor function in tumour cells.

Conclusions

Delphinidin has a strong anti-tumour effect by inducing tumour cell autophagic flux blockage and apoptosis by inhibiting of both MDR1 and DDX17 expression.
Clonidine ameliorates cisplatin-induced nephrotoxicity: impact on OCT2 and p38 MAPK pathway
Authors: Fawzy Mariam H , Khodeer Dina M , Elsayed Norhan M , Ahmed Yasser M , Saeed Noha M
Published: May 2022

Objectives

To explore clonidine (Clon) nephroprotective effects as an inhibitor of organic cationic transporter 2 (OCT2) and p38 mitogen-activated protein kinase (p38 MAPK) against cisplatin (CP)-induced nephrotoxicity. OCT2 is mainly responsible for renal accumulation of CP. Clon has been recently recognized as an OCT2 inhibitor and exerts beneficial effects on renal function and p38 MAPK. This study further investigates its underlying anti-inflammatory, antioxidative and antiapoptotic effects.

Methods

Rats were randomly assigned into five groups: (I) CON, (II) CP, (III) CP + Clon 0.125, (IV) CP + Clon 0.25, (V) CP + Clon 0.5, and (VI) Clon 0.5 alone. Clon was administered orally at 0.125, 0.25 and 0.5 mg/kg/day dosages for 10 days. On day 7, rats in groups from (II) to (V) received a single intraperitoneal injection of CP (10 mg/kg).

Key findings

Clon 0.25 mg/kg displayed the best nephroprotective outcomes, justified by the significant amelioration of parameters like renal function, oxidative stress, and inflammatory status, as well as modulated the OCT2 expression, phosphorylation of p38 and p53, compared with Clon 0.125 and 0.5 mg/kg.

Conclusion

This study suggests the promising nephroprotective impact of Clon as an OCT2 inhibitor against CP nephrotoxicity and its proficient role in attenuating oxidative stress, inflammatory status and apoptotic status.
Serial (1–3)-beta-D-Glucan (BDG) monitoring shows high variability among premature neonates
Authors: Ferreras-Antolin Laura , Aziz Nasreen , Warris Adilia
Published: May 2022

This study aimed to characterize the baseline values and dynamics of serum (1,3)-Beta-D-Glucan (BDG) in neonates at high risk of neonatal invasive candidiasis (NIC); as well as to determine the effect of various clinical variables on these levels. Single center prospective cohort study was performed including 20 high-risk neonates (gestational age < 29 weeks and/or birth weight ≤ 1000 gr). Samples for BDG (Fungitell® assay) were obtained twice weekly during 6 weeks. Nineteen neonates were enrolled with a median gestational age of 25 weeks (IQR 24–27), median birth weight of 730 gr (IQR 650–810). None of the neonates was diagnosed with NIC. 190 serum samples were included. The median BDG value was 59 pg/ml (IQR 30–148), mean was 119 pg/ml (SD ± 154). A total of 42.1% (80/190) samples showed values ≥80 pg/ml, with all the neonates presenting at least one test above this cut-off. Neonatal age did not show an association with BDG levels. Exposure to steroids and the use of a heel prick as sampling method were associated with statistically significant higher BDG levels. The BDG levels showed high variability and in a significant proportion of samples values were above the threshold for positivity (e.g., ≥80 pg/ml) in the absence of NIC. The exposure to postnatal steroids and the heel prick as the method of blood sampling were associated with higher BDG levels.

Lay Summary

Neonatal invasive candidiasis (NIC) presents high morbi-mortality. The diagnosis of NIC is often challenging. Blood cultures have limitations and better diagnostic tools are needed. Beta-D-glucan is a diagnostic marker which could be potentially used, although still more clinical data are required.
Galaxy correlation function and local density from photometric redshifts using the stochastic order redshift technique (SORT)
Authors: Kakos James , Primack Joel R , Rodríguez-Puebla Aldo , Tejos Nicolas , Yung L Y Aaron , Somerville Rachel S
Published: May 2022

The stochastic order redshift technique (sort) is a simple, efficient, and robust method to improve cosmological redshift measurements. The method relies upon having a small (∼10 per cent) reference sample of high-quality redshifts. Within pencil-beam-like sub-volumes surrounding each galaxy, we use the precise dN/dz distribution of the reference sample to recover new redshifts and assign them one-to-one to galaxies such that the original rank order of redshifts is preserved. Preserving the rank order is motivated by the fact that random variables drawn from Gaussian probability density functions with different means but equal standard deviations satisfy stochastic ordering. This process is repeated for sub-volumes surrounding each galaxy in the survey. This results in every galaxy being assigned multiple ‘recovered’ redshifts from which a new redshift estimate is determined. An earlier paper applied sort to a mock Sloan Digital Sky Survey at z ≲ 0.2 and accurately recovered the two-point correlation function (2PCF) on scales ≳ 4 h−1Mpc. In this paper, we test the performance of sort in surveys spanning the redshift range 0.75 < z < 2.25. We used two mock surveys extracted from the Small MultiDark–Planck and Bolshoi–Planck N-body simulations with dark matter haloes that were populated by the Santa Cruz semi-analytic model. We find that sort overall improves redshift estimates, accurately recovers the redshift-space 2PCF ξ(s) on scales ≳ 2.5 h−1Mpc, and provides improved local density estimates in regions of average or higher density, which may allow for improved understanding of how galaxy properties relate to their environments.
Annotation Query (AnnoQ): an integrated and interactive platform for large-scale genetic variant annotation
Authors: Liu Zhu , Mushayahama Tremayne , Queme Bryan , Ebert Dustin , Muruganujan Anushya , Mills Caitlin , Thomas Paul D , Mi Huaiyu
Published: May 2022

The Annotation Query (AnnoQ) (http://annoq.org/) is designed to provide comprehensive and up-to-date functional annotations for human genetic variants. The system is supported by an annotation database with ∼39 million human variants from the Haplotype Reference Consortium (HRC) pre-annotated with sequence feature annotations by WGSA and functional annotations to Gene Ontology (GO) and pathways in PANTHER. The database operates on an optimized Elasticsearch framework to support real-time complex searches. This implementation enables users to annotate data with the most up-to-date functional annotations via simple queries instead of setting up individual tools. A web interface allows users to interactively browse the annotations, annotate variants and search variant data. Its easy-to-use interface and search capabilities are well-suited for scientists with fewer bioinformatics skills such as bench scientists and statisticians. AnnoQ also has an API for users to access and annotate the data programmatically. Packages for programming languages, such as the R package, are available for users to embed the annotation queries in their scripts. AnnoQ serves researchers with a wide range of backgrounds and research interests as an integrated annotation platform.
Structures of nonsense-mediated mRNA decay factors UPF3B and UPF3A in complex with UPF2 reveal molecular basis for competitive binding and for neurodevelopmental disorder-causing mutation
Authors: Bufton Joshua C , Powers Kyle T , Szeto Jenn-Yeu A , Toelzer Christine , Berger Imre , Schaffitzel Christiane
Published: May 2022

UPF3 is a key nonsense-mediated mRNA decay (NMD) factor required for mRNA surveillance and eukaryotic gene expression regulation. UPF3 exists as two paralogs (A and B) which are differentially expressed depending on cell type and developmental stage and believed to regulate NMD activity based on cellular requirements. UPF3B mutations cause intellectual disability. The underlying molecular mechanisms remain elusive, as many of the mutations lie in the poorly characterized middle-domain of UPF3B. Here, we show that UPF3A and UPF3B share structural and functional homology to paraspeckle proteins comprising an RNA-recognition motif-like domain (RRM-L), a NONA/paraspeckle-like domain (NOPS-L), and extended α-helical domain. These domains are essential for RNA/ribosome-binding, RNA-induced oligomerization and UPF2 interaction. Structures of UPF2′s third middle-domain of eukaryotic initiation factor 4G (MIF4GIII) in complex with either UPF3B or UPF3A reveal unexpectedly intimate binding interfaces. UPF3B’s disease-causing mutation Y160D in the NOPS-L domain displaces Y160 from a hydrophobic cleft in UPF2 reducing the binding affinity ∼40-fold compared to wildtype. UPF3A, which is upregulated in patients with the UPF3B-Y160D mutation, binds UPF2 with ∼10-fold higher affinity than UPF3B reliant mainly on NOPS-L residues. Our characterization of RNA- and UPF2-binding by UPF3′s middle-domain elucidates its essential role in NMD.
PCGA: a comprehensive web server for phenotype-cell-gene association analysis
Authors: Xue Chao , Jiang Lin , Zhou Miao , Long Qihan , Chen Ying , Li Xiangyi , Peng Wenjie , Yang Qi , Li Miaoxin
Published: May 2022

Most complex disease-associated loci mapped by genome-wide association studies (GWAS) are located in non-coding regions. It remains elusive which genes the associated loci regulate and in which tissues/cell types the regulation occurs. Here, we present PCGA (https://pmglab.top/pcga), a comprehensive web server for jointly estimating both associated tissues/cell types and susceptibility genes for complex phenotypes by GWAS summary statistics. The web server is built on our published method, DESE, which represents an effective method to mutually estimate driver tissues and genes by integrating GWAS summary statistics and transcriptome data. By collecting and processing extensive bulk and single-cell RNA sequencing datasets, PCGA has included expression profiles of 54 human tissues, 2,214 human cell types and 4,384 mouse cell types, which provide the basis for estimating associated tissues/cell types and genes for complex phenotypes. We develop a framework to sequentially estimate associated tissues and cell types of a complex phenotype according to their hierarchical relationships we curated. Meanwhile, we construct a phenotype-cell-gene association landscape by estimating the associated tissues/cell types and genes of 1,871 public GWASs. The association landscape is generally consistent with biological knowledge and can be searched and browsed at the PCGA website.
Cytosolic microRNA-inducible nuclear translocation of Cas9 protein for disease-specific genome modification
Authors: Shin Cheol-Hee , Park Su Chan , Park Il-Geun , Kim Hyerim , An Byoungha , Lee Choongil , Kim Sang-Heon , Lee Juyong , Lee Ji Min , Oh Seung Ja
Published: May 2022

MicroRNA-dependent mRNA decay plays an important role in gene silencing by facilitating posttranscriptional and translational repression. Inspired by this intrinsic nature of microRNA-mediated mRNA cleavage, here, we describe a microRNA-targeting mRNA as a switch platform called mRNA bridge mimetics to regulate the translocation of proteins. We applied the mRNA bridge mimetics platform to Cas9 protein to confer it the ability to translocate into the nucleus via cleavage of the nuclear export signal. This system performed programmed gene editing in vitro and in vivo. Combinatorial treatment with cisplatin and miR-21-EZH2 axis-targeting CRISPR Self Check-In improved sensitivity to chemotherapeutic drugs in vivo. Using the endogenous microRNA-mediated mRNA decay mechanism, our platform is able to remodel a cell's natural biology to allow the entry of precise drugs into the nucleus, devoid of non-specific translocation. The mRNA bridge mimetics strategy is promising for applications in which the reaction must be controlled via intracellular stimuli and modulates Cas9 proteins to ensure safe genome modification in diseased conditions.
Allosteric regulation of noncoding RNA function by microRNAs
Authors: Gorbea Carlos , Elhakiem Abdalla , Cazalla Demián
Published: May 2022

HSUR1 and HSUR2, two noncoding RNAs expressed by the oncogenic Herpesvirus saimiri, bind host microRNAs miR-142-3p, miR-16, and miR-27 with different purposes. While binding of miR-27 to HSUR1 triggers the degradation of the microRNA, miR-16 is tethered by HSUR2 to target host mRNAs to repress their expression. Here we show that the interaction with miR-142-3p is required for the activity of both HSURs. Coimmunoprecipitation experiments revealed that miR-142-3p allosterically regulates the binding of miR-27 and miR-16 to HSUR1 and HSUR2, respectively. The binding of two different miRNAs to each HSUR is not cooperative. HSURs can be engineered to be regulated by other miRNAs, indicating that the identity of the binding miRNA is not important for HSUR regulation. Our results uncover a mechanism for allosteric regulation of noncoding RNA function and a previously unappreciated way in which microRNAs can regulate gene expression.
Adrenal insufficiency is common amongst kidney transplant recipients receiving maintenance prednisolone and can be predicted using morning cortisol
Authors: Tomkins Maria , Martin-Grace Julie , Kennedy Carmel , McEnroe Olive , Heverin Karen , Srinivasan Shari , Little Dilly , Conlon Peter , De Freitas Declan , Denton Mark , Magee Colm , O'Seaghdha Conall , O'Reilly Michael W , Thompson Chris J , Sherlock Mark
Published: May 2022

Background

Long-term glucocorticoid therapy is a key component of immunosuppression for kidney transplant recipients (KTRs), leading to significant cumulative glucocorticoid exposure. The aims of this study are to investigate the prevalence of adrenal insufficiency (AI) in KTRs taking prednisolone and to develop a screening algorithm to identify patients at the highest risk of AI.

Methods

In this cross-sectional cohort study, 67 KTRs receiving prednisolone underwent a short synacthen test (SST) and measurement of cumulative glucocorticoid exposure.

Results

A total of 72% (n = 48) of participants failed the SST. Participants with AI had a higher daily prednisolone dose (4.9 versus 4.2 mg/day; P = .002) and greater cumulative glucocorticoid exposure (289 versus 111 mg/kg; P = .03) than those with intact adrenal function. Participants with AI had lower baseline cortisol than participants with intact adrenal function (143 versus 303 nmol/L; P < .001). Morning cortisol of >288 nmol/L predicted a normal SST with 100% specificity [95% confidence interval (CI) 92–100] and 70% sensitivity (95% CI 56–78%), therefore excluding AI.

Conclusions

Our results suggest KTRs are at a higher risk for AI than previously reported. A morning serum cortisol measurement is a useful screening tool in this cohort, reducing the need for stimulatory testing by 44%. KTRs with AI need education regarding glucocorticoid sick rules, similar to patients with other forms of AI.
End-proximal tubule phosphate concentration increases as GFR falls in humans: measurement by means of a lithium clearance-based methodology
Authors: Colussi Giacomo , Menegotto Alberto , Querques Marialuisa , Ravera Federica , Verdesca Simona , Colombo Valeriana , Minetti Enrico E
Published: May 2022

Background

Microscopic nephrocalcinosis secondary to intratubular calcium phosphate (CaP) precipitation is thought to accelerate progression to end-stage renal failure in chronic kidney diseases. In phosphorus (P)-loaded uninephrectomized rats, intratubular CaP crystal formation and progressive tubular damage occurred when end-proximal tubule P concentration (ePTpc) increased above a threshold level.

Methods

We have calculated ePTpc in humans by urine P and creatinine concentration, with the end-proximal tubule fluid volume calculated either as lithium (Li) clearance (ePTpc-Li) or as a fixed 0.7 fraction of glomerular filtration rate (GFR), as published (ePTpc-70). Healthy people undergoing living transplant kidney donation before (DON-pre, n = 70) and after (DON-post, n = 64) nephrectomy and 25 patients with stage 2–5 CKD were investigated while on regular free diet.

Results

ePTpc showed a stepwise increase with decreasing functional renal mass (DON-pre 2.51 ± 0.99 and 1.56 ± 0.47 mg/dL for ePTpc-Li and -70 calculation, respectively; DON-post 3.43 ± 1.14 and 2.18 ± 0.44;  CKD 5.68 ± 3.30 and 3.00 ± 1.30, P < .001 for all); ePTpc was inversely correlated with Ccr and directly with PTH, fractional P excretion and excretion (UpV) corrected for GFR (P < .001 for all), but not with Pp. ePTpc-Li and ePTpc-70 were significantly correlated (r = 0.62, P < .001), but ePTpc-70 was lower than the corresponding ePTpc-Li. Levels of ePTpc increased above a suggested dangerous threshold when daily UpV/GFR was higher than about 10 mg/mLCcr.

Conclusions

ePTpc progressively increases in humans as functional renal mass falls independently from plasma P levels. Main determinants of ePTpc rise are GFR fall, degree of phosphaturia per unit GFR and P intake corrected for GFR. It may become a novel, potentially useful, indicator to guide management of CKD patients.
Lung toxicity of lomustine in the treatment of progressive gliomas
Authors: Seliger Corinna , Nürnberg Christina , Wick Wolfgang , Wick Antje
Published: May 2022

Background

Pulmonary fibrosis is a rare, but dangerous side effect of CCNU (lomustine). CCNU is a frequently used chemotherapeutic agent in the setting of recurrent or progressive glioblastoma. At present, CCNU is also administered in patients with newly diagnosed gliomas in combination with temozolomide. There is only little evidence if, and how, lung function should be monitored on treatment with CCNU.

Methods

We retrospectively collected data on patient characteristics, lung function analyses, and relevant toxicities among 166 brain tumor patients treated with CCNU at a German University Hospital and National Cancer Center.

Results

The patient collective mainly included patients with recurrent glioblastoma who received a mean number of 2.64 ± 1.57 cycles. There was overall no statistically significant change in parameters of pulmonary restriction among patients treated with CCNU. On an individual patient basis, a >10% decrease in the absolute vital capacity was primarily seen in patients with prior lung diseases and smokers. Other severe toxicities mainly included thrombocytopenia, leukopenia, nausea, and vomiting.

Conclusions

Our findings support to limit lung function analyses on CCNU to patients with gliomas and pulmonary risk factors. However, all patients should be closely followed for clinical symptoms of pulmonary restriction.
Intrinsically flexible displays: key materials and devices
Authors: Zhao Zhiyuan , Liu Kai , Liu Yanwei , Guo Yunlong , Liu Yunqi
Published: May 2022

Continuous progress in flexible electronics is bringing more convenience and comfort to human lives. In this field, interconnection and novel display applications are acknowledged as important future directions. However, it is a huge scientific and technical challenge to develop intrinsically flexible displays due to the limited size and shape of the display panel. To address this conundrum, it is crucial to develop intrinsically flexible electrode materials, semiconductor materials and dielectric materials, as well as the relevant flexible transistor drivers and display panels. In this review, we focus on the recent progress in this field from seven aspects: background and concept, intrinsically flexible electrode materials, intrinsically flexible organic semiconductors and dielectric materials for organic thin film transistors (OTFTs), intrinsically flexible organic emissive semiconductors for electroluminescent devices, and OTFT-driven electroluminescent devices for intrinsically flexible displays. Finally, some suggestions and prospects for the future development of intrinsically flexible displays are proposed.
Skin and respiratory ill-health attributed to occupational face mask use
Authors: Seed M J , Fowler K , Byrne L , Carder M , Daniels S , Iskandar I Y K , Feary J , Gawkrodger D J , van Tongeren M
Published: May 2022

Background

Face mask use in the workplace has become widespread since the onset of the Covid-19 pandemic and has been anecdotally linked to adverse health consequences.

Aims

To examine reports of adverse health consequences of occupational face mask use received by The Health and Occupation Research (THOR) network before and after the pandemic onset.

Methods

THOR databases were searched to identify all cases of ill-health attributed to ‘face mask’ or similar suspected causative agent between 1 January 2010 and 30 June 2021.

Results

Thirty two cases were identified in total, 18 reported by occupational physicians and 14 by dermatologists. Seventy-five per cent of cases were reported after the pandemic onset and 91% cases were in the health and social care sector. 25 of the 35 (71%) diagnoses were dermatological, the most frequent diagnoses being contact dermatitis (14 cases) and folliculitis/acne (6 cases). Of the seven respiratory diagnoses, four were exacerbation of pre-existing asthma.

Conclusions

There is evidence of an abrupt increase in reports of predominantly dermatological ill-health attributed to occupational face mask use since the start of the pandemic. Respiratory presentations have also occurred.
Management of Acral and Mucosal Melanoma: Medical Oncology Perspective
Authors: Jung Seungyeon , Johnson Douglas B
Published: May 2022

Acral and mucosal melanomas (MM) are rare subtypes of melanoma that are biologically and clinically distinct from cutaneous melanoma. Despite the progress in the treatment of cutaneous melanomas with the development of targeted and immune therapies, the therapeutic options for these less common subtypes remain limited. Difficulties in early diagnosis, the aggressive nature of the disease, and the frequently occult sites of origin have also contributed to the poor prognosis associated with acral and MM, with substantially worse long-term prognosis. The rarity of these subtypes has posed significant barriers to better understanding their biological features and investigating novel therapies. Consequently, establishing standardized treatment guidelines has been a challenge. In this review, we provide a brief overview of the current knowledge regarding acral and MM, focusing on their epidemiology, genetic backgrounds, and unique clinical characteristics. Further discussion centers around the management of primary and advanced disease and the role of emerging targeted and immune therapies for these subtypes, specifically focusing on issues relevant to medical oncologists.
Sleep restriction and age effects on waking alpha EEG activity in adolescents
Authors: Campbell Ian G , Kim Elizabeth I , Darchia Nato , Feinberg Irwin
Published: May 2022

Study Objectives

To understand how sleep need changes across adolescence our laboratory is carrying out a longitudinal dose–response study on the effects of sleep duration on daytime sleepiness and performance. This report focuses on the relation of the waking alpha (8–12 Hz) electroencephalogram (EEG) to prior sleep duration, whether this relation changes with age, and whether decreased waking alpha power is related to changes in daytime sleepiness, vigilance, and executive functioning.

Methods

Study participants (n = 77) entered the study at ages ranging from 9.86 to 13.98 years and were studied annually for 3 years. Each year participants completed each of three time in bed (TIB) conditions (7, 8.5, or 10 h) for four consecutive nights. Waking EEG was recorded on the day following the fourth night.

Results

TIB restriction and resultant sleep loss were associated with reduced alpha power with the effect being stronger for the eyes closed condition. TIB restriction altered the power spectrum within the alpha range by increasing the frequency of maximum alpha power. Alpha power decreased with age, but the effect of TIB restriction did not decrease with age. Reduced alpha power was associated with small but significant increases in subjective and objective sleepiness but was not associated with changes in vigilance or executive functioning.

Conclusions

We interpret the alpha depression following sleep loss as incomplete sleep dependent recuperation that contributes to daytime sleepiness. The absence of a decrease in TIB effects with age indicates that this sleep need measure does not decrease over early to mid-adolescence.
Evidence for Elicitation of an Oxidative Burst in Vitis vinifera by Xylella fastidiosa Cold Shock Protein Peptide csp20
Authors: Burbank Lindsey P. , Ochoa Joanna
Published: May 2022

Plant response to pathogen challenge involves recognition by specific receptors of conserved molecular patterns associated with pathogenic organisms. Understanding a wider range of pathogen detection pathways in different plant species is valuable for identification and development of pathogen-resistant plant material. Xylella fastidiosa is an important bacterial pathogen of several agricultural crops including table and wine grapes. Although some pathogen recognition pathways have been identified for X. fastidiosa in host plants, there are likely several other molecular interactions that could be exploited to increase plant resistance to this pathogen. This study identified a conserved bacterial cold shock protein component (Xfcsp20) as an elicitor of reactive oxygen species production by Vitis vinifera plant tissue, an indication of pathogen recognition response. Characterization of Xfcsp20 as an elicitor of an oxidative burst in grapevine hosts of X. fastidiosa will be useful to continued work in the areas of bacterial-plant interactions and plant resistance.

[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Influence of Deep Serratus Anterior Plane Block on Chronic Pain at 3 Months After Breast-Conserving Surgery
Authors: Fuzier Régis , Salvignol Geneviève , Gilbert Olivier , Bremaud Marc , Bataille Benoît , Izard Philippe
Published: May 2022

Objectives:

In 2015, we evaluated our practices regarding pain after breast-conserving surgery. Thereafter, we have adapted our practices by performing a systematic deep serratus plane block before the surgical incision. In 2019, we assessed the impact of these changes in terms of chronic pain. The main objective of this study was to evaluate the prevalence of chronic pain 3 months after this type of surgery.

Materials and Methods:

All patients treated with breast-conserving surgery as outpatients were included in this prospective study between April and July 2019. After inducing general anesthesia, 20 mL of ropivacaine 3.75 mg/mL were injected under the serratus muscle. Morphine titration was performed in the recovery room according to pain scores. A pain and quality of life questionnaire was sent 3 months after surgery. A backward logistic regression model was applied to calculate the adjusted odds ratios.

Results:

The final analysis involved 137 patients. Three months after surgery, 43 patients (31%) reported persistent pain related to the surgery. Maximum pain in the last 24 hours was moderate to severe in 60% of cases, 16 patients (35%) took painkillers. Morphine titration in the recovery room was required in 25 patients (18%). Younger age and the use of lidocaine to prevent after injection of propofol during general anesthesia induction appeared to be protective factors for the risk of pain at 3 months (secondary endpoints).

Discussion:

No persistent pain at 3 months was reported in 69% of cases. Furthermore, the use of a deep serratus anterior plane block before the surgical incision has limited the need for morphine titration in the recovery room to <1 patient in 5. These evaluations of professional practices should be encouraged.
Church Contextual Factors Associated With Latinx Physical Activity and Park Use
Authors: Perez Lilian G. , Cohen Deborah A. , Seelam Rachana , Han Bing , Arredondo Elva M. , Castro Gabriela , Rodriguez Claudia , Mata Michael A. , Larson Anne , Derose Kathryn P.
Published: May 2022

Churches can be important settings for promoting physical activity (PA) among Latinx populations. Little is known about what factors across the church context—social, organizational, and physical (outdoor spaces)—are associated with Latinx PA to inform faith-based PA interventions. This study investigated associations of church contextual factors with Latinx PA. We used cross-sectional data from a Latinx adult sample recruited from 6 churches that each had a nearby park in Los Angeles, California (n = 373). Linear or logistic regression models examined associations of church PA social support, PA social norms, perceived quality and concerns about the park near one's church, and church PA programming with 4 outcomes: accelerometer-based moderate-to-vigorous PA (MVPA) and self-reported adherence to PA recommendations, use of the park near one's church, and park-based PA. Park quality and concerns were positively associated with using the park near one's church. Church PA programming was positively associated with park-based PA. None of the factors were related to accelerometer-based MVPA or meeting PA recommendations. Findings suggest targeting church PA programming and nearby parks may be key to improving Latinx park use. Church and local parks department partnerships may help enhance park conditions to support churchgoing Latinx PA and health.
Geriatric Falls: A Registry-Based Study in the Netherlands
Authors: Verbeek Frank H. O. , Ham Wietske H. W. , Verbeek André L. M. , de Man-van Ginkel Janneke M. , van Os-Medendorp Harmieke , Westers Paul , Leenen Luke P. H.
Published: May 2022

BACKGROUND:

Falls in people 65 years and older evaluated in the emergency department are increasing. Of all unintentional injury-related deaths among older people, 55% are due to falls. The impact of falls, especially concerning Dutch older people with the highest proportion of living independently worldwide, is unclear.

OBJECTIVE:

To identify the influence of age, gender, health conditions, and type of fall on the severity of injury, hospital length of stay, mortality, and discharge destination.

METHODS:

A total number of 6,084 patients from a comprehensive regional trauma care system, 65 years and older and hospitalized after a fall, were included. Groups were compared for patient-related factors and multivariable logistic regression analysis to explore the consequences.

RESULTS:

Mean age was 82 years (SD = 8.3), and 70% were female. Most falls (66.4%) were due to “slipping and tripping” or “falls on the same level,” 57.4% had Injury Severity Scores between 9 and 12, and 43.3% were discharged home. Higher age and type of fall increased the likelihood of severe injuries. Men experienced shorter hospital stays than women and were less frequently discharged home. Mortality was higher in males (10.8%) than in females (6.7%) and increased with the American Society of Anesthesiologists scores for preexisting health conditions.

CONCLUSION:

Advanced age, gender, type of fall, and prior health status play a significant role in the severity of injuries, length of hospital stay, 30-day mortality, and higher discharge destination to care homes in older people hospitalized after a fall.
Evaluation of Stop the Bleed Training Among High School Personnel: A Qualitative Study
Authors: Jones Allison R. , Strickland Virginia , Brown Michelle R.
Published: May 2022

BACKGROUND:

Uncontrolled hemorrhage is the primary preventable cause of death following trauma. Stop the Bleed training exists to promote identification and basic treatment of life-threatening bleeding in the prehospital or community setting. Limited qualitative research is available on participant evaluation of hemorrhage control training for laypersons.

OBJECTIVE:

To evaluate the experience and satisfaction with Stop the Bleed training among lay community members in an urban public school setting.

METHODS:

Three group interviews were conducted with public high school personnel (faculty and staff) who received Stop the Bleed training. Personnel were asked to evaluate the training and provide suggestions for improvement. Responses were digitally recorded and transcribed verbatim. Content analysis for common themes was performed using NVivo.

RESULTS:

A total of eight participants were interviewed. Participants expressed satisfaction with hands-on training and dissatisfaction with crowded and rushed training conditions. Major themes included: (1) skill acquisition, retention, and decay, (2) training format and setting, and (3) use of simulation.

CONCLUSIONS:

Current Stop the Bleed training is considered satisfactory among public school educators. Suggestions for improvement include annual retraining programs and simulation-enhanced training opportunities.