bluuebunny/crossref_metadata_2025 huggingface dataset:
Wrestlemania! Summit Diplomacy and Foreign Policy Performance after Trump
Authors: Day Benjamin S , Wedderburn Alister
Published: June 2022

In this article, we propose the category of “foreign policy performance” in order to argue that a recognition of foreign policy's theatricality can illuminate its contribution to generative processes of social construction and world-making. We focus on the practice of summit diplomacy, which operates according to a “theatrical rationality” that blurs the boundary between substantive and symbolic politics. Noting that Donald Trump's presidency called into question many of international relations’ prevailing assumptions regarding foreign policy's formulation and execution, we suggest that a performance-oriented analytic can facilitate a critical reckoning both with Trump himself and with the “statesmanlike” norms he eschewed. We read Trump's performances at international summits with reference to professional wrestling, which for all its melodramatic absurdity is a venerable and complex theatrical tradition with a highly developed critical language. Guided by four pieces of wrestling argot (“heat,” “heel,” “kayfabe,” and “cutting a promo”), we use process-tracing techniques to develop a wrestling-oriented reading of Trump's 2018 summit with Kim Jong-Un in Singapore. We argue that using wrestling in order to read Trump and Kim's deviation from the conventional norms and repertoires of foreign policy performance enables a critical assessment of the stakes at play in their reconstruction and re-establishment.
Using Data to Create Change? Interrogating the Role of Data in Ending Attacks on Healthcare
Authors: Fast Larissa , Read Róisín
Published: June 2022

This article explores the non-straightforward role of data about attacks on health in creating policy and normative change to safeguard access to healthcare and protect healthcare providers in conflict. Acknowledging the importance of data as a key component in the quest to reduce instances of attacks, we take this one step further, asking: what is the relationship between data, action, and change processes? While scholars have examined the efficacy of transnational advocacy, rarely has the specific role of data been the focus of analysis. Here we consider two pathways for creating change: operational change designed to prevent or mitigate the impact of attacks on health at the level of those affected by attacks, and normative change that leads to a reduction in the frequency of attacks, at the level of those perpetrating attacks. Drawing on research investigating the influence of data in humanitarian decision-making and security management and research on transnational advocacy, we discuss the lessons for responding to the problem of attacks on healthcare. We end by broadening the scope of our conclusions to highlight the non-straightforward role of data in operational and normative change processes more generally.
Engineering a CRISPR interference system targeting AcrAB-TolC efflux pump to prevent multidrug resistance development in Escherichia coli
Authors: Wan Xiulin , Li Qingyang , Olsen Rikke Heidemann , Meng Hecheng , Zhang Zhigang , Wang Junlin , Zheng Hanyu , Li Lili , Shi Lei
Published: June 2022

Objectives

We engineered a CRISPR interference (CRISPRi) system targeting the AcrAB-TolC efflux pump to prevent MDR development in Escherichia coli.

Methods

Nine specific single-guide RNAs (sgRNAs) were designed to target the components of the AcrAB-TolC efflux pump, namely AcrA, AcrB and TolC. A total of thirteen CRISPRi recombinant plasmids were constructed with single or clustered sgRNAs. The transcriptional levels of the target genes, MICs of multiple antibiotics and biofilm formation in each CRISPRi strain were tested.

Results

The CRISPRi system expressing sgRNA clusters targeting acrB and tolC simultaneously exhibited the highest inhibitory effect on AcrAB-TolC efflux pump activity in E. coli HB101, with 78.3%, 90.0% and 65.4% inhibition rates on the transcriptional levels of acrA, acrB and tolC, respectively. The CRISPRi system resulted in ∼2-, ∼8- and 16-fold increased susceptibility to rifampicin, erythromycin and tetracycline, respectively. In addition, the constructed CRISPRi system reduced biofilm formation with inhibition rates in the range of 11.2% to 58.2%.

Conclusions

To the best of our knowledge, this is the first report on the construction of an inducible CRISPRi system targeting the AcrAB-TolC efflux pump to prevent MDR development in E. coli. This study provides insights for future regulation and manipulation of AcrAB-TolC activity and bacterial MDR by a CRISPRi system.
A framework for the oversight and local deployment of safe and high-quality prediction models
Authors: Bedoya Armando D , Economou-Zavlanos Nicoleta J , Goldstein Benjamin A , Young Allison , Jelovsek J Eric , O’Brien Cara , Parrish Amanda B , Elengold Scott , Lytle Kay , Balu Suresh , Huang Erich , Poon Eric G , Pencina Michael J
Published: June 2022

Artificial intelligence/machine learning models are being rapidly developed and used in clinical practice. However, many models are deployed without a clear understanding of clinical or operational impact and frequently lack monitoring plans that can detect potential safety signals. There is a lack of consensus in establishing governance to deploy, pilot, and monitor algorithms within operational healthcare delivery workflows. Here, we describe a governance framework that combines current regulatory best practices and lifecycle management of predictive models being used for clinical care. Since January 2021, we have successfully added models to our governance portfolio and are currently managing 52 models.
Short Communication: Influence of estrus activity and reproductive tract size and position scores on fertility in Bos indicus and Bos taurus suckled beef cows
Authors: Speckhart Savannah L , Oliveira Filho Ramiro V , Franco Gessica A , Vasconcelos Jose L M , Schrick F Neal , Edwards J Lannett , Pohler Ky G
Published: June 2022

The primary objective of this study was to determine if estrus activity and reproductive tract size and position score (SPS) are associated with pregnancy outcomes in Bos indicus (Nelore) and Bos taurus (Angus) beef cows. In study 1, multiparous Nelore cows (n = 1,280) were artificially inseminated at a fixed time (FTAI, day 0) using an estradiol and progesterone (P4)-based estrus synchronization protocol. In study 2, multiparous Angus cows (n = 764) were artificially inseminated at a fixed time (FTAI, day 0) using a gonadotropin-releasing hormone and P4-based estrus synchronization protocol. Estrus activity was assessed using Estrotect heat detector patches and scored on day 0 using the following scoring system: 0 (patch was lost, most likely due to repeated mounting), 1 (<25% activation), 2 (≥25%, <50% activation), 3 (≥50%, <75% activation), or 4 (>75% activation) where patch scores of 1 and 2 signified no or limited estrus activity, whereas scores of 0, 3, and 4 had increased estrus activity. Reproductive tract SPS were assigned on day 0 as SPS1: small and compact resting within the pelvic cavity; SPS2: intermediate, resting partially outside the pelvic cavity; and SPS3: larger and resting outside the pelvic cavity. Pregnancy diagnosis was performed by ultrasound on day 30 and 100 after FTAI. Cows were determined as undergoing pregnancy loss if a viable embryo with heartbeat was detected at day 30 but was no longer present at day 100. Pregnancy rate at day 30 was influenced by estrus activity and SPS in both Nelore (P = 0.004) and Angus (P = 0.009) cows. Specifically, cows with smaller reproductive tracts (SPS1) had greater (P < 0.001) pregnancy rate when estrus was expressed before FTAI. There was no effect of estrus activity nor reproductive tract size on pregnancy loss between day 30 and 100 for both breeds. In summary, estrus activity before FTAI may influence reproductive outcomes differently depending on size and position of the reproductive tract at time of breeding.
Effects of bamboo leaf extract intervention on the growth performance, antioxidant capacity, and hepatic apoptosis in suckling piglets
Authors: Yu Ge , Ji Shuli , Yun Yang , Cheng Kang , Zhang Hao , Jia Peilu , Wang Tian , Zhang Lili
Published: June 2022

This study investigated whether bamboo leaf extract (BLE) could improve the growth performance, antioxidant capacity, and inhibit hepatic apoptosis in suckling piglets. Sixty-four suckling piglets were orally gavaged with vehicle (CON group) or 100, 200, or 300 mg BLE/kg body weight (BL, BM, and BH groups) at 3 d of age for 21 d (n = 8). The results showed that BLE treatment had no effects on the growth performance (P > 0.05). Compared with the CON group, the BM and BH groups decreased (P < 0.05) the jejunal and hepatic malondialdehyde (MDA) contents. Supplementation with BLE increased antioxidant enzymes activities and the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and several targeted genes in the jejunum and liver of suckling piglets. The hepatic apoptosis rate was lower (P < 0.05) in BLE treatment than in the CON group. Compared with the CON group, the BLE groups showed increased (P < 0.05) mRNA levels of B-cell-lymphoma protein 2 (BCL-2), whereas decreased (P < 0.05) BCL-2-associated X (BAX) and cysteine aspartate specific protease-3 (caspase-3) mRNA levels. The results of protein expressions of BCL-2 and caspase-3 were consistent with those of mRNA levels. Altogether, our results indicated that BLE intervention can improve the antioxidant capacity and inhibit hepatic apoptosis in suckling piglets.
The Value-Translation Model of Consumer Activism: How Consumer Watchdog Organizations Change Markets
Authors: Nøjgaard Mikkel
Published: June 2022

How do consumer watchdog organizations (CWOs) change markets? Research on consumer activism has prioritized studying grassroots movements of ordinary consumers over more formalized activist actors, resulting in a paucity of theoretical resources for understanding the activism of powerful consumer organizations such as CWOs. This article draws on the sociology of valuation and evaluation to develop a new theoretical model of consumer activism, the value-translation model, which departs from previous research in shifting the focus from activists’ efforts to change which higher-order values govern markets to activists’ efforts to change how they govern markets. Through a historical study of a Danish CWO associated with the comparative-testing movement, the article shows how CWOs “translate” higher-order values into “trials of value” (i.e., practical evaluation procedures that “test” the strength of the connection between goods and higher-order values) and “evaluation agents” (i.e., market actors capable of carrying out and acting on evaluations). Such translations structure how higher-order values influence markets and are therefore critical to manage for directing market change. The study extends our understanding of how objects are systemically valorized and revalorized and how formalized forms of consumer activism can play an important role in such processes.
Revision of the Educator Group ofCulex(Melanoconion) (Diptera, Culicidae)
Authors: Rodrigues de Sá Ivy Luizi , Hutchings Rosa Sá Gomes , Hutchings Roger William , Sallum Maria Anice Mureb
Published: June 2022

The Educator Group of the Melanoconion Section of Culex (Melanoconion) (Diptera, Culicidae) is reviewed. Currently, the group includes the following valid species: Culex (Melanoconion) aphyllusTalaga, 2020, Culex (Melanoconion) cristovaoi Duret, 1968, Culex (Melanoconion) educatorDyar & Knab, 1906, Culex (Melanoconion) eknomiosForattini & Sallum, 1992, Culex (Melanoconion) inadmirabilisDyar, 1928, Culex (Melanoconion) rachoui Duret, 1968, Culex (Melanoconion) theobaldi (Lutz), 1904, Culex (Melanoconion) vaxusDyar, 1920, Culex (Melanoconion) angularis Sá & Sallum n. sp., Culex (Melanoconion) spiniformis Sá & Hutchings n. sp., Culex (Melanoconion) longistriatus Sá & Hutchings n. sp., Culex (Melanoconion) anelesDyar & Ludlow, 1922, Culex (Melanoconion) apeteticus Howard, Dyar & Ludlow, 1913, and Culex (Melanoconion) bibulusDyar, 1920. The last three species were resurrected from synonymy of either Cx. educator or Cx. vaxus. Descriptions, differential diagnoses, bionomics, and geographical data are provided for each species when available.
Reproductive Factors and Colorectal Cancer Risk: A Population-Based Case-Control Study
Authors: Amitay Efrat L , Niedermaier Tobias , Alwers Elizabeth , Chang-Claude Jenny , Hoffmeister Michael , Brenner Hermann
Published: June 2022

Background

Hormone-replacement therapy (HRT) is associated with lower colorectal cancer (CRC) risk among postmenopausal women. However, little is known about the effects of lifetime exposure of women to varying levels of estrogen and progesterone through reproductive factors such as parity, use of oral contraceptives (OC), breastfeeding, and menstruation on CRC risk.

Methods

We assessed associations between reproductive factors and CRC risk among 2650 female CRC patients aged 30+ years and 2175 matched controls in a population-based study in Germany, adjusting for potential confounders by multiple logistic regression.

Results

Inverse associations with CRC risk were found for numbers of pregnancies (odds ratio [OR] per pregnancy = 0.91, 95% confidence interval [CI] = 0.86 to 0.97), breastfeeding for 12 months and longer (OR = 0.74, 95% CI = 0.61 to 0.90), and use of either OC or HRT (OR = 0.75, 95% CI = 0.64 to 0.87) or both (OR = 0.58, 95% CI = 0.48 to 0.70). Similar results were found for postmenopausal women only and when adjusting for number of pregnancies and for all reproductive factors analyzed together. Breastfeeding duration of 12 months and longer was associated with lower risk of cancer only in the proximal colon (OR = 0.58, 95% CI = 0.45 to 0.74).

Conclusions

Several reproductive factors were associated with lower CRC risk in women, including number of pregnancies, breastfeeding duration, and use of OC and HRT. This suggests that women’s exposure to female reproductive hormones plays a key role in the difference in CRC risk between women and men and in site-specific CRC risk.
Novel rice iron biofortification approaches using expression of ZmYS1 and OsTOM1 controlled by tissue-specific promoters
Authors: Kawakami Yuta , Gruissem Wilhelm , Bhullar Navreet K
Published: June 2022

Intrinsic improvement of iron (Fe) concentration in rice grains, called rice Fe biofortification, is a promising countermeasure against widespread human Fe deficiency. In this study, two novel rice Fe biofortification approaches are reported. The first approach (Y approach) involved the expression of maize YELLOW STRIPE 1 controlled by the HEAVY METAL ATPASE 2 promoter. The Y approach increased the polished grain Fe concentrations up to 4.8-fold compared with the non-transgenic (NT) line. The second approach (T approach) involved the expression of rice TRANSPORTER OF MUGINEIC ACID 1 controlled by the FERRIC REDUCTASE DEFECTIVE LIKE 1 promoter. The T approach increased the polished grain Fe concentrations by up to 3.2-fold. No synergistic increases in the polished grain Fe concentrations were observed when Y and T approaches were combined (YT approach). However, the polished grain Fe concentrations further increased by 5.1- to 9.3-fold compared with the NT line, when YT approach was combined with the endosperm-specific expression of FERRITIN (YTF approach), or when YTF approach was combined with the constitutive expression of NICOTIANAMINE SYNTHASE (YTFN approach). Total grain weight per plant in most Y, T, YT, and YTFN lines was comparable to that in the NT line, while it was significantly decreased in most YTF lines. The novel approaches reported in this study expand the portfolio of genetic engineering strategies that can be used for Fe biofortification in rice.
Gamma-rays from the circumgalactic medium of M31
Authors: Roy Manami , Nath Biman B
Published: June 2022

We discuss the production of γ-rays from cosmic rays (CR) in the circumgalactic medium (CGM) of Andromeda (M31) in light of the recent detection of γ-rays from an annular region of ∼5.5–120 kpc away from the M31 disc. We consider the CRs accelerated as a result of the star formation in the M31 disc, which are lifted to the CGM by advection due to outflow and CR diffusion. The advection time-scale due to bulk flow of gas triggered by star formation activity in the M31 disc is comparable (∼Gyr) to the diffusion time-scale with diffusion coefficient ≥1029 cm2 s−1 for the propagation of CR protons with energy ∼412 GeV that are responsible for the highest energy photons observed. We show that a leptonic origin of the γ-rays from cosmic ray (CR) electrons has difficulties, as the inverse Compton time-scale (∼Myr) is much lower than advection time-scale (∼Gyr) to reach 120 kpc. Invoking CR electrons accelerated by accretion shocks in the CGM at ∼100–120 kpc does not help since it would lead to diffuse X-ray features that are not observed. We, therefore, study the production of γ-rays via hadronic interaction between CR protons and CGM gas with the help of numerical two-fluid (thermal + CR) hydrodynamical simulation. We find that a combination of these mechanisms that are related to the star formation processes in M31 in the last ∼Gyr, along with diffusion and hadronic interaction, can explain the observed flux from the CGM of M31.
The Visayan Warty Pig (Sus cebifrons) Genome Provides Insight Into Chromosome Evolution and Sensory Adaptation in Pigs
Authors: Liu Langqing , Megens Hendrik-Jan , Crooijmans Richard P.M.A. , Bosse Mirte , Huang Qitong , van Sonsbeek Linda , Groenen Martien A.M. , Madsen Ole
Published: June 2022

It is largely unknown how mammalian genomes evolve under rapid speciation and environmental adaptation. An excellent model for understanding fast evolution is provided by the genus Sus, which diverged relatively recently and lacks postzygotic isolation. Here, we present a high-quality reference genome of the Visayan warty pig, which is specialized to a tropical island environment. Comparing the genome sequences and chromatin contact maps of the Visayan warty pig (Sus cebifrons) and domestic pig (Sus scrofa), we characterized the dynamics of chromosomal structure evolution during Sus speciation, revealing the similar chromosome conformation as the potential biological mechanism of frequent postdivergence hybridization among Suidae. We further investigated the different signatures of adaptive selection and domestication in Visayan warty pig and domestic pig with specific emphasize on the evolution of olfactory and gustatory genes, elucidating higher olfactory diversity in Visayan warty pig and positive and relaxed evolution of bitter and fat taste receptors, respectively, in domestic pig. Our comprehensive evolutionary and comparative genome analyses provide insight into the dynamics of genomes and how these change over relative short evolutionary times, as well as how these genomic differences encode for differences in the phenotypes.
How Placenta Promotes the Successful Reproduction in High-Altitude Populations: A Transcriptome Comparison between Adaptation and Acclimatization
Authors: Wu Deng , Liu Yunao , Chen Wei , Shao Jianming , Zhuoma Pubu , Zhao Dexiong , Yu Yang , Liu Tianzi , Yu Ruoxuan , Gan Yongna , Yuzheng Baima , Huang Yongshu , Zhang Haikun , Bi Xiaoman , Tao Chengcheng , Lai Shujuan , Luo Qiaoxia , Zhang Dake , Wang Hongmei , Zhaxi Pingcuo , Zhang Jianqing , Qiao Jie , Zeng Changqing
Published: June 2022

As the best adapted high altitude population, Tibetans feature a relatively high offspring survival rate. Genome-wide studies have identified hundreds of candidate SNPs related to high altitude adaptation of Tibetans, although most of them have unknown functional relevance. To explore the mechanisms behind successful reproduction at high altitudes, we compared the placental transcriptomes of Tibetans, sea level Hans (SLHan), and Han immigrants (ImHan). Among the three populations, placentas from ImHan showed a hyperactive gene expression pattern. Their increased activation demonstrates a hypoxic stress response similar to sea level individuals experiencing hypoxic conditions. Unlike ImHan, Tibetan placentas were characterized by the significant up-regulation of placenta-specific genes, and the activation of autophagy and the tricarboxylic acid (TCA) cycle. Certain conserved hypoxia response functions, including the antioxidant system and angiogenesis, were activated in both ImHan and Tibetans, but mediated by different genes. The coherence of specific transcriptome features linked to possible genetic contribution was observed in Tibetans. Furthermore, we identified a novel Tibetan-specific EPAS1 isoform with a partial deletion at exon six, which may be involved in the adaption to hypoxia through the EPAS1-centred gene network in the placenta. Overall, our results show that the placenta grants successful pregnancies in Tibetans by strengthening the natural functions of the placenta itself. On the other hand, the placenta of ImHan was in an inhabiting time-dependent acclimatization process representing a common hypoxic stress response pattern.
Luxury iron uptake and storage in pennate diatoms from the equatorial Pacific Ocean
Authors: Twining Benjamin S , Baines Stephen B
Published: June 2022

Iron is a key micronutrient for ocean phytoplankton, and the availability of iron controls primary production and community composition in large regions of the ocean. Pennate diatoms, a phytoplankton group that responds to iron additions in low-iron areas, can have highly variable iron contents, and some groups such as Pseudo-nitzschia, are known to use ferritin to store iron for later use. We quantified and mapped the intracellular accumulation of iron by a natural population of Pseudo-nitzschia from the Fe-limited equatorial Pacific Ocean. A total of 48 h after iron addition, nearly half of the accumulated iron was localized in storage bodies adjacent to chloroplasts believed to represent ferritin. Over the subsequent 48 h, stored iron was distributed to the rest of the cell through subsequent growth and division, partially supporting the iron contents of the daughter cells. This study provides the first quantitative view into the cellular trafficking of iron in a globally relevant phytoplankton group and demonstrates the unique capabilities of synchrotron-based element imaging approaches.
A novel, rapid and sensitive flow cytometry method reveals degradation of promoter proximal paused RNAPII in the presence and absence of UV
Authors: Bay Lilli T E , Syljuåsen Randi G , Landsverk Helga B
Published: June 2022

RNA polymerase II (RNAPII) is emerging as an important factor in DNA damage responses, but how it responds to genotoxic stress is not fully understood. We have developed a rapid and sensitive flow cytometry method to study chromatin binding of RNAPII in individual human cells through the cell cycle. Indicating enhanced transcription initiation at early timepoints, levels of RNAPII were increased at 15–30min after UV-induced DNA damage. This was particularly evident for the S5 phosphorylated form of RNAPII (pRNAPII S5), which is typically associated with promoter proximal pausing. Furthermore, degradation of pRNAPII S5 frequently occurs, as its levels on chromatin were strongly enhanced by the proteasome inhibitor MG132 with and without UV. Remarkably, inhibiting pause release with 5,6-dichloro-1-beta-ribo-furanosyl benzimidazole (DRB) further promoted UV-induced degradation of pRNAPII S5, suggesting enhanced initiation may lead to a phenomenon of ‘promoter proximal crowding’ resulting in premature termination via degradation of RNAPII. Moreover, pRNAPII S2 levels on chromatin were more stable in S phase of the cell cycle 2h after UV, indicating cell cycle specific effects. Altogether our results demonstrate a useful new method and suggest that degradation of promoter proximal RNAPII plays an unanticipated large role both during normal transcription and after UV.
NetSurfP-3.0: accurate and fast prediction of protein structural features by protein language models and deep learning
Authors: Høie Magnus Haraldson , Kiehl Erik Nicolas , Petersen Bent , Nielsen Morten , Winther Ole , Nielsen Henrik , Hallgren Jeppe , Marcatili Paolo
Published: June 2022

Recent advances in machine learning and natural language processing have made it possible to profoundly advance our ability to accurately predict protein structures and their functions. While such improvements are significantly impacting the fields of biology and biotechnology at large, such methods have the downside of high demands in terms of computing power and runtime, hampering their applicability to large datasets. Here, we present NetSurfP-3.0, a tool for predicting solvent accessibility, secondary structure, structural disorder and backbone dihedral angles for each residue of an amino acid sequence. This NetSurfP update exploits recent advances in pre-trained protein language models to drastically improve the runtime of its predecessor by two orders of magnitude, while displaying similar prediction performance. We assessed the accuracy of NetSurfP-3.0 on several independent test datasets and found it to consistently produce state-of-the-art predictions for each of its output features, with a runtime that is up to to 600 times faster than the most commonly available methods performing the same tasks. The tool is freely available as a web server with a user-friendly interface to navigate the results, as well as a standalone downloadable package.
Enhanced nucleosome assembly at CpG sites containing an extended 5-methylcytosine analogue
Authors: Tomkuvienė Miglė , Meier Markus , Ikasalaitė Diana , Wildenauer Julia , Kairys Visvaldas , Klimašauskas Saulius , Manelytė Laura
Published: June 2022

Methylation of cytosine to 5-methylcytosine (mC) at CpG sites is a prevalent reversible epigenetic mark in vertebrates established by DNA methyltransferases (MTases); the attached methyl groups can alter local structure of DNA and chromatin as well as binding of dedicated proteins. Nucleosome assembly on methylated DNA has been studied extensively, however little is known how the chromatin structure is affected by larger chemical variations in the major groove of DNA. Here, we studied the nucleosome formation in vitro on DNA containing an extended 5mC analog, 5-(6-azidohex-2-ynyl)cytosine (ahyC) installed at biological relevant CpG sites. We found that multiple ahyC residues on 80-Widom and Hsp70 promoter DNA fragments proved compatible with nucleosome assembly. Moreover, unlike mC, ahyC increases the affinity of histones to the DNA, partially altering nucleosome positioning, stability, and the action of chromatin remodelers. Based on molecular dynamics calculations, we suggest that these new features are due to increased DNA flexibility at ahyC-modified sites. Our findings provide new insights into the biophysical behavior of modified DNA and open new ways for directed design of synthetic nucleosomes.
Utilizing RNA origami scaffolds in Saccharomyces cerevisiae for dCas9-mediated transcriptional control
Authors: Pothoulakis Georgios , Nguyen Michael T A , Andersen Ebbe S
Published: June 2022

Designer RNA scaffolds constitute a promising tool for synthetic biology, as they can be genetically expressed to perform specific functions in vivo such as scaffolding enzymatic cascades and regulating gene expression through CRISPR-dCas9 applications. RNA origami is a recently developed RNA design approach that allows construction of large RNA nanostructures that can position aptamer motifs to spatially organize other molecules, including proteins. However, it is still not fully understood how positioning multiple aptamers on a scaffold and the orientation of a scaffold affects functional properties. Here, we investigate fusions of single-guide RNAs and RNA origami scaffolds (termed sgRNAO) capable of recruiting activating domains for control of gene expression in yeast. Using MS2 and PP7 as orthogonal protein-binding aptamers, we observe a gradual increase in transcriptional activation for up to four aptamers. We demonstrate that different aptamer positions on a scaffold and scaffold orientation affect transcriptional activation. Finally, sgRNAOs are used to regulate expression of enzymes of the violacein biosynthesis pathway to control metabolic flux. The integration of RNA origami nanostructures at promoter sites achieved here, can in the future be expanded by the addition of functional motifs such as riboswitches, ribozymes and sensor elements to allow for complex gene regulation.
The legacy effect of a home walking exercise programme in kidney failure patients on dialysis
Authors: Manfredini Fabio , D'arrigo Graziella , Lamberti Nicola , Torino Claudia , Tripepi Giovanni , Mallamaci Francesca , Zoccali Carmine
Published: June 2022

Background

The EXerCise Introduction To Enhance performance (EXCITE) trial (J Am Soc Nephrol 28: 1259–1268, 2017) in dialysis patients showed that a 6-month home walking exercise programme improves physical function and two dimensions of the Kidney Disease Quality of Life Short Form (KDQOLSF-SF™) questionnaire. Whether improvements in physical function achieved by exercise interventions are maintained in the long term has never been tested in the dialysis population.

Methods

In this post-trial study embedded in the EXCITE trial, we tested the response to the 6 min walking test (6MWT) and the 5-time Sit-To-Stand (5STS) tests and the KDQOLSF-SF™ from the 6th month (end of the trial) to the 36th month.

Results

Among the 227 patients of the EXCITE trial cohort, 162 underwent at least three out of four testing visits (baseline, 6, 18 and/or 36 months) contemplated by the study protocol and 89 during all four testing visits. In the primary analysis by the linear mixed model, the gain in walking distance achieved in the 6th month in the exercise group [between-arms difference: +36 m, 95% confidence interval (CI): 22–51, P < .001] was maintained at the 18th month (between-arms difference: +37 m, 95% CI: 19–57, P < .001) and reduced to 23 m (95% CI: −4 to 49 meters, P = .10) at the 36th month. Overall, the post-trial difference in walking distance trajectories between the two study arms was highly significant (P = .004). Furthermore, the walking distance changes at the 6th (r = 0.34, P = .018) and 18th month (r = 0.30, P = .043) were directly related to the number of structured exercise sessions completed during the trial (i.e. the first 6 month). No such effect was registered in the response to the 5STS or in quality of life as measured by the KDQOLSF-SF™.

Conclusions

In dialysis patients, the benefits of a 6-month structured walking programme outlast the duration of the intervention and postpone the loss of walking performance which naturally occurs in this population, but does not affect the quality of life (QoL) and the response to the STS test.
Inhibit progression of coronary artery calcification with vitamin K in hemodialysis patients (the iPACK-HD study): a randomized, placebo-controlled multi-center, pilot trial
Authors: Holden Rachel M , Booth Sarah L , Zimmerman Deborah , Moist Louise , Norman Patrick A , Day Andrew G , Menard Alex , Fu Xueyan , Shea M Kyla , Babiolakis Corinne S , Nolan Robert , Turner Mandy E , Ward Emilie , Kaufmann Martin , Adams Michael A , Heyland Daren K
Published: June 2022

Background

Vitamin K activates matrix Gla protein (MGP), a key inhibitor of vascular calcification. There is a high prevalence of sub-clinical vitamin K deficiency in patients with end-stage kidney disease.

Methods

A parallel randomized placebo-controlled pilot trial was designed to determine whether 10 mg of phylloquinone thrice weekly versus placebo modifies coronary artery calcification progression over 12 months in patients requiring hemodialysis with a coronary artery calcium score (CAC) ≥30 Agatston Units (ClinicalTrials.gov identifier NCT01528800). The primary outcome was feasibility (recruitment rate, compliance with study medication, study completion and adherence overall to study protocol). CAC score was used to assess calcification at baseline and 12 months. Secondary objectives were to explore the impact of phylloquinone on vitamin K-related biomarkers (phylloquinone, dephospho-uncarboxylated MGP and the Gla-osteocalcin to Glu-osteocalcin ratio) and events of clinical interest.

Results

A total of 86 patients with a CAC score ≥30 Agatston Units were randomized to either 10 mg of phylloquinone or a matching placebo three times per week. In all, 69 participants (80%) completed the trial. Recruitment rate (4.4 participants/month) and medication compliance (96%) met pre-defined feasibility criteria of ≥4.17 and ≥90%, respectively. Patients randomized to phylloquinone for 12 months had significantly reduced levels of dephospho-uncarboxylated MGP (86% reduction) and increased levels of phylloquinone and Gla-osteocalcin to Glu-osteocalcin ratio compared with placebo. There was no difference in the absolute or relative progression of coronary artery calcification between groups.

Conclusion

We demonstrated that phylloquinone treatment improves vitamin K status and that a fully powered randomized trial may be feasible.
Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) for small cell lung cancer reduces hippocampal atrophy compared to conventional PCI
Authors: de Ruiter Michiel B , Groot Paul F C , Deprez Sabine , Pullens Pim , Sunaert Stefan , de Ruysscher Dirk , Schagen Sanne B , Belderbos José
Published: June 2022

Background

Reducing radiation dose to the hippocampus with hippocampal avoidance prophylactic cranial irradiation (HA-PCI) is proposed to prevent cognitive decline. It has, however, not been investigated whether hippocampal atrophy is actually mitigated by this approach. Here, we determined whether HA-PCI reduces hippocampal atrophy. Additionally, we evaluated neurotoxicity of (HA-)PCI to other brain regions. Finally, we evaluated associations of hippocampal atrophy and brain neurotoxicity with memory decline.

Methods

High-quality research MRI scans were acquired in the multicenter, randomized phase 3 trial NCT01780675. Hippocampal atrophy was evaluated for 4 months (57 HA-PCI patients and 46 PCI patients) and 12 months (28 HA-PCI patients and 27 PCI patients) after (HA-)PCI. We additionally studied multimodal indices of brain injury. Memory was assessed with the Hopkins Verbal Learning Test–Revised (HVLT-R).

Results

HA-PCI reduced hippocampal atrophy at 4 months (1.8% for HA-PCI and 3.0% for PCI) and at 12 months (3.0% for HA-PCI and 5.8% for PCI). Both HA-PCI and PCI were associated with considerable reductions in gray matter and normal-appearing white matter, increases in white matter hyperintensities, and brain aging. There were no significant associations between hippocampal atrophy and memory.

Conclusions

HA-PCI reduces hippocampal atrophy at 4 and 12 months compared to regular PCI. Both types of radiotherapy are associated with considerable brain injury. We did not find evidence for excessive brain injury after HA-PCI relative to PCI. Hippocampal atrophy was not associated with memory decline in this population as measured with HVLT-R. The usefulness of HA-PCI is still subject to debate.
Differential seasonal avoidance of anthropogenic features and woody vegetation by Lesser Prairie-Chickens
Authors: Lawrence Andrew J , Boggie Matthew A , Gould William R , Carleton Scott A , Nichols Clay T
Published: June 2022

The influence of seasonal variation on animal behavior is a critical component of habitat selection analyses. To examine this relationship, we conducted multi-scale analyses of Lesser Prairie-Chicken (Tympanuchus pallidicinctus) habitat selection in relation to anthropogenic infrastructure associated with oil and gas development, mesquite, and trees during the spring and summer at home range and lek area scales. We tracked 159 Lesser Prairie-Chickens using VHF radiotelemetry or PTT-GPS transmitters in the sand shinnery oak prairie region of eastern New Mexico, USA. We used discrete choice models and logistic regression to assess seasonal patterns of habitat selection at home range and lek area scales, respectively. The static habitat features we examined allowed us to observe differential patterns of habitat selection between the two seasons, revealing an overall increase in the degree of avoidance following the spring season. Results of our home range scale analysis indicate that utility pole density, mesquite cover, and proximity to active well pads, private roads, and mesquite have significant negative effects on habitat selection during both seasons. Avoidance of high utility pole densities was significantly greater during the summer compared to spring. Lek area habitat selection results were similar, but differences in sensitivity to features between seasons were stronger. Avoidance of high mesquite cover and utility pole and tree densities, in particular, was significantly greater in the summer. The effects of density and cover of these features, which have previously been understudied in Lesser Prairie-Chicken research, provide critical information for future conservation practices. Furthermore, our study highlights the importance of accounting for potential seasonal patterns of study species to best examine habitat selection.
Determination of sampling time interval for investigating ecological trends of tintinnids
Authors: Baek Sang-Soo , Kim Young Ok , Choi Jungmin , Cho Hong Yeon , Jang Min-Chul
Published: June 2022

Tintinnids are a major group of planktonic ciliates. To determine a desirable sampling interval for analyzing the temporal dynamics of tintinnids, intensive monitoring was conducted on the southern coast of Korea. The mean sampling interval was 1.5 days. The abundance of tintinnids were analyzed by microscopy. The high- frequency temporal pattern showed detailed changes in concentrations and a distinct seasonality in the abundance of tintinnids. An optimal monitoring interval for tintinnid abundance estimations was determined by polynomial interpolation and statistical analysis, involving three steps, namely, interpolation by increasing the number of sampling intervals, graphical analysis with interpolated data and determination of the changepoint depending on the interpolated results. The value of changepoint was 7 days, indicating the optimal monitoring interval. Therefore, data collection at weekly intervals is sufficient and desirable for tracing the temporal signals of tintinnid ecology and its long-term trends.
Plant–microbe interactions that have impacted plant terrestrializations
Authors: Puginier Camille , Keller Jean , Delaux Pierre-Marc
Published: June 2022

Plants display a tremendous diversity of developmental and physiological features, resulting from gains and losses of functional innovations across the plant phylogeny. Among those, the most impactful have been undoubtedly the ones that allowed plant terrestrializations, the transitions from an aquatic to a terrestrial environment. Although the embryophyte terrestrialization has been particularly scrutinized, others occurred across the plant phylogeny with the involvement of mutualistic symbioses as a common theme. Here, we review the current pieces of evidence supporting that the repeated colonization of land by plants has been facilitated by interactions with mutualistic symbionts. In that context, we detail two of these mutualistic symbioses: the arbuscular mycorrhizal symbiosis in embryophytes and the lichen symbiosis in chlorophyte algae. We suggest that associations with bacteria should be revisited in that context, and we propose that overlooked symbioses might have facilitated the emergence of other land plant clades.
The Incidence of Student Loan Subsidies: Evidence from the PLUS Program
Authors: Kargar Mahyar , Mann William
Published: June 2022

How much do students benefit from student loan subsidies? We investigate this question, exploiting a natural experiment: a demand shock due to the 2011 tightening of credit standards in the PLUS program. We first establish that the Bennett hypothesis is best explained by colleges charging large markups over their marginal costs, rather than by advantageous selection. Then we use our results to estimate that students plausibly capture less than 60 cents of each dollar of resources expended on loan subsidies. We discuss alternative approaches that would more directly benefit students.
Horizon Bias and the Term Structure of Equity Returns
Authors: Cassella Stefano , Golez Benjamin , Gulen Huseyin , Kelly Peter
Published: June 2022

We label the degree to which individuals are more optimistic at long horizons relative to short horizons as the horizon bias. We examine whether time-series variation in the horizon bias can explain the time-series variation in the equity term structure. We use analyst earnings forecasts to measure the degree of the horizon bias in the stock market. Consistent with the intuition from a stylized present value model, we find that periods of above-average horizon bias are associated with negative term premiums, whereas periods of below-average horizon bias are associated with positive term premiums.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Impact of lung function and baseline clinical characteristics on patient-reported outcome measures in systemic sclerosis-associated interstitial lung disease
Authors: Kreuter Michael , Hoffmann-Vold Anna-Maria , Matucci-Cerinic Marco , Saketkoo Lesley Ann , Highland Kristin B , Wilson Hilary , Alves Margarida , Erhardt Elvira , Schoof Nils , Maher Toby M
Published: June 2022

Objective

The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with SSc-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken.

Methods

Patient-reported outcome (PRO) measures [St. George’s Respiratory Questionnaire (SGRQ), Functional Assessment of Chronic Illness Therapy (FACIT)-Dyspnoea, and HAQ–Disability Index (HAQ-DI), incorporating the Scleroderma HAQ visual analogue scale (SHAQ VAS)] at baseline and week 52 were assessed for associations to SSc-ILD severity.

Results

At baseline and at week 52, forced vital capacity (FVC) <70% predicted was associated with worse PRO measure scores compared with FVC ≥70% predicted [week 52: SGRQ 45.1 vs 34.0 (P < 0.0001); FACIT-Dyspnoea 48.9 vs 44.5 (P < 0.0001); HAQ-DI 0.7 vs 0.6 (P < 0.0228); SHAQ VAS breathing problems 3.6 vs 2.6 (P < 0.0001)]. Patients with diffuse cutaneous SSc and other characteristics associated with SSc-ILD severity had worse PRO measure scores. Patients requiring oxygen or with >30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (>10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (P < 0.001).

Conclusion

Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL.

Trial registration

clinicaltrials.gov, www.clinicaltrials.gov, NCT02597933
Private Company Valuations by Mutual Funds
Authors: Agarwal Vikas , Barber Brad , Cheng Si , Hameed Allaudeen , Yasuda Ayako
Published: June 2022

Mutual fund families set and report values of their private startup holdings, which affect the fund net asset value (NAV) at which investors buy/sell fund shares. We test three hypotheses related to the valuation practice: (i) information cost/access, (ii) litigation risk, and (iii) strategic NAV management. Consistent with (i), families with larger PE holdings and/or stronger information access update valuations more frequently in the absence of public information releases, their updates co-move less with other families, and their fund returns jump less at follow-on financings. We find no support for hypotheses (ii) or (iii). We also find that high-PE-exposure funds are subject to greater financial fragility.
Psychosocial Impact of Sickle Cell Disease and Diabetes Mellitus on Affected Children and Their Parents in Khartoum State, Sudan
Authors: Yousif Magda , Abdelrahman Abdalla , Al Jamea Lamiaa H , Al-Yami Fatimah S , Woodman Alexander
Published: June 2022

This study aimed to assess the psychosocial impact of sickle cell disease (SCD) and diabetes mellitus on children and their parents in Sudan, and the relationship between socioeconomic status and psychosocial issues. A descriptive, cross-sectional study was conducted among n = 320 children aged 6–12 years, of whom n = 170 were diagnosed with SCD, n = 150 children with diabetes mellitus and their parents. The strengths and difficulties questionnaire (SDQ scale) was used to assess the psychosocial aspect of children. Depression, Anxiety, Stress Scale -21 Items (DASS 21) was used to assess the psychological well-being of the caregivers. Data on psychological problems of children with SCD showed that 66.5% had emotional symptoms, 18.2% had conduct problems and 19.4% hyperactivity. Data of parents showed that 45.9% of parents did not experience depression; 27.9% were moderately depressed group. Data on psychological problems among children with diabetes showed that 57.3% experienced emotional symptoms, conduct problems were close to the average among 66%. Data on psychological problems among parents of children with diabetes showed that 45.3% of parents did not experience depression; 22.7% belonged to the moderately depressed group. Psychosocial problems were common both among children and parents. More research is needed in the context of caring for a child with chronic diseases and the role of health care providers in adapting and mitigating psychological problems among both parents and children.
Molecular epidemiology of HIV-1 in Oryol Oblast, Russia
Authors: Safina Ksenia R , Sidorina Yulia , Efendieva Natalya , Belonosova Elena , Saleeva Darya , Kirichenko Alina , Kireev Dmitry , Pokrovsky Vadim , Bazykin Georgii A
Published: June 2022

The HIV/AIDS epidemic in Russia is growing, with approximately 100,000 people infected annually. Molecular epidemiology can provide insight into the structure and dynamics of the epidemic. However, its applicability in Russia is limited by the weakness of genetic surveillance, as viral genetic data are only available for <1 per cent of cases. Here, we provide a detailed description of the HIV-1 epidemic for one geographic region of Russia, Oryol Oblast, by collecting and sequencing viral samples from about a third of its known HIV-positive population (768 out of 2,157 patients). We identify multiple introductions of HIV-1 into Oryol Oblast, resulting in eighty-two transmission lineages that together comprise 66 per cent of the samples. Most introductions are of subtype A (315/332), the predominant HIV-1 subtype in Russia, followed by CRF63 and subtype B. Bayesian analysis estimates the effective reproduction number Re for subtype A at 2.8 [1.7–4.4], in line with a growing epidemic. The frequency of CRF63 has been growing more rapidly, with the median Re of 11.8 [4.6–28.7], in agreement with recent reports of this variant rising in frequency in some regions of Russia. In contrast to the patterns described previously in European and North American countries, we see no overrepresentation of males in transmission lineages; meanwhile, injecting drug users are overrepresented in transmission lineages. This likely reflects the structure of the HIV-1 epidemic in Russia dominated by heterosexual and, to a smaller extent, people who inject drugs transmission. Samples attributed to men who have sex with men (MSM) transmission are associated with subtype B and are less prevalent than expected from the male-to-female ratio for this subtype, suggesting underreporting of the MSM transmission route. Together, our results provide a high-resolution description of the HIV-1 epidemic in Oryol Oblast, Russia, characterized by frequent interregional transmission, rapid growth of the epidemic, and rapid displacement of subtype A with the recombinant CRF63 variant.