bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the illicit market in veterinary medicines: An exploratory online study with pet owners in the United Kingdom
Authors: Pons-Hernandez Monica , Wyatt Tanya , Hall Alexandra
Published: September 2022

The illicit market in veterinary medicines is an overlooked issue despite threatening the health of non-human and human animals. It is thought to be increasing within the major markets of the global North due to the growth of e-commerce and social media sites. This paper examines the online market in illicit veterinary medicines through an exploratory study of the public’s online experiences as pet owners in the UK. To this end, we collected data through literature-based research and an online survey. Drawing on Passas’ criminogenic asymmetries framework, the research found that the confluence of legal, political, cultural, economic and knowledge asymmetries likely facilitate the market in illicit veterinary medicines in the UK. Our research concludes that, while previous reports suggest the illicit market is dominated by medicines to treat pets, it increasingly consists of medicines for farmed animals. This brings its own set of challenges and risks, and a pressing need for further research on the market’s dynamics.
Beliefs About the Need to Control One’s Thoughts and Cognitive Self-consciousness Are Associated with Sexual Stigma
Authors: Aydın Orkun , Kaya Aygül , Cengiz Zümra , Kesen Esra Sena , Ünal-Aydın Pınar , Spada Marcantonio M.
Published: September 2022

Introduction

Sexual stigma has been found to be related to a variety of factors including age, ethnicity, religion, gender, and education. However, we still know relatively little about the association of cognitive constructs with homonegativity. In the current study, we aimed to explore the associations between metacognitions and sexual stigma among young adults.

Methods

Five hundred thirty-eight individuals participated in the study. The following self-report measures were administered: Attitudes Toward Lesbians and Gay Men-Short Version (ATLG-S), Hudson and Ricketts Homophobia Scale (HRHS), and the Metacognitions Questionnaire 30 (MCQ-30). Pearson product-moment correlations and multiple linear regression analyses were run to explore the associations between ATLG-S, HRHS, and MCQ-30.

Results

Negative beliefs about thoughts and beliefs about the need to control thoughts were correlated with ATLG-S and HRHS scores; however, multiple linear regression analyses demonstrated that beliefs about the need to control thoughts and cognitive self-consciousness were associated with ATLG-S and HRHS scores after controlling for sociodemographic variables including age, gender, and education.

Conclusion

We concluded that the beliefs about the need to control thoughts and cognitive self-consciousness may play a significant role in sexual stigma. Psychological techniques which are aimed at specific metacognitions and mindfulness may help reduce sexual prejudice among young adults.
Rigidity results for complete spacelike submanifolds in plane fronted waves
Authors: Palomo Francisco J. , Pelegrín José A. S. , Romero Alfonso
Published: September 2022

New rigidity results for complete non-compact spacelike submanifolds of arbitrary codimension in plane fronted waves are obtained. Under appropriate assumptions, we prove that a complete spacelike submanifold in these spacetimes is contained in a characteristic lightlike hypersurface. Moreover, for a complete codimension two extremal submanifold in a plane fronted wave we show sufficient conditions to guarantee that it is a (totally geodesic) wavefront.
Seeking Supremacy
Authors: Kureshi Yasser
Published: September 2022

The emergence of the judiciary as an assertive and confrontational center of power has been the most consequential new feature of Pakistan's political system. This book maps out the evolution of the relationship between the judiciary and military in Pakistan, explaining why Pakistan's high courts shifted from loyal deference to the military to open competition, and confrontation, with military and civilian institutions. Yasser Kureshi demonstrates that a shift in the audiences shaping judicial preferences explains the emergence of the judiciary as an assertive power center. As the judiciary gradually embraced less deferential institutional preferences, a shift in judicial preferences took place and the judiciary sought to play a more expansive and authoritative political role. Using this audience-based approach, Kureshi roots the judiciary in its political, social and institutional context, and develops a generalizable framework that can explain variation and change in judicial-military relations around the world.
Social Science Experiments
Authors: Green Donald P.
Published: September 2022

This book is designed for an undergraduate, one-semester course in experimental research, primarily targeting programs in sociology, political science, environmental studies, psychology, and communications. Aimed at those with limited technical background, this introduction to social science experiments takes a practical, hands-on approach. After explaining key features of experimental designs, Green takes students through exercises designed to build appreciation for the nuances of design, implementation, analysis, and interpretation. Using applications and statistical examples from many social science fields, the textbook illustrates the breadth of what may be learned through experimental inquiry. A chapter devoted to research ethics introduces broader ethical considerations, including research transparency. The culminating chapter prepares readers for their own social science experiments, offering examples of studies that can be conducted ethically, inexpensively, and quickly. Replication datasets and R code for all examples and exercises are available online.
The Company's Sword
Authors: Welsch Christina
Published: September 2022

In the late eighteenth century, it was a cliché that the East India Company ruled India 'by the sword.' Christina Welsch shows how Indian and European soldiers shaped and challenged the Company's political expansion and how elite officers turned those dynamics into a bid for 'stratocracy' – a state dominated by its army. Combining colonial records with Mughal Persian sources from Indian states, The Company's Sword offers new insight into India's eighteenth-century military landscape, showing how elite officers positioned themselves as the sole actors who could navigate, understand, and control those networks. Focusing on south India, rather than the Company's better-studied territories in Bengal, the analysis provides a new approach, chronology, and geography through which to understand the Company Raj. It offers a fresh perspective of the Company's collapse after the rebellions of 1857, tracing the deep roots of that conflict to the Company's eighteenth-century development.
The Universe Waking Up: A Useful Idea for Atheists
Authors: MILEM BRUCE
Published: September 2022

Some writers have described human beings as participating in the universe waking up or serving as the means by which the universe comes to know itself. In this paper I argue that this idea can be given a straightforward explanation with minimal metaphysical commitments. As long as one grants that the universe has a kind of unity and that human beings are conscious, it is possible to see human beings as vehicles for the universe's consciousness and knowledge of itself. I also argue that this idea can be useful for atheists because it can satisfy what Thomas Nagel calls ‘the yearning for cosmic reconciliation’ (2010: 3) better than secular humanism can.
Prevalence and treatment of postobstructive pneumonia among older adults with advanced cancer
Authors: Lee Seohyuk , O’Donovan Lisa , Cohen Avi J. , Gautam Samir , Quagliarello Vincent , Juthani-Mehta Manisha , Datta Rupak
Published: September 2022

Among 124 older adults with advanced cancer who were hospitalized with pneumonia, 7.3% met criteria for postobstructive pneumonia. There were no differences in antibiotic duration, antibiotic spectrum, 30-day and 90-day readmissions, or mortality between those with and without postobstructive pneumonia. Bacteria were identified in 5 patients with postobstructive pneumonia.
Correlation of the renormalized Hilbert length for convex projective surfaces
Authors: DAI XIAN , MARTONE GIUSEPPE
Published: September 2022

In this paper, we focus on dynamical properties of (real) convex projective surfaces. Our main theorem provides an asymptotic formula for the number of free homotopy classes with roughly the same renormalized Hilbert length for two distinct convex real projective structures. The correlation number in this asymptotic formula is characterized in terms of their Manhattan curve. We show that the correlation number is not uniformly bounded away from zero on the space of pairs of hyperbolic surfaces, answering a question of Schwartz and Sharp. In contrast, we provide examples of diverging sequences, defined via cubic rays, along which the correlation number stays larger than a uniform strictly positive constant. In the last section, we extend the correlation theorem to Hitchin representations.
Scaling of small-scale wall turbulence
Authors: Tang S.L. , Antonia R.A.
Published: September 2022

In the vicinity of walls, turbulence is anisotropic. Since the classical hypotheses of Kolmogorov (Dokl. Akad. Nauk SSSR, vol. 30, 1941, pp. 299–303), Obukhov (Izv. Akad. Nauk SSSR Geogr. Geofiz, vol. 13, 1949, pp. 58–69) and Corrsin (J. Appl. Phys., vol. 22, 1951, pp. 469–473) require small-scale turbulence to be isotropic, they have only limited relevance to wall-bounded turbulent flows. Here, we put forward a hypothesis whereby small-scale near-wall statistics, when suitably normalized, are independent of the type of flow as well as of the Reynolds and Péclet numbers. The relatively large amount of available wall turbulence direct numerical simulations data, related mainly to second-order statistics, in a channel flow and a boundary layer provides good support for the independence with respect to the Reynolds number. To fully validate the hypothesis, more data are required for higher-order statistics as well as for other wall flows and for different surface conditions.
Foundations of a New Democracy: Schooling, Inequality, and Voting in the Early Republic
Authors: PAULSEN TINE , SCHEVE KENNETH , STASAVAGE DAVID
Published: September 2022

Democratic theorists have long argued that states can create more resilient democracies through education. Educational investments are thought to produce more economic equality and instill in citizens greater capacity and responsibility to participate in politics. Using a geographic regression discontinuity design and township-level data from Antebellum New York State, we examine whether state funding for common schools led to higher voter turnout as well as higher earnings and lower inequality. Our estimates support the view that a participatory democratic culture emerged not only because of initial favorable endowments but also because of subsequent government decisions to fund education. New York townships that received more school funding later had higher median earnings, lower earnings inequality, and higher levels of voter turnout. Our findings support the view that maintaining democracy requires active investments by the state, something that has important implications for other places and other times—including today.
Can Elections Motivate Responsiveness in a Single-Party Regime? Experimental Evidence from Vietnam
Authors: MALESKY EDMUND J. , TODD JASON DOUGLAS , TRAN ANH
Published: September 2022

A growing body of evidence attests that legislators are sometimes responsive to the policy preferences of citizens in single-party regimes, yet debate surrounds the mechanisms driving this relationship. We experimentally test two potential responsiveness mechanisms—elections versus mandates from party leaders—by provisioning delegates to the Vietnamese National Assembly with information on the policy preferences of their constituents and reminding them of either (1) the competitiveness of the upcoming 2021 elections or (2) a central decree that legislative activities should reflect constituents’ preferences. Consistent with existing work, delegates informed of citizens’ preferences are more likely to speak on the parliamentary floor and in closed-session caucuses. Importantly, we find that such responsiveness is entirely driven by election reminders; upward incentive reminders have virtually no effect on behavior.
Cohort fertility heterogeneity during the fertility decline period in Turkey
Authors: Keskin Faruk , Çavlin Alanur
Published: September 2022

The decline in fertility, rapid urbanization and the increase in women’s education levels in Turkey are simultaneous transformations. The coexistence and interaction of these transformations is the focal point for the interpretation of fertility trajectories in Turkey. This article explores Turkey’s heterogeneous fertility structure by examining the fertility trajectories of women between 1949 and 1978 cohorts. It also examines changes in these trajectories in light of Turkey’s fertility decline and interprets those changes through comparisons of women whose fertility behaviors are similar. Using three waves (1998, 2008 and 2018) of the Turkey Demographic and Health Survey data, we employed sequence analysis to calculate fertility trajectories and form clusters from these trajectories. The background similarities of women in the same fertility clusters were investigated with distance analysis, and we calculated predicted probabilities from multinomial logistic regression results and predicted cluster membership. The heterogeneous nature of fertility in Turkey during the demographic transition period shaped the transition process and it can be predicted that such heterogeneity will shape post-transition fertility. The behavior of having two children became the norm during this period, and greater spacing between births or even stopping after the first child became a preferred option among educated women who grew up in cities. For women who grew up in rural areas and uneducated women, we observed a transition from higher parities to three-norm.
Foreign Ties That Bind: Cross-Border Firm Expansions and Fund Portfolio Allocation Around the World
Authors: Moshirian Fariborz , Pham Peter K. , Tian Shu , Wu Eliza
Published: September 2022

We investigate whether international operations enhance information links between firms and foreign investors. Exploiting novel subsidiary-level data and within-location variations, we show that, after expanding into another country, a firm attracts greater investment allocation from funds from that country than from other foreign funds. This increase is economically significant, equivalent to one-fifth of the average firm weight in a country-specific portfolio. The observed effect cannot be attributed to funds’ influence, persists even when funds are already familiar with the firm, and helps them generate superior risk-adjusted returns. Our results suggest that firms’ cross-border economic activities contribute to global financial interconnectedness.
Current (but not ex) cigarette smoking is associated with worse cognitive performances in schizophrenia: results from the FACE-SZ cohort
Authors: Mallet Jasmina , Godin Ophélia , Dansou Yecodji , Mazer Nicolas , Scognamiglio Claire , Berna Fabrice , Boyer Laurent , Capdevielle Delphine , Chéreau Isabelle , D'Amato Thierry , Dubreucq Julien , Fond Guillaume , Leigner Sylvain , Llorca Pierre-Michel , Misdrahi David , Passerieux Christine , Rey Romain , Pignon Baptiste , Urbach Mathieu , Schorr Benoit , Schürhoff Franck , Yann Le Strat , Dubertret Caroline ,   FACE-SZ (FondaMental Academic Center of Expertise for Schizophrenia) Group
Published: September 2022

Background

Tobacco use is common in subjects with schizophrenia (SZ) and has sometimes been associated with better functioning in short-term studies. Only few studies embrace an extensive examination of tobacco influence on clinical, cognitive and therapeutic characteristics in stabilized SZ outpatients. The objective of the present study was to assess the association between cognitive performances and smoking status in SZ subjects.

Methods

In total, 1233 SZ participants (73.9% men, mean age 31.5) were included and tested with a comprehensive battery. Tobacco status was self-declared (never-, ex-, or current smokers). Multivariable analyses including principal component analyses (PCA) were used.

Results

In total, 53.7% were smokers with 33.7% of them nicotine-dependent. Multiple factor analysis revealed that current tobacco smoking was associated with impaired general intellectual ability and abstract reasoning (aOR 0.60, 95% IC 0.41–0.88, p = 0.01) and with a lifetime alcohol use disorder (p = 0.026) and a lifetime cannabis use disorder (p < 0.001). Ex- and never-smokers differed for age, mean outcome, cannabis history and medication [ex-smokers being older (p = 0.047), likely to have higher income (p = 0.026), a lifetime cannabis use disorder (p < 0.001) and higher CPZeq doses (p = 0.005)]. Premorbid IQ in the three groups significantly differed with, from higher to lower: ex-smokers, never-smoker, current smokers (all p < 0.001).

Conclusions

This study is the largest to date providing strong evidence that chronic smoking is associated with cognitive impairment in SZ, arguing against the self-medication hypothesis as a contributor to the high prevalence of smoking in SZ. Ex-smokers may also represent a specific subgroup. Longitudinal studies are warranted to determine the developmental impact of tobacco on neurocognition.
Perinatal and post-weaning exposure to a high-fat diet causes histomorphometric, neuroplastic, and histopathological changes in the rat ileum
Authors: Cordeiro Gabriele S. , Góis Marcelo B. , Santos Lucimeire S. , Espírito-Santo Djane A. , Silva Rafael T. , Pereira Márcia U. , Santos Jean N. , Conceição-Machado Maria E. P. , Deiró Tereza C. B. J. , Barreto-Medeiros Jairza M.
Published: September 2022

Exposure to a diet with a high saturated fat content can influence the characteristics of the gastrointestinal tract, causing losses in the absorption of nutrients and favoring the appearance of diseases. The objective was to assess the effects of a high-fat diet (HFD) in the perinatal (pregnancy and lactation) and post-weaning period on the histomorphometry, neuroplasticity, and histopathology of the ileum. Wistar rats were divided into four subgroups: Control/Control (CC, n = 10) rats fed a control diet (C) throughout the trial period; Control/HFD (CH, n = 9) rats fed diet C (perinatal) and HFD after weaning; HFD/Control (HC, n = 10) rats fed HFD (perinatal) and diet C (post-weaning); HFD/HFD (HH, n = 9) rats fed HFD throughout the experimental period. There was atrophy of the Ileum wall with a reduction in the muscular tunic, submucosa, and mucosa thickness in the HH group of 37%, 28%, and 46%, respectively (p < 0.0001). The depth of the crypts decreased by 29% (p < 0.0001) and height increased by 5% (p < 0.0013). Villus height decreased by 41% and 18% in HH and HC groups (p < 0.0001) and width decreased by 11% in the HH (p < 0.0001). The height of the enterocytes decreased by 18% in the HH (p < 0.0001). There was a decrease in the area of the myenteric and submucosal plexus ganglia in the HH and HC groups (p < 0.0001). The number, occupation, and granules of Paneth cells increased in the HH and HC groups (p < 0.0001). Intraepithelial lymphocytes (IELs) increased in all groups exposed to the HFD. Goblet cells decreased in groups CH and HH (p < 0.0001). The evidence from this study suggests that the HFD had altered the histomorphometry, neuroplasticity, and histopathology of the ileum of the rats.
Differences in DNA Methylation-Based Age Prediction Within Twin Pairs Discordant for Cancer
Authors: Bode Hannes F. , Heikkinen Aino , Lundgren Sara , Kaprio Jaakko , Ollikainen Miina
Published: September 2022

DNA methylation-based age acceleration (DNAmAA) is associated with cancer, with both cancer tissue and blood showing increased DNAmAA. We aimed to investigate whether DNAmAA is associated with cancer risk within twin pairs discordant for cancer, and whether DNAmAA has the potential to serve as a biomarker for such. The study included 47 monozygotic and 48 same-sex-dizygotic cancer-discordant twin pairs from the Finnish Twin Cohort study with blood samples available between 17 and 31 years after the cancer diagnosis. We studied all cancers (95 pairs), then separately breast cancer (24 pairs) and all sites other than breast cancer (71 pairs). DNAmAA was calculated for seven models: Horvath, Horvath intrinsic epigenetic age acceleration, Hannum, Hannum intrinsic epigenetic age acceleration, Hannum extrinsic epigenetic age acceleration, PhenoAge and GrimAge. Within-pair differences in DNAmAA were analyzed by pairedttests and linear regression. Twin pairs sampled before cancer diagnosis did not differ significantly in DNAmAA. However, the within-pair differences in DNAmAA before cancer diagnosis increased significantly the closer the cancer diagnosis was, and this acceleration extended for years after the diagnosis. Pairs sampled after the diagnosis differed for DNAmAA with the Horvath models capturing cancer diagnosis-associated DNAmAA across all three cancer groupings. The results suggest that DNAmAA in blood is associated with cancer diagnosis. This may be due to epigenetic alterations in relation to cancer, its treatment or associated lifestyle changes. Based on the current study, the biomarker potential of DNAmAA in blood appears to be limited.
Tracing metabolic flux in vivo: basic model structures of tracer methodology
Authors: Kim Il-Young , Park Sanghee , Kim Yeongmin , Kim Hee-Joo , Wolfe Robert R.
Published: September 2022

Molecules in living organisms are in a constant state of turnover at varying rates, i.e., synthesis, breakdown, oxidation, and/or conversion to different compounds. Despite the dynamic nature of biomolecules, metabolic research has focused heavily on static, snapshot information such as the abundances of mRNA, protein, and metabolites and/or (in)activation of molecular signaling, often leading to erroneous conclusions regarding metabolic status. Over the past century, stable, non-radioactive isotope tracers have been widely used to provide critical information on the dynamics of specific biomolecules (metabolites and polymers including lipids, proteins, and DNA), in studies in vitro in cells as well as in vivo in both animals and humans. In this review, we discuss (1) the historical background of the use of stable isotope tracer methodology in metabolic research; (2) the importance of obtaining kinetic information for a better understanding of metabolism; and (3) the basic principles and model structures of stable isotope tracer methodology using 13C-, 15N-, or 2H-labeled tracers.
Thermoregulation and golden hour practices in extremely preterm infants: an international survey
Authors: Jani Pranav , Mishra Umesh , Buchmayer Julia , Walker Karen , Gözen Duygu , Maheshwari Rajesh , D’Çruz Daphne , Lowe Krista , Wright Audrey , Marceau James , Culcer Mihaela , Priyadarshi Archana , Kirby Adrienne , Moore James E. , Oei Ju Lee , Shah Vibhuti , Vaidya Umesh , Khashana Abdelmoneim , Godambe Sunit , Cheah Fook Choe , Zhou Wenhao , Xiaojing Hu , Satardien Muneerah
Published: September 2022

Background

Are thermoregulation and golden hour practices in extremely preterm (EP) infants comparable across the world? This study aims to describe these practices for EP infants based on the neonatal intensive care unit’s (NICUs) geographic region, country’s income status and the lowest gestational age (GA) of infants resuscitated.

Methods

The Director of each NICU was requested to complete the e-questionnaire between February 2019 and August 2021.

Results

We received 848 responses, from all geographic regions and resource settings. Variations in most thermoregulation and golden hour practices were observed. Using a polyethylene plastic wrap, commencing humidity within 60 min of admission, and having local protocols were the most consistent practices (>75%). The odds for the following practices differed in NICUs resuscitating infants from 22 to 23 weeks GA compared to those resuscitating from 24 to 25 weeks: respiratory support during resuscitation and transport, use of polyethylene plastic wrap and servo-control mode, commencing ambient humidity >80% and presence of local protocols.

Conclusion

Evidence-based practices on thermoregulation and golden hour stabilisation differed based on the unit’s region, country’s income status and the lowest GA of infants resuscitated. Future efforts should address reducing variation in practice and aligning practices with international guidelines.

Impact

A wide variation in thermoregulation and golden hour practices exists depending on the income status, geographic region and lowest gestation age of infants resuscitated.

Using a polyethylene plastic wrap, commencing humidity within 60 min of admission and having local protocols were the most consistent practices.

This study provides a comprehensive description of thermoregulation and golden hour practices to allow a global comparison in the delivery of best evidence-based practice.

The findings of this survey highlight a need for reducing variation in practice and aligning practices with international guidelines for a comparable health care delivery.
Modelling aggressive prostate cancers of young men in immune-competent mice, driven by isogenic Trp53 alterations and Pten loss
Authors: Mejía-Hernández Javier Octavio , Keam Simon P. , Saleh Reem , Muntz Fenella , Fox Stephen B. , Byrne David , Kogan Arielle , Pang Lokman , Huynh Jennifer , Litchfield Cassandra , Caramia Franco , Lozano Guillermina , He Hua , You James M. , Sandhu Shahneen , Williams Scott G. , Haupt Ygal , Haupt Sue
Published: September 2022

Understanding prostate cancer onset and progression in order to rationally treat this disease has been critically limited by a dire lack of relevant pre-clinical animal models. We have generated a set of genetically engineered mice that mimic human prostate cancer, initiated from the gland epithelia. We chose driver gene mutations that are specifically relevant to cancers of young men, where aggressive disease poses accentuated survival risks. An outstanding advantage of our models are their intact repertoires of immune cells. These mice provide invaluable insight into the importance of immune responses in prostate cancer and offer scope for studying treatments, including immunotherapies. Our prostate cancer models strongly support the role of tumour suppressor p53 in functioning to critically restrain the emergence of cancer pathways that drive cell cycle progression; alter metabolism and vasculature to fuel tumour growth; and mediate epithelial to mesenchymal-transition, as vital to invasion. Importantly, we also discovered that the type of p53 alteration dictates the specific immune cell profiles most significantly disrupted, in a temporal manner, with ramifications for disease progression. These new orthotopic mouse models demonstrate that each of the isogenic hotspot p53 amino acid mutations studied (R172H and R245W, the mouse equivalents of human R175H and R248W respectively), drive unique cellular changes affecting pathways of proliferation and immunity. Our findings support the hypothesis that individual p53 mutations confer their own particular oncogenic gain of function in prostate cancer.
Pushing the limits of remote RF sensing by reading lips under the face mask
Authors: Hameed Hira , Usman Muhammad , Tahir Ahsen , Hussain Amir , Abbas Hasan , Cui Tie Jun , Imran Muhammad Ali , Abbasi Qammer H.
Published: September 2022

The problem of Lip-reading has become an important research challenge in recent years. The goal is to recognise speech from lip movements. Most of the Lip-reading technologies developed so far are camera-based, which require video recording of the target. However, these technologies have well-known limitations of occlusion and ambient lighting with serious privacy concerns. Furthermore, vision-based technologies are not useful for multi-modal hearing aids in the coronavirus (COVID-19) environment, where face masks have become a norm. This paper aims to solve the fundamental limitations of camera-based systems by proposing a radio frequency (RF) based Lip-reading framework, having an ability to read lips under face masks. The framework employs Wi-Fi and radar technologies as enablers of RF sensing based Lip-reading. A dataset comprising of vowels A, E, I, O, U and empty (static/closed lips) is collected using both technologies, with a face mask. The collected data is used to train machine learning (ML) and deep learning (DL) models. A high classification accuracy of 95% is achieved on the Wi-Fi data utilising neural network (NN) models. Moreover, similar accuracy is achieved by VGG16 deep learning model on the collected radar-based dataset.
Pharmacogenomics polygenic risk score for drug response prediction using PRS-PGx methods
Authors: Zhai Song , Zhang Hong , Mehrotra Devan V. , Shen Judong
Published: September 2022

Polygenic risk scores (PRS) have been successfully developed for the prediction of human diseases and complex traits in the past years. For drug response prediction in randomized clinical trials, a common practice is to apply PRS built from a disease genome-wide association study (GWAS) directly to a corresponding pharmacogenomics (PGx) setting. Here, we show that such an approach relies on stringent assumptions about the prognostic and predictive effects of the selected genetic variants. We propose a shift from disease PRS to PGx PRS approaches by simultaneously modeling both the prognostic and predictive effects and further make this shift possible by developing a series of PRS-PGx methods, including a novel Bayesian regression approach (PRS-PGx-Bayes). Simulation studies show that PRS-PGx methods generally outperform the disease PRS methods and PRS-PGx-Bayes is superior to all other PRS-PGx methods. We further apply the PRS-PGx methods to PGx GWAS data from a large cardiovascular randomized clinical trial (IMPROVE-IT) to predict treatment related LDL cholesterol reduction. The results demonstrate substantial improvement of PRS-PGx-Bayes in both prediction accuracy and the capability of capturing the treatment-specific predictive effects while compared with the disease PRS approaches.
The impact of repeated rapid test strategies on the effectiveness of at-home antiviral treatments for SARS-CoV-2
Authors: Menkir Tigist F. , Donnelly Christl A.
Published: September 2022

Regular rapid testing can provide twofold benefilts: identifying infectious individuals and providing positive tests sufficiently early during infection that treatment with antivirals can effectively inhibit development of severe disease. Here, we provide a quantitative illustration of the extent of nirmatrelvir-associated treatment benefits that are accrued among high-risk populations when rapid tests are administered at various intervals. Strategies for which tests are administered more frequently are associated with greater reductions in the risk of hospitalization, with weighted risk ratios for testing every other day to once every 2 weeks ranging from 0.17 (95% CI: 0.11–0.28) to 0.77 (95% CI: 0.69–0.83) and correspondingly, higher proportions of the infected population benefiting from treatment, ranging from 0.26 (95% CI: 0.18–0.34) to 0.92 (95% CI: 0.80–0.98), respectively. Importantly, reduced treatment delays, coupled with increased test and treatment coverage, have a critical influence on average treatment benefits, confirming the significance of access.
Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling
Authors: Adachi Yusuke , Ueda Kazutaka , Nomura Seitaro , Ito Kaoru , Katoh Manami , Katagiri Mikako , Yamada Shintaro , Hashimoto Masaki , Zhai Bowen , Numata Genri , Otani Akira , Hinata Munetoshi , Hiraike Yuta , Waki Hironori , Takeda Norifumi , Morita Hiroyuki , Ushiku Tetsuo , Yamauchi Toshimasa , Takimoto Eiki , Komuro Issei
Published: September 2022

Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 (Nrg4) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.
Microbial biofilms as living photoconductors due to ultrafast electron transfer in cytochrome OmcS nanowires
Authors: Neu Jens , Shipps Catharine C. , Guberman-Pfeffer Matthew J. , Shen Cong , Srikanth Vishok , Spies Jacob A. , Kirchhofer Nathan D. , Yalcin Sibel Ebru , Brudvig Gary W. , Batista Victor S. , Malvankar Nikhil S.
Published: September 2022

Light-induced microbial electron transfer has potential for efficient production of value-added chemicals, biofuels and biodegradable materials owing to diversified metabolic pathways. However, most microbes lack photoactive proteins and require synthetic photosensitizers that suffer from photocorrosion, photodegradation, cytotoxicity, and generation of photoexcited radicals that are harmful to cells, thus severely limiting the catalytic performance. Therefore, there is a pressing need for biocompatible photoconductive materials for efficient electronic interface between microbes and electrodes. Here we show that living biofilms of Geobacter sulfurreducens use nanowires of cytochrome OmcS as intrinsic photoconductors. Photoconductive atomic force microscopy shows up to 100-fold increase in photocurrent in purified individual nanowires. Photocurrents respond rapidly (<100 ms) to the excitation and persist reversibly for hours. Femtosecond transient absorption spectroscopy and quantum dynamics simulations reveal ultrafast (~200 fs) electron transfer between nanowire hemes upon photoexcitation, enhancing carrier density and mobility. Our work reveals a new class of natural photoconductors for whole-cell catalysis.
Comparing the levelized cost of electric vehicle charging options in Europe
Authors: Lanz Lukas , Noll Bessie , Schmidt Tobias S. , Steffen Bjarne
Published: September 2022

With rapidly decreasing purchase prices of electric vehicles, charging costs are becoming ever more important for the diffusion of electric vehicles as required to decarbonize transport. However, the costs of charging electric vehicles in Europe are largely unknown. Here we develop a systematic classification of charging options, gather extensive market data on equipment cost, and employ a levelized cost approach to model charging costs in 30 European countries (European Union 27, Great Britain, Norway, Switzerland) and for 13 different charging options for private passenger transport. The findings demonstrate a large variance of charging costs across countries and charging options, suggesting different policy options to reduce charging costs. A specific analysis on the impacts and relevance of publicly accessible charging station utilization is performed. The results reveal charging costs at these stations to be competitive with fuel costs at typical utilization rates exhibited already today.
Meta-analysis reveals weak but pervasive plasticity in insect thermal limits
Authors: Weaving Hester , Terblanche John S. , Pottier Patrice , English Sinead
Published: September 2022

Extreme temperature events are increasing in frequency and intensity due to climate change. Such events threaten insects, including pollinators, pests and disease vectors. Insect critical thermal limits can be enhanced through acclimation, yet evidence that plasticity aids survival at extreme temperatures is limited. Here, using meta-analyses across 1374 effect sizes, 74 studies and 102 species, we show that thermal limit plasticity is pervasive but generally weak: per 1 °C rise in acclimation temperature, critical thermal maximum increases by 0.09 °C; and per 1 °C decline, critical thermal minimum decreases by 0.15 °C. Moreover, small but significant publication bias suggests that the magnitude of plasticity is marginally overestimated. We find juvenile insects are more plastic than adults, highlighting that physiological responses of insects vary through ontogeny. Overall, we show critical thermal limit plasticity is likely of limited benefit to insects during extreme climatic events, yet we need more studies in under-represented taxa and geographic regions.
TENT2, TUT4, and TUT7 selectively regulate miRNA sequence and abundance
Authors: Yang Acong , Bofill-De Ros Xavier , Stanton Ryan , Shao Tie-Juan , Villanueva Patricia , Gu Shuo
Published: September 2022

TENTs generate miRNA isoforms by 3’ tailing. However, little is known about how tailing regulates miRNA function. Here, we generate isogenic HEK293T cell lines in which TENT2, TUT4 and TUT7 are knocked out individually or in combination. Together with rescue experiments, we characterize TENT-specific effects by deep sequencing, Northern blot and in vitro assays. We find that 3’ tailing is not random but highly specific. In addition to its known adenylation, TENT2 contributes to guanylation and uridylation on mature miRNAs. TUT4 uridylates most miRNAs whereas TUT7 is dispensable. Removing adenylation has a marginal impact on miRNA levels. By contrast, abolishing uridylation leads to dysregulation of a set of miRNAs. Besides let-7, miR-181b and miR-222 are negatively regulated by TUT4/7 via distinct mechanisms while the miR-888 cluster is upregulated specifically by TUT7. Our results uncover the selective actions of TENTs in generating 3’ isomiRs and pave the way to investigate their functions.
Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis
Authors: Brown Derek W. , Zhou Weiyin , Wang Youjin , Jones Kristine , Luo Wen , Dagnall Casey , Teshome Kedest , Klein Alyssa , Zhang Tongwu , Lin Shu-Hong , Lee Olivia W. , Khan Sairah , Vo Jacqueline B. , Hutchinson Amy , Liu Jia , Wang Jiahui , Zhu Bin , Hicks Belynda , Martin Andrew St. , Spellman Stephen R. , Wang Tao , Deeg H. Joachim , Gupta Vikas , Lee Stephanie J. , Freedman Neal D. , Yeager Meredith , Chanock Stephen J. , Savage Sharon A. , Saber Wael , Gadalla Shahinaz M. , Machiela Mitchell J.
Published: September 2022

Myelofibrosis is a rare myeloproliferative neoplasm (MPN) with high risk for progression to acute myeloid leukemia. Our integrated genomic analysis of up to 933 myelofibrosis cases identifies 6 germline susceptibility loci, 4 of which overlap with previously identified MPN loci. Virtual karyotyping identifies high frequencies of mosaic chromosomal alterations (mCAs), with enrichment at myelofibrosis GWAS susceptibility loci and recurrently somatically mutated MPN genes (e.g., JAK2). We replicate prior MPN associations showing germline variation at the 9p24.1 risk haplotype confers elevated risk of acquiring JAK2V617F mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2V617F mutations. Germline variation associated with longer telomeres is associated with increased myelofibrosis risk. Myelofibrosis cases with high-frequency JAK2 mCAs have marked reductions in measured telomere length – suggesting a relationship between telomere biology and myelofibrosis clonal expansion. Our results advance understanding of the germline-somatic interaction at JAK2 and implicate mCAs involving JAK2 as strong promoters of clonal expansion of those mutated clones.
High-throughput continuous evolution of compact Cas9 variants targeting single-nucleotide-pyrimidine PAMs
Authors: Huang Tony P. , Heins Zachary J. , Miller Shannon M. , Wong Brandon G. , Balivada Pallavi A. , Wang Tina , Khalil Ahmad S. , Liu David R.
Published: September 2022

Despite the availability of Cas9 variants with varied protospacer-adjacent motif (PAM) compatibilities, some genomic loci—especially those with pyrimidine-rich PAM sequences—remain inaccessible by high-activity Cas9 proteins. Moreover, broadening PAM sequence compatibility through engineering can increase off-target activity. With directed evolution, we generated four Cas9 variants that together enable targeting of most pyrimidine-rich PAM sequences in the human genome. Using phage-assisted noncontinuous evolution and eVOLVER-supported phage-assisted continuous evolution, we evolved Nme2Cas9, a compact Cas9 variant, into variants that recognize single-nucleotide pyrimidine-PAM sequences. We developed a general selection strategy that requires functional editing with fully specified target protospacers and PAMs. We applied this selection to evolve high-activity variants eNme2-T.1, eNme2-T.2, eNme2-C and eNme2-C.NR. Variants eNme2-T.1 and eNme2-T.2 offer access to N4TN PAM sequences with comparable editing efficiencies as existing variants, while eNme2-C and eNme2-C.NR offer less restrictive PAM requirements, comparable or higher activity in a variety of human cell types and lower off-target activity at N4CN PAM sequences.
Five years calibrated observations from the University of Bonn X-band weather radar (BoXPol)
Authors: Pejcic Velibor , Soderholm Joshua , Mühlbauer Kai , Louf Valentin , Trömel Silke
Published: September 2022

Polarimetric weather radars offer a wealth of new information compared to conventional technology, not only to enhance quantitative precipitation estimation, warnings, and short-term forecasts, but also to improve our understanding of precipitation generating processes and their representation in numerical weather prediction models. To support such research opportunities, this paper describes an open-access dataset between 2014–2019 collected by the polarimetric Doppler X-band weather radar in Bonn (BoXPol), western Germany. To complement this dataset, the technical radar characteristics, scanning strategy and the best-practice for radar data processing are detailed. In addition, an investigation of radar calibration is presented. Reflectivity measurements from the Dual-frequency Precipitation Radar operating on the core satellite of the Global Precipitation Mission are compared to those of BoXPol to provide absolute calibration offsets with the dataset. The Relative Calibration Adjustment technique is applied to identify stable calibration periods. The absolute calibration of differential reflectivity is determined using the vertical scan and provided with the BoxPol dataset.
Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease
Authors: Pourtaher Hormoz , Hasaninejad Alireza , Iraji Aida
Published: September 2022

The objective of this study was to design new polysubstituted pyrrole derivatives as selective acetylcholinesterase (AChE) inhibitors to target Alzheimer's disease. In this context, a highly efficient, one-pot, sequential, multi-component synthesis of a diverse range of polysubstituted pyrroles was developed through a sequential domino strategy by the condensation of amines with 1,1-bis(methylthio)-2-nitroethene (BMTNE), Knovenagle reaction of arylglyoxals with malono derivatives and subsequent Michael addition and intramolecular cyclization reaction in EtOH at reflux. Thirty-nine synthesized compounds were evaluated as AChE and butyrylcholinesterase (BChE) inhibitors. Among the synthesized compounds, compound 4ad (IC50 = 2.95 ± 1.31 µM) was the most potent and selective AChE inhibitor with no significant inhibition against butyrylcholinesterase BChE. A kinetic study of 4ad revealed that this compound inhibited AChE in an uncompetitive mode. Based on a molecular modeling study, compound 4ad due to its small size properly fitted into the active site of AChE compared to BChE and stabilized by H-bond and hydrophobic interactions with the critical residues of the AChE binding pocket. Consequently, it was proposed that the 4ad derivative can be an ideal lead candidate against AD with a simple and practical operation of synthetic procedures.
Fission in a colonial marine invertebrate signifies unique life history strategies rather than being a demographic trait
Authors: Ben-Hamo Oshrat , Izhaki Ido , Ben-Shlomo Rachel , Rinkevich Baruch
Published: September 2022

Each of the few known life-history strategies (e.g., r/K and parity [semelparity and iteroparity]), is a composite stratagem, signified by co-evolved sets of trade-offs with stochastically distributed variations that do not form novel structured strategies. Tracking the demographic traits of 81Botryllus schlosseri(a marine urochordate) colonies, from birth to death, we revealed three co-existing novel life-history strategies in this long-standing laboratory-bred population, all are bracketed through colonial fission (termed NF, FA and FB for no fission, fission after and fission before reaching maximal colony size, respectively) and derived from organisms maintained in a benign, highly invariable environment. This environment allows us to capture the strategists’ blueprints and their net performance through 13 traits, each branded by high within-strategy variation. Yet, six traits differed significantly among the strategies and, in two, the FB was notably different. These results frame fissions in colonial organisms not as demographic traits, but as pivotal agents for life-history strategies.