bluuebunny/crossref_metadata_2025 huggingface dataset:
Economic policy uncertainty, geopolitical risk, market sentiment, and regional stocks: asymmetric analyses of the EU sectors
Authors: Bossman Ahmed , Gubareva Mariya , Teplova Tamara
Published: September 2023

The purpose of this study is to investigate the asymmetric effects of economic policy uncertainty (EPU), geopolitical risk (GPR), and market sentiment (VIX) on European Union (EU) stocks by sectors of economic activity. The design and methodological approach of our research are rooted in parametric and nonparametric quantile-based techniques. We employ monthly data covering eleven sectors of economic activity in addition to GPR, Global EPU, European Union EPU, United States EPU, and VIX. Our dataset covers the period between February 2013 and September 2022. Our findings show a generally low predictive power of the considered EPU measures on the stock returns of the EU sectors. Notwithstanding, the analysis reveals that EPU from the EU has the highest predictive ability on the EU sectoral stock returns while EPU from the US has no significant predictive ability on the stock returns from the EU. Our findings also highlight the asymmetric effects of various EPUs on EU stocks. Moreover, certain sectoral exposure to EU stocks, found to serve just as diversifiers in normal market conditions, could become a hedge and safe-haven against GPR in extreme economic conditions. Our findings also highlight the role of the VIX as a good gauge to hedge against the downside risks of the EU stocks. The originality of our work is two-fold. First, we extend the study of how global factors influence the EU stock market to the most recent period including the Russia–Ukraine conflict. Second, we perform this study on a sectoral basis. Therefore, the value of our findings is that they provide notable implications for market regulation and portfolio management.
A Sustainable Philosophy for Teaching Ethics and Morals to Build Character, Pro-social Skills and Well-being in Children
Authors: Khanna Dipankar
Published: September 2023

This paper looks at frameworks for the practice of moral and ethical values for children, drawn from Yoga and Buddhist Philosophies. Verily the purpose is to inculcate a repository of thought and behaviour through which they align moral and ethical behaviours by becoming important cogs in establishing harmony in the world that we exist. Harmony between one child and another child, harmony between children and their families, harmony between the families and larger society and harmony between society and other sentient beings and life forms is what constitutes cosmic-harmony. In this sense, Confucius’ triadic cosmic-harmony and the timeless Vedic Ṛta are not merely a philosophical thought or idea envisaged in ivory towers but real-time experiencing or darsana. This is realized through disciplined individual behaviours in balancing of our purusharthas with our dharma; aligning these with a sense of universal responsibility out of care and concern for one another. This would ensure in connecting and building synergy with all that surrounds us since these practices fostering morals and ethics could also be befitting measures to counter the Anthropocene epoch’s negative geologic impact on our planet. This paper is being written from the perspective of human beings and their practice of humanism via moral and ethical behaviour. The point of departure being that humans are placed as a dominant species at the centre of our planet with unprecedented power to influence the fate of other species, the environment and the future of the quality of bio-diversity of life on earth.
Graph construction on complex spatiotemporal data for enhancing graph neural network-based approaches
Authors: Bloemheuvel Stefan , van den Hoogen Jurgen , Atzmueller Martin
Published: September 2023

Graph neural networks (GNNs) haven proven to be an indispensable approach in modeling complex data, in particular spatial temporal data, e.g., relating to sensor data given as time series with according spatial information. Although GNNs provide powerful modeling capabilities on such kind of data, they require adequate input data in terms of both signal and the underlying graph structures. However, typically the according graphs are not automatically available or even predefined, such that typically an ad hoc graph representation needs to be constructed. However, often the construction of the underlying graph structure is given insufficient attention. Therefore, this paper performs an in-depth analysis of several methods for constructing graphs from a set of sensors attributed with spatial information, i.e., geographical coordinates, or using their respective attached signal data. We apply a diverse set of standard methods for estimating groups and similarities between graph nodes as location-based as well as signal-driven approaches on multiple benchmark datasets for evaluation and assessment. Here, for both areas, we specifically include distance-based, clustering-based, as well as correlation-based approaches for estimating the relationships between nodes for subsequent graph construction. In addition, we consider two different GNN approaches, i.e., regression and forecasting in order to enable a broader experimental assessment. Typically, no predefined graph is given, such that (ad hoc) graph creation is necessary. Here, our results indicate the criticality of factoring in the crucial step of graph construction into GNN-based research on spatial temporal data. Overall, in our experimentation no single approach for graph construction emerged as a clear winner. However, in our analysis we are able to provide specific indications based on the obtained results, for a specific class of methods. Collectively, the findings highlight the need for researchers to carefully consider graph construction when employing GNNs in the analysis of spatial temporal data.
Detecting Fusarium oxysporum f. sp. elaeidis by using loop-mediated isothermal amplification
Authors: Adusei-Fosu Kwasi , Dickinson Matthew
Published: September 2023

We developed a Loop-Mediated Isothermal Amplification (LAMP) to detect Fusarium oxysporum f. sp. elaeidis (FOE) causal agent of fusarium wilt in oil palm. The assay was designed based on partial sequences of effector protein Secreted In Xylem (SIX8, SIX10 and SIX13) and P450 cytochrome-oxidase. The isolates used were classified as FOE, presumed-FOE and non-FOE/other Fusarium spp. based on previously published pathogenicity assay studies. The LAMP assay detected FOE DNA isolated from root tissues of oil palm seedlings. The SIX8 primers detected all FOE isolates, including other presumed-FOE and non-FOE isolates. The SIX10 and SIX13 could not detect FOE and presumed-FOE isolates. The P450 cytochrome-oxidase primer detected all isolates of FOE, presumed-FOE and non-FOE. Without isolating FOE DNA from soil, the LAMP assay could not detect FOE directly in inoculated soil. Detection time for all primers was below 30 min. Annealing derivative curves were used for assessing the level of specificity for both SIX8 and P450 cytochrome-oxidase, but none of the LAMP primers could distinguish between FOE, presumed-FOE and non-FOE isolates. This assay could be suitable for FOE detection of oil palm in nurseries and serve as an important biosecurity tool to screen oil palm germplasm exchanged between oil palm growing countries.
Vom Ertasten eines Elefanten in einem dunklen Raum: Philosophische, psychologische und literaturwissenschaftliche Perspektiven auf demenzielle Erkrankungen
Authors: Hutmacher Fabian
Published: September 2023

Demenzielle Erkrankungen sind mehr als neurodegenerative Erkrankungen des Gehirns. Um diese These plausibel zu machen, präsentiert der vorliegende Aufsatz philosophische, psychologische und literaturwissenschaftliche Perspektiven auf demenzielle Erkrankungen. Aus einer philosophisch-psychologischen Perspektive wird dabei zunächst gezeigt, dass das Selbst von Menschen mit Demenz auch mit fortschreitendem Krankheitsverlauf nicht seine lebensgeschichtliche Tiefe verliert. In einem zweiten Schritt wird darauf aufbauend argumentiert, dass demenzielle Erkrankungen nicht nur die erkrankte Person selbst, sondern immer auch ein soziales Beziehungsgefüge betreffen. Als eine Option, mit den daraus resultierenden Belastungen umzugehen, wird die Beschäftigung mit kreativen Aktivitäten vorgestellt. Basierend darauf wird schließlich die Frage erörtert, welche Einsichten die Auseinandersetzung mit literarischen Demenzdarstellungen bereithalten kann. Hervorgehoben wird dabei neben der Möglichkeit der mimetischen Annäherung an die Innenperspektive erkrankter Personen vor allem das Potenzial, gedankliche Resonanz- und Assoziationsräume zu öffnen. Mit der Beschreibung dieser unterschiedlichen disziplinären Perspektiven liefert der vorliegende Aufsatz keine umfassende Analyse demenzieller Erkrankungen, sondern versteht sich vielmehr als Einladung, weitere Sichtweisen ins Spiel zu bringen und so das Gesamtbild zu vervollständigen.
PMDedu: Assessing the educational needs of startups and academic investigators focused on pediatric medical device development
Authors: Shah Payal , Snitman Alexis , McCaney Jennifer , Rose Lynn M. , Sheridan David , Espinoza Salomon Juan
Published: September 2023

Background:

The pediatric medical device development (PMDD) process is highly complex, beset by a variety of financial, technical, medical, and regulatory barriers. Startup company innovators and academic investigators often struggle with accessing specialized knowledge relating to regulatory requirements, product development, research, and marketing strategies.

Objectives:

The West Coast Consortium for Technology & Innovation in Pediatrics (CTIP) conducted an educational needs assessment to understand knowledge gaps and inform our educational strategy.

Methods:

We surveyed a total of 49 medical device startups and 52 academic investigators. Electronic surveys were developed for each group on Qualtrics and focused on manufacturing, regulatory, research, commercialization, and funding. Descriptive statistics were used.

Results:

A larger proportion of academic investigator respondents had a clinical background compared to the startup respondents (45% vs. 22%). The biggest barriers for academic investigators were understanding regulatory and safety requirements testing (52%) and finding and obtaining non-dilutive funding was the most difficult (54%). Among startups, understanding clinical research methods and requirements was the biggest barrier (79%).

Conclusion:

Startup companies and academic investigators have similar, but not identical, educational needs to better understand the PMD development process. Investigators need more support in identifying funding sources, while startup companies identified an increased need for education on research regulatory topics. These findings can help guide curriculum development as well as opportunities for partnerships between academia and startups.
On the quasi-ergodicity of absorbing Markov chains with unbounded transition densities, including random logistic maps with escape
Authors: CASTRO MATHEUS M. , GOVERSE VINCENT P. H. , LAMB JEROEN S. W. , RASMUSSEN MARTIN
Published: September 2023

In this paper, we consider absorbing Markov chains
$X_n$
admitting a quasi-stationary measure
$\mu $
on M where the transition kernel
${\mathcal P}$
admits an eigenfunction
$0\leq \eta \in L^1(M,\mu )$
. We find conditions on the transition densities of
${\mathcal P}$
with respect to
$\mu $
which ensure that
$\eta (x) \mu (\mathrm {d} x)$
is a quasi-ergodic measure for
$X_n$
and that the Yaglom limit converges to the quasi-stationary measure
$\mu $
-almost surely. We apply this result to the random logistic map
$X_{n+1} = \omega _n X_n (1-X_n)$
absorbed at
${\mathbb R} \setminus [0,1],$
where
$\omega _n$
is an independent and identically distributed sequence of random variables uniformly distributed in
$[a,b],$
for
$1\leq a <4$
and
$b>4.$
Low infectivity among asymptomatic patients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) admission test at a tertiary care center, 2020–2022
Authors: Tayyar Ralph , Kiener Melanie A. , Liang Jane W. , Contreras Gustavo , Rodriguez-Nava Guillermo , Zimmet Alex N. , Contag Caitlin A. , Srinivasan Krithika , McIntyre Karen , Subramanian Aruna , Shepard John , Tompkins Lucy S. , Pinsky Benjamin A. , Salinas Jorge L.
Published: September 2023

We used a strand-specific RT-qPCR to evaluate viral replication as a surrogate for infectiousness among 242 asymptomatic inpatients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) admission test. Only 21 patients (9%) had detectable SARS-CoV-2 minus-strand RNA. Because most patients were found to be noninfectious, our findings support the suspension of asymptomatic admission testing.
‘Visible’ compulsions: OCD and the politics of science in British clinical psychology, 1948–1975
Authors: Surawy Stepney Eva
Published: September 2023

This article historicizes a single stage in how the contemporary obsessive–compulsive disorder (OCD) category was built. Starting from the position that the two central components which make up OCD are ‘obsessions’ and ‘compulsions’, it illustrates how these concepts were taken apart by a small group of clinical psychologists working at the Institute of Psychiatry and the Maudsley psychiatric hospital in south London in the early 1970s, and why compulsions were investigated whilst obsessions were ignored. The decision to distinguish the previously undifferentiated symptoms is attributed to the commitment amongst psychologists at the Maudsley, most notably Stanley Rachman, to an empirical conception of science which emphasized observability. Two aspects of this are discussed. First, compulsions were deemed ‘visible’ through their correspondence with animal behaviour. Second, the symptom was seen as open to an experimental modification procedure which privileged visible outcomes. Ultimately, the article concludes that the historical division between ‘obsessions’ and ‘compulsions’, and the extensive investigation of the latter, has had substantial implications for the development of OCD as a category centred on visible behaviours and treated through behavioural means.
The impact of welfare on maternal investment and sibling competition: evidence from Serbian Roma communities
Authors: Čvorović Jelena
Published: September 2023

Siblings compete for limited parental resources, which can result in a trade-off between family size and child growth outcomes. Welfare incentives may improve parental circumstances in large families by compensating for the additional costs of an extra child and increasing the resources available to a family. The improvements in conditions may influence parents to increase their investment, expecting greater returns from the investment in child survival and development, while in turn increase sibling competition for the investment. This study assessed whether welfare benefits have influenced parental investment trade-offs and competition between siblings among Serbian Roma, a population largely dependent on welfare. Using data from the UNICEF Multiple Indicator Cluster Survey 6, this study assessed the associations between maternal investment, child cash benefits, sibship size, and child anthropometry, as an indicator of health, among 1096 Serbian Roma children aged 0 to 59 months. Living in a small family benefited Roma children, while the incentives increased competition between siblings. Maternal investment was negatively associated with incentives, as the improvements brought about were insufficient to influence a change in maternal perceptions about the local setting uncertainty and thus promote an increase in investment.
Stress Testing Banks’ Digital Capabilities: Evidence from the COVID-19 Pandemic
Authors: Kwan Alan , Lin Chen , Pursiainen Vesa , Tai Mingzhu
Published: September 2023

Banks’ information technology (IT) capabilities affect their ability to serve customers during the COVID-19 pandemic, which generates an unexpected and unprecedented shock that shifts banking services from in-person to digital. Amid mobility restrictions, banks with better IT experience larger reductions in physical branch visits and larger increases in website traffic, implying a larger shift to digital banking. Stronger IT banks are able to originate more Paycheck Protection Program loans to small business borrowers, especially in areas with more severe COVID-19 outbreaks, higher internet use, and higher bank competition. Those banks also attract more deposit flows and receive better mobile customer reviews during the pandemic.
Factors associated with adverse pregnancy outcomes of maternal syphilis in Henan, China, 2016–2022
Authors: Zhang Meng , Qu Huimin , Xu Feng , Xia Junfen , Hui Xiaoqing , Zhang Hongyan , Shi Cannan , He Junjian , Cao Yuan , Hu Mengcai
Published: September 2023

Maternal syphilis not only seriously affects the quality of life of pregnant women themselves but also may cause various adverse pregnancy outcomes (APOs). This study aimed to analyse the association between the related factors and APOs in maternal syphilis. 7,030 pregnant women infected with syphilis in Henan Province between January 2016 and December 2022 were selected as participants. Information on their demographic and clinical characteristics, treatment status, and pregnancy outcomes was collected. Multivariate logistic regression models and chi-squared automatic interaction detector (CHAID) decision tree models were used to analyse the factors associated with APOs. The multivariate logistic regression results showed that the syphilis infection history (OR = 1.207, 95% CI, 1.035–1.409), the occurrence of abnormality during pregnancy (OR = 5.001, 95% CI, 4.203–5.951), not receiving standard treatment (OR = 1.370, 95% CI, 1.095–1.716), not receiving any treatment (OR = 1.313, 95% CI, 1.105–1.559), and a titre ≥1:8 at diagnosis (OR = 1.350, 95%CI, 1.079–1.690) and before delivery (OR = 1.985, 95%CI, 1.463–2.694) were risk factors. A total of six influencing factors of APOs in syphilis-infected women were screened using the CHAID decision tree model. Integrated prevention measures such as early screening, scientific eugenics assessment, and standard syphilis treatment are of great significance in reducing the incidence of APOs for pregnant women infected with syphilis.
From simple row of dots to the rain god calendar: Interpretation of the pecked cross petroglyph from the Late Postclassic Tetzcotzinco
Authors: Prusaczyk Daniel
Published: September 2023

This article presents and analyzes a newly discovered petroglyph from Tetzcotzinco (mun. Texcoco, Mexico) in the form of arranged pecked dots. Based on what is known about Mesoamerican divinatory systems, calendars, and the perception of space, the interpretation takes into account both the encoded numerical values and the layout of the dots. The main argument is that this and similar representations’ function was not limited to simple counting of days or serving as a kind of astronomical marker, in which the arms of the cross indicated, for example, equinoxes, which is by far their most common interpretation in academic literature. Instead, it represented calendrical cycles through the numbers, as suggested by some scholars. Based on this hypothesis, the article explores the possible connection between numbers registered in Tetzcotzinco's “pecked cross” and specific diagrams from indigenous divinatory books. Therefore, the plausible interpretation of the symbolism of this petroglyph is that it either expressed a series of meanings related to the agrarian period(s) and rain god(s) or less-known Mesoamerican calendrical cycles, such as half trecenas or seven- and nine-day periods.
The role of oral vocabulary when L2 speakers read novel words: A complex word training study
Authors: Behzadnia Ali , Wegener Signy , Bürki Audrey , Beyersmann Elisabeth
Published: September 2023

The present study asked whether oral vocabulary training can facilitate reading in a second language (L2). Fifty L2 speakers of English received oral training over three days on complex novel words, with predictable and unpredictable spellings, composed of novel stems and existing suffixes (i.e.,vishing,vishes,vished). After training, participants read the novel word stems for the first time (i.e., trained and untrained), embedded in sentences, and their eye movements were monitored. The eye-tracking data revealed shorter looking times for trained than untrained stems, and for stems with predictable than unpredictable spellings. In contrast to monolingual speakers of English, the interaction between training and spelling predictability was not significant, suggesting that L2 speakers did not generate orthographic skeletons that were robust enough to affect their eye-movement behaviour when seeing the trained novel words for the first time in print.
The Role of Family Background and Education in shaping inequalities. Evidence from the Spanish regions
Authors: Suárez Álvarez Ana , López Menéndez Ana Jesús
Published: September 2023

Family background characteristics and educational resources are crucial in shaping individuals’ income and therefore a potential source of income inequality and inequality of opportunity. This article analyses inequalities in the Spanish diverse regions using data from the European Survey of Income and Living Conditions (EU-SILC). Along this article we analyse the relevance of family background characteristics in shaping individuals’ opportunities as well as the role education plays in income inequality. Our findings show that family background characteristics are of great importance in shaping individuals’ performance and opportunities of achieving a certain level of income, well-being and education; also, educational variables at regional level, such as the education expenditure per student, are highly correlated to the levels of inequality. In view of the results, it would be advisable to implement public policies targeting vulnerable groups to ensure equal opportunities and invest in education given its potential as equalizer of income inequality.
Conflict or Coordination? The Spatiotemporal Relationship Between Humans and Nature on the Qinghai‐Tibet Plateau
Authors: Liu Haimeng , Cheng Yi , Liu Zhifeng , Li Qirui , Zhang Haiyan , Wei Wei
Published: September 2023

As the Earth's Third Pole and the Asian water tower, the Qinghai‐Tibet Plateau (QTP) plays a key role in global climate regulation and biodiversity maintenance. Living in harmony with nature is vital for local and global sustainable development. Current research on the conflicted or coordinated relationship between humans and nature on the QTP at a fine spatial scale remains limited. To fill the gap, we developed the human activity intensity index (HAI) and eco‐environmental quality index (EQI) at 1‐km resolution and proposed a four‐quadrant diagram approach to explore the dynamics between them. The results show a coordinated development on the QTP as the HAI and EQI both increased from 2000 to 2020, and the ratio of coordinated areas to conflicted areas was 5:1. High HAI areas were mainly in big cities such as Xining, Lhasa, Haidong, Xigaze, and along traffic lines. The significant conflicted areas were mainly outside the Lhasa metropolitan, south of the Hengduan Mountains, and along some new roads, and reduced by 8% between 2000–2010 and 2010–2020. The area of high HAI but low EQI was the smallest proportion, mainly in southern Qinghai Lake, southern Brahlung Zangbo River, Gobi oases, and western transport lines, but it implies the highest risk of ecosystem degradation. This research expands the fundamental methodology to address complex human‐natural relationships and provides implications for the sustainable development of fragile ecosystems.
Robust Weakening of the Gulf Stream During the Past Four Decades Observed in the Florida Straits
Authors: Piecuch Christopher G. , Beal Lisa M.
Published: September 2023

The Gulf Stream is a vital limb of the North Atlantic circulation that influences regional climate, sea level, and hurricane activity. Given the Gulf Stream's relevance to weather and climate, many studies have attempted to estimate trends in its volumetric transport from various data sets, but results have been inconclusive, and no consensus has emerged whether it is weakening with climate change. Here we use Bayesian analysis to jointly assimilate multiple observational data sets from the Florida Straits to quantify uncertainty and change in Gulf Stream volume transport since 1982. We find with virtual certainty (probability P > 99%) that Gulf Stream volume transport through the Florida Straits declined by 1.2 ± 1.0 Sv in the past 40 years (95% credible interval). This significant trend has emerged from the data set only over the past ten years, the first unequivocal evidence for a recent multidecadal decline in this climate‐relevant component of ocean circulation.
Non-small cell lung cancers (NSCLCs) oncolysis using coxsackievirus B5 and synergistic DNA-damage response inhibitors
Authors: Cui Bopei , Song Lifang , Wang Qian , Li Kelei , He Qian , Wu Xing , Gao Fan , Liu Mingchen , An Chaoqiang , Gao Qiushuang , Hu Chaoying , Hao Xiaotian , Dong Fangyu , Zhou Jiuyue , Liu Dong , Song Ziyang , Yan Xujia , Zhang Jialu , Bai Yu , Mao Qunying , Yang Xiaoming , Liang Zhenglun
Published: September 2023

With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy. Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identifies an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a potential therapy for NSCLCs.
Inflammasome activation occurs in CD4+ and CD8+ T cells during graft-versus-host disease
Authors: Talley Sarah , Rademacher David J. , Campbell Edward M.
Published: September 2023

A severe complication of hematopoietic stem cell transplantation is graft-versus-host disease (GvHD), a reaction that occurs following the transfer of donor immune cells (the graft) into an allogeneic host. Transplanted cells recognize host alloantigens as foreign, resulting in the activation of donor T cells and migration of these pathological cells into host tissues. In this study, we found that caspase-1 is activated in alloreactive murine and human CD4+ and CD8+ T cells early during acute GvHD (aGvHD). The presence of inflammasome-bound active caspase-1 (p33) and ASC-speck formation confirmed inflammasome activation in these cells. We further measured gasdermin D (GSDMD) cleavage and IL-18 secretion from alloreactive T cells ex vivo. Isolated T cells with high levels of active caspase-1 had a strong inflammatory transcriptional signature and a metabolic phenotype similar to inflammatory myeloid cells, including the upregulation of proinflammatory cytokines and metabolic switch from oxidative phosphorylation to aerobic glycolysis. We also observed oxidative stress, mitochondrial dysfunction, and cell death phenotypes consistent with inflammatory cell death in alloreactive T cells. For the first time, this study characterizes caspase-1 activation in transplanted T cells during aGvHD, using mouse and human models, adding to a body of literature supporting inflammasome function in cells of the adaptive immune system.
Sodium glucose cotransporter 2 inhibitor suppresses renal injury in rats with renal congestion
Authors: Endo Akari , Hirose Takuo , Sato Shigemitsu , Ito Hiroki , Takahashi Chika , Ishikawa Risa , Kamada Ayaka , Oba-Yabana Ikuko , Kimura Tomoyoshi , Takahashi Kazuhiro , Mori Takefumi
Published: September 2023

Renal congestion is an issue of cardiorenal syndrome in patients with heart failure. Recent clinical and basic studies suggest a renoprotective potential of sodium–glucose cotransporter (SGLT) 2 inhibitors. However, the effect on renal congestion and its mechanism is not fully understood. Thus, we aimed to clarify the effect of SGLT inhibition in a renal congestion model. Renal congestion was induced in the left kidney of male Sprague-Dawley rats by ligation of the inferior vena cava between the renal veins. The SGLT2 inhibitor tofogliflozin or vehicle was orally administered daily from the day before IVC ligation until two days after surgery. On the third postoperative day, both the right control kidney and the left congested kidney were harvested and analyzed. Kidney weight and water content was increased, and renal injury and fibrosis were observed in the left congested kidney. Kidney weight gain and hydration were improved with tofogliflozin treatment. Additionally, this treatment effectively reduced renal injury and fibrosis, particularly in the renal cortex. SGLT2 expression was observed in the congested kidney, but suppressed in the damaged tubular cells. Molecules associated with inflammation were increased in the congested kidney and reversed by tofogliflozin treatment. Mitochondrial dysfunction provoked by renal congestion was also improved by tofogliflozin treatment. Tofogliflozin protects against renal damage induced by renal congestion. SGLT2 inhibitors could be a candidate strategy for renal impairment associated with heart failure.
A Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils
Authors: Ozberk Victoria , Zaman Mehfuz , Lepletier Ailin , Eskandari Sharareh , Kaden Jacqualine , Mills Jamie-Lee , Calcutt Ainslie , Dooley Jessica , Huo Yongbao , Langshaw Emma L. , Ulett Glen C. , Batzloff Michael R. , Good Michael F. , Pandey Manisha
Published: September 2023

Mucosally active subunit vaccines are an unmet clinical need due to lack of licensed immunostimulants suitable for vaccine antigens. Here, we show that intranasal administration of liposomes incorporating: the Streptococcus pyogenes peptide antigen, J8; diphtheria toxoid as a source of T cell help; and the immunostimulatory glycolipid, 3D(6-acyl) PHAD (PHAD), is able to induce long-lived humoral and cellular immunity. Mice genetically deficient in either mucosal antibodies or total antibodies are protected against S. pyogenes respiratory tract infection. Utilizing IL-17-deficient mice or depleting cellular subsets using antibodies, shows that the cellular responses encompassing, CD4+ T cells, IL-17, macrophages and neutrophils have important functions in vaccine-mediated mucosal immunity. Overall, these data demonstrate the utility of a mucosal vaccine platform to deliver multi-pronged protective responses against a highly virulent pathogen.
Evolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients
Authors: Fontana Diletta , Crespiatico Ilaria , Crippa Valentina , Malighetti Federica , Villa Matteo , Angaroni Fabrizio , De Sano Luca , Aroldi Andrea , Antoniotti Marco , Caravagna Giulio , Piazza Rocco , Graudenzi Alex , Mologni Luca , Ramazzotti Daniele
Published: September 2023

Recurring sequences of genomic alterations occurring across patients can highlight repeated evolutionary processes with significant implications for predicting cancer progression. Leveraging the ever-increasing availability of cancer omics data, here we unveil cancer’s evolutionary signatures tied to distinct disease outcomes, representing “favored trajectories” of acquisition of driver mutations detected in patients with similar prognosis. We present a framework named ASCETIC (Agony-baSed Cancer EvoluTion InferenCe) to extract such signatures from sequencing experiments generated by different technologies such as bulk and single-cell sequencing data. We apply ASCETIC to (i) single-cell data from 146 myeloid malignancy patients and bulk sequencing from 366 acute myeloid leukemia patients, (ii) multi-region sequencing from 100 early-stage lung cancer patients, (iii) exome/genome data from 10,000+ Pan-Cancer Atlas samples, and (iv) targeted sequencing from 25,000+ MSK-MET metastatic patients, revealing subtype-specific single-nucleotide variant signatures associated with distinct prognostic clusters. Validations on several datasets underscore the robustness and generalizability of the extracted signatures.
Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk
Authors: Ying Pingting , Chen Can , Lu Zequn , Chen Shuoni , Zhang Ming , Cai Yimin , Zhang Fuwei , Huang Jinyu , Fan Linyun , Ning Caibo , Li Yanmin , Wang Wenzhuo , Geng Hui , Liu Yizhuo , Tian Wen , Yang Zhiyong , Liu Jiuyang , Huang Chaoqun , Yang Xiaojun , Xu Bin , Li Heng , Zhu Xu , Li Ni , Li Bin , Wei Yongchang , Zhu Ying , Tian Jianbo , Miao Xiaoping
Published: September 2023

Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05–1.16, P = 4.02 × 10−5) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology.
A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes
Authors: Sanderson Theo , Hisner Ryan , Donovan-Banfield I’ah , Hartman Hassan , Løchen Alessandra , Peacock Thomas P. , Ruis Christopher
Published: September 2023

Molnupiravir, an antiviral medication widely used against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus and many will be lethal; thus, molnupiravir-induced elevated mutation rates reduce viral load1,2. However, if some patients treated with molnupiravir do not fully clear the SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses. Here we show that SARS-CoV-2 sequencing databases contain extensive evidence of molnupiravir mutagenesis. Using a systematic approach, we find that a specific class of long phylogenetic branches, distinguished by a high proportion of G-to-A and C-to-T mutations, are found almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age groups with widespread use of the drug. We identify a mutational spectrum, with preferred nucleotide contexts, from viruses in patients known to have been treated with molnupiravir and show that its signature matches that seen in these long branches, in some cases with onward transmission of molnupiravir-derived lineages. Finally, we analyse treatment records to confirm a direct association between these high G-to-A branches and the use of molnupiravir.
Dissecting key regulators of transcriptome kinetics through scalable single-cell RNA profiling of pooled CRISPR screens
Authors: Xu Zihan , Sziraki Andras , Lee Jasper , Zhou Wei , Cao Junyue
Published: September 2023

We present a combinatorial indexing method, PerturbSci-Kinetics, for capturing whole transcriptomes, nascent transcriptomes and single guide RNA (sgRNA) identities across hundreds of genetic perturbations at the single-cell level. Profiling a pooled CRISPR screen targeting various biological processes, we show the gene expression regulation during RNA synthesis, processing and degradation, miRNA biogenesis and mitochondrial mRNA processing, systematically decoding the genome-wide regulatory network that underlies RNA temporal dynamics at scale.
Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women
Authors: Cherubini Alessandro , Ostadreza Mahnoosh , Jamialahmadi Oveis , Pelusi Serena , Rrapaj Eniada , Casirati Elia , Passignani Giulia , Norouziesfahani Marjan , Sinopoli Elena , Baselli Guido , Meda Clara , Dongiovanni Paola , Dondossola Daniele , Youngson Neil , Tourna Aikaterini , Chokshi Shilpa , Bugianesi Elisabetta ,   EPIDEMIC Study Investigators, Ronzoni Luisa , Bianco Cristiana , Cerami Laura , Torcianti Veronica , Periti Giulia , Margarita Sara , Carpani Rossana , Malvestiti Francesco , Marini Ilaria , Tomasi Melissa , Lombardi Angela , Rondena Jessica , Maggioni Marco , D’Ambrosio Roberta , Vaira Valentina , Fracanzani Anna Ludovica , Rosso Chiara , Pennisi Grazia , Petta Salvatore , Liguori Antonio , Miele Luca , Tavaglione Federica , Vespasiani-Gentilucci Umberto , Dallio Marcello , Federico Alessandro , Soardo Giorgio , Pihlajamäki Jussi , Männistö Ville , Della Torre Sara , Prati Daniele , Romeo Stefano , Valenti Luca
Published: September 2023

Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown and understudied reasons some develop rapidly progressive disease at the menopause. The patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M variant accounts for the largest fraction of inherited FLD variability. In the present study, we show that there is a specific multiplicative interaction between female sex and PNPLA3 p.I148M in determining FLD in at-risk individuals (steatosis and fibrosis, P < 10−10; advanced fibrosis/hepatocellular carcinoma, P = 0.034) and in the general population (P < 10−7 for alanine transaminase levels). In individuals with obesity, hepatic PNPLA3 expression was higher in women than in men (P = 0.007) and in mice correlated with estrogen levels. In human hepatocytes and liver organoids, PNPLA3 was induced by estrogen receptor-α (ER-α) agonists. By chromatin immunoprecipitation and luciferase assays, we identified and characterized an ER-α-binding site within a PNPLA3 enhancer and demonstrated via CRISPR–Cas9 genome editing that this sequence drives PNPLA3 p.I148M upregulation, leading to lipid droplet accumulation and fibrogenesis in three-dimensional multilineage spheroids with stellate cells. These data suggest that a functional interaction between ER-α and PNPLA3 p.I148M variant contributes to FLD in women.
Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity
Authors: West Clare E. , Karim Mohd , Falaguera Maria J. , Speidel Leo , Green Charlotte J. , Logie Lisa , Schwartzentruber Jeremy , Ochoa David , Lord Janet M. , Ferguson Michael A. J. , Bountra Chas , Wilkinson Graeme F. , Vaughan Beverley , Leach Andrew R. , Dunham Ian , Marsden Brian D.
Published: September 2023

Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application.
Identification and evolution of nsLTPs in the root nodule nitrogen fixation clade and molecular response of Frankia to AgLTP24
Authors: Gasser Mélanie , Keller Jean , Fournier Pascale , Pujic Petar , Normand Philippe , Boubakri Hasna
Published: September 2023

Non-specific lipid transfer proteins (nsLTPs) are antimicrobial peptides, involved in several plant biological processes including root nodule nitrogen fixation (RNF). Nodulating plants belonging to the RNF clade establish symbiosis with the nitrogen-fixing bacteria rhizobia (legumes symbiosis model) and Frankia (actinorhizal symbiosis model) leading to root nodule formation. nsLTPs are involved in processes active in early step of symbiosis and functional nodule in both models. In legumes, nsLTPs have been shown to regulate symbiont entry, promote root cortex infection, membrane biosynthesis, and improve symbiosis efficiency. More recently, a nsLTP, AgLTP24 has been described in the context of actinorhizal symbiosis between Alnus glutinosa and Frankia alni ACN14a. AgLTP24 is secreted at an early step of symbiosis on the deformed root hairs and targets the symbiont in the nitrogen-fixing vesicles in functional nodules. nsLTPs are involved in RNF, but their functions and evolutionary history are still largely unknown. Numerous putative nsLTPs were found up-regulated in functional nodules compared to non-infected roots in different lineages within the RNF clade. Here, results highlight that nodulating plants that are co-evolving with their nitrogen-fixing symbionts appear to have independently specialized nsLTPs for this interaction, suggesting a possible convergence of function, which opens perspectives to investigate nsLTPs functions in RNF.
Segmental hair analysis as a retrospective testosterone diary: possibilities and pitfalls
Authors: Preinbergs Julia K. , Ström Jakob O. , Theodorsson Elvar , Ingberg Edvin
Published: September 2023

Testosterone is thought to be incorporated in growing hair strands so that specific hair segments reflect average free hormone concentrations from the corresponding time period. However, the exact mechanisms of hormone integration in scalp hair have not yet been established and it is not known how testosterone is stored in the hair segments over time. The aim of this study was to investigate the stability of testosterone concentrations in hair as it grows and to determine if segmental hair analysis can be used as a retrospective testosterone diary. Thirty men and 40 women provided two hair samples and 16 saliva samples during a period of three months. Hair growth between the two samplings was measured. Hair samples were cut into 10 mm segments resulting in three segments from the first sampling and six segments from the second sampling. Hair samples were pulverised and extracted with methanol. Hair testosterone concentrations were analysed using an in-house radioimmunoassay. Salivary testosterone was analysed using a commercial enzyme-linked immunosorbent assay (Demeditec). The results demonstrated that there is a degree of segmental hormone conservation over time (rho = 0.405–0.461, p < 0.001, n = 66–67), but also highlighted three potential confounders. Firstly, testosterone concentrations were higher in distal hair segments (mean concentration ratio most distal by most scalp-near was 1.55, SD 0.70), which may be due to continuous hormone integration from sebum and changes in hair matrix composition. Secondly, more frequent hair washing stunted the increase in testosterone concentrations in distal segments (rho = −0.404, p =  < 0.001, n = 66). And lastly, intra- and inter- individual variability in hair growth rate influenced the temporal resolution along the hair, although mean growth rate was indeed 30.0 mm for three months. In a multiple regression model the biological sex, natural hair colour, and relationship status were significant explanatory variables to hair testosterone concentrations. The current results indicate that repeated hair sampling near the hair roots during a study may be preferable to analysing concentration changes between proximal and distal segments within the same hair sample. Also, hair testosterone analysis needs to be adjusted for sex and the natural hair colour.
FGF-23 is a biomarker of RV dysfunction and congestion in patients with HFrEF
Authors: Benes Jan , Kroupova Katerina , Kotrc Martin , Petrak Jiri , Jarolim Petr , Novosadova Vendula , Kautzner Josef , Melenovsky Vojtech
Published: September 2023

There is no biomarker reflecting right ventricular dysfunction in HFrEF patients used in clinical practice. We have aimed to look for a circulating marker of RV dysfunction employing a quantitative proteomic strategy. The Olink Proteomics Multiplex panels (Cardiovascular Disease II, III, Cardiometabolic, and Inflammation Target Panels) identified FGF-23 to be the most differentially abundant (more than 2.5-fold) in blood plasma of HF patients with severe RV dysfunction (n = 30) compared to those with preserved RV function (n = 31). A subsequent ELISA-based confirmatory analysis of circulating FGF-23 in a large cohort of patients (n = 344, 72.7% NYHA III/IV, LVEF 22.5%, 54.1% with moderate/severe RV dysfunction), followed by multivariable regression analysis, revealed that the plasma FGF-23 level was most significantly associated with RV dysfunction grade (p = 0.0004) and congestion in the systemic circulation (p = 0.03), but not with LV-ejection fraction (p = 0.69) or estimated glomerular filtration rate (eGFR, p = 0.08). FGF-23 was associated with the degree of RV dysfunction in both sub-cohorts (i.e. in patients with and without congestion, p < 0.0001). The association between FGF-23 and RV-dysfunction remained significant after the adjustment for BNP (p = 0.01). In contrast, when adjusted for BNP, FGF-23 was no longer associated with LV dysfunction (p = 0.59). The Cox proportional hazard model revealed that circulating FGF-23 was significantly associated with adverse outcomes even after adjusting for BNP, LVEF, RV dysfunction grade and eGFR. Circulating FGF-23 is thus a biomarker of right ventricular dysfunction in HFrEF patients regardless of congestion status.