bluuebunny/crossref_metadata_2025 huggingface dataset:
Filter and sensor delay synchronization in incremental flight control laws
Authors: Steffensen Rasmus , Steinert Agnes , Mbikayi Zoe , Raab Stefan , Angelov Jorg , Holzapfel Florian
Published: January 2023

This paper introduces and investigates several methods of filtering and delay synchronization in incremental control law structures. It is shown that proper filter and delay synchronization is of great importance for both the performance and stability of the control laws. It is derived how to synthesize complementary filters in case of sensor dynamics, sensor delays and internal control law filtering such as roll-off filters and notch filters. The complementary filters are compared to common synchronization approaches previously applied in incremental control laws. It is shown that the proposed methods are beneficial for Multiple Input Multiple Output (MIMO) systems in case that different delays and filtering is present in the different measurement signals. In case of strongly coupled input effectiveness, the synchronization on the actuator feedback may become even unstable, where the complementary filter approach recovers the design closed-loop behavior. In addition, it is derived how to initialize the complementary filters for a transient-free engagement in non-steady-state conditions. The results are compared in simulation with a roll rate control law for a fixed wing aircraft.
The mediating role of exogenous shocks in green purchase intention: evidence from italian fashion industry in the Covid-19 era
Authors: Annunziata Eleonora , Pucci Tommaso , Cammeo Jacopo , Zanni Lorenzo , Frey Marco
Published: January 2023

This work investigates how the COVID-19 outbreak has affected consumers’ green purchasing intention in the fashion industry. It examines how this exogenous shock has influenced the relationship between consumer green purchasing intention and its three relevant antecedents (environmental knowledge (EK), environmental concern (EC), eco-friendly behaviour (EFB)). A survey of 1433 Italian consumers was carried out. The data were analysed through a structural equation modelling method to evaluate the direct and indirect mediating effects of the COVID-19 shock on the relationship between green purchasing intention and its antecedents (i.e., EK, EC and EFB) by considering traditional and online purchasing channels. The results of the model confirmed a positive relationship between green purchasing intention and its antecedents. The COVID-19 pandemic was also found to positively mediate the relationship between green purchase intention and two out of its three antecedents (i.e., EK and EC) in both traditional and online purchasing channels. This paper contributes to the literature on sustainable consumption by assessing magnitude of the relationship between green purchasing intention and its antecedents, and the mediating role exerted by a complex exogenous shock such as the COVID-19 outbreak.
Vertical industry and strategic trade policy
Authors: Fanti Luciano , Buccella Domenico
Published: January 2023

This paper investigates whether and how vertical industries have the characteristics to be targeted with the subsidy policy instrument. Under both price and quantity competition, the results of the established literature are reversed when exporters are in vertical relations. In particular, the conventional result that the emerging subsidising equilibrium is Pareto inefficient (the well-known prisoner's dilemma outcome) vanishes in the following cases: (1) under quantity competition, when products are sufficiently differentiated, and (2) under price competition, when products are neither too differentiated nor too substitutes. In such cases, the policy intervention leads to welfare improvement with respect to the free trade regime in both producing countries. Moreover, under price competition, export subsidization becomes the rule instead of taxation. Our results suggest that, depending on the degree of competition, vertical industries can be efficiently targeted through the subsidy policy.
Teaching, learning and assessment methods for sustainability education on the land–sea interface
Authors: Bryhn Andreas C. , Belgrano Andrea
Published: January 2023

The Land–Sea Interface (LSI) is where land and sea meet, not only in physical terms, but also with regards to a large variety of ecological and societal aspects. The United Nations has proclaimed the period 2021–2030 the Ocean Decade, which entails striving for a sustainable use of the ocean and teaching and learning about ocean related issues. Teaching and learning about the LSI are also tightly connected with several Sustainable Development Goals (Global Goals) such as Life Below Water, Zero Hunger and Sustainable Cities and Communities. Teaching and learning about sustainability lacks a uniform pedagogy, and it is probably wise to maintain that apparently adaptive diversity. In this globally relevant methods overview, we present a wide range of relatively new and/or successful and mostly largely learner-centered methods. We also discuss how effective and popular they are, and give examples on how most of these methods are already used in LSI sustainability teaching. There will probably not be any successful “one size fits all” model developing for LSI teaching and learning, and each module, course and programme will have to develop its own recipe for successful teaching and learning, possibly with support from one or several methods discussed in this paper.
Biochar nanoparticles-mediated transport of organic contaminants in porous media: dependency on contaminant properties and effects of biochar aging
Authors: Ma Pengkun , Qi Zhichong , Wu Xuan , Ji Rong , Chen Wei
Published: January 2023

Land application of biochar has been recommended as an effective soil amendment measure. Nonetheless, the applied biochar can accumulate co-existing contaminants. Meanwhile, nanoparticles formed due to biochar disintegration may facilitate contaminant transport in vadose zone and groundwater, posing a potential risk to the subsurface environment. Here, we show that the presence of pinewood- and rice straw-derived biochar nanoparticles (BCNPs) at parts per million level (~ 20 mg/L) can result in significant mobilization of hydrophobic, nonpolar contaminants (naphthalene and pyrene) and positively charged polar contaminants (trimethoprim and ciprofloxacin) in saturated sandy soil, but slightly inhibits the transport of negatively charged or neutral hydrophilic compounds (sulfamethoxazole and bisphenol A). With supplemental adsorption and desorption experiments we show that the ability of BCNPs in mediating contaminant transport (either enhancing or inhibiting) relies primarily on the extent of irreversible binding of a contaminant to the BCNPs. Sulfide reduction and leaching of organic carbon, two relatively mild (in terms of modification of physicochemical properties, e.g., surface O/C ratio) but widely occurring aging processes, facilitate co-transport of pyrene and bisphenol A with the BCNPs. However, this is mainly the result of increased mobility of the BCNPs (i.e., the carrier), rather than enhanced interactions between the BCNPs and the contaminants being carried. The findings underline the significant effects of BCNPs on the fate and transport of environmental contaminants, and further highlight the important role of aging in affecting environmental behaviors and effects of biochar materials.

Graphical Abstract
Theory, History, and the Study of Religion in Late Antiquity
Authors: Kotrosits Maia
Published: January 2023

Theory is not a set of texts, it is a style of approach. It is to engage in the act of speculation: gestures of abstraction that re-imagine and dramatize the crises of living. This Element is a both a primer for understanding some of the more predominant strands of critical theory in the study of religion in late antiquity, and a history of speculative leaps in the field. It is a history of dilemmas that the field has tried to work out again and again - questions about subjectivity, the body, agency, violence, and power. This Element additionally presses us on the ethical stakes of our uses of theory, and asks how the field's interests in theory help us understand what's going on, half-spoken, in the disciplinary unconscious.
Autophagy of naïve CD4+T cells in aging – the role of body adiposity and physical fitness
Authors: Padilha Camila S. , Kushkestani Mehdi , Baptista Liliana P. , Krüger Karsten , Lira Fábio Santos
Published: January 2023

Life expectancy has increased exponentially in the last century accompanied by disability, poor quality of life, and all-cause mortality in older age due to the high prevalence of obesity and physical inactivity in older people. Biologically, the aging process reduces the cell’s metabolic and functional efficiency, and disrupts the cell’s anabolic and catabolic homeostasis, predisposing older people to many dysfunctional conditions such as cardiovascular disease, neurodegenerative disorders, cancer, and diabetes. In the immune system, aging also alters cells' metabolic and functional efficiency, a process known as ‘immunosenescence’, where cells become more broadly inflammatory and their functionality is altered. Notably, autophagy, the conserved and important cellular process that maintains the cell’s efficiency and functional homeostasis may protect the immune system from age-associated dysfunctional changes by regulating cell death in activated CD4+ T cells. This regulatory process increases the delivery of the dysfunctional cytoplasmic material to lysosomal degradation while increasing cytokine production, proliferation, and differentiation of CD4+ T cell-mediated immune responses. Poor proliferation and diminished responsiveness to cytokines appear to be ubiquitous features of aged T cells and may explain the delayed peak in T cell expansion and cytotoxic activity commonly observed in the ‘immunosenescence’ phenotype in the elderly. On the other hand, physical exercise stimulates the expression of crucial nutrient sensors and inhibits the mechanistic target of the rapamycin (mTOR) signaling cascade which increases autophagic activity in cells. Therefore, in this perspective review, we will first contextualize the overall view of the autophagy process and then, we will discuss how body adiposity and physical fitness may counteract autophagy in naïve CD4+ T cells in aging.
From snapshots to manifolds – a tale of shear flows
Authors: Farzamnik E. , Ianiro A. , Discetti S. , Deng N. , Oberleithner K. , Noack B.R. , Guerrero V.
Published: January 2023

We propose a novel nonlinear manifold learning from snapshot data and demonstrate its superiority over proper orthogonal decomposition (POD) for shedding-dominated shear flows. Key enablers are isometric feature mapping, Isomap, as encoder and,$K$-nearest neighbours ($K$NN) algorithm as decoder. The proposed technique is applied to numerical and experimental datasets including the fluidic pinball, a swirling jet and the wake behind a couple of tandem cylinders. Analysing the fluidic pinball, the manifold is able to describe the pitchfork bifurcation and the chaotic regime with only three feature coordinates. These coordinates are linked to the vortex-shedding phases and the force coefficients. The manifold coordinates of the swirling jet are comparable to the POD mode amplitudes, yet allow for a more distinct and less noise-sensitive manifold identification. A similar observation is made for the wake of two tandem cylinders. The tandem cylinders are aligned and located at a streamwise distance which corresponds to the transition between the single bluff body and the reattachment regimes of vortex shedding. Isomap unveils these two shedding regimes while the Lissajous plot of the first two POD mode amplitudes features a single circle. The reconstruction error of the manifold model is small compared with the fluctuation level, indicating that the low embedding dimensions contain the coherent structure dynamics. The proposed Isomap–$K$NN manifold learner is expected to be of great importance in estimation, dynamic modelling and control for a large range of configurations with dominant coherent structures.
Reaction-induced Kelvin–Helmholtz instability in a layered channel flow
Authors: Maharana Surya Narayan , Sahu Kirti Chandra , Mishra Manoranjan
Published: January 2023

We show that a vertical viscosity stratification at a localized region caused by a chemical reaction yields an inconspicuous shear layer. A chemo-hydrodynamic Kelvin–Helmholtz instability or cat-eye-shaped morphology develops at one reaction front, while the other front diffuses steadily over time. Through linear stability and nonlinear simulations, the existence of such instabilities is established if the log-mobility ratio exceeds a critical value. We find unique scalings between the stable and unstable zones that demonstrate how the influence of variations in solute diffusion on instability can be eliminated. The observed unstable patterns agree with existing experimental results.
Latest Ordovician to earliest Silurian graptolites of northwest Peninsular Malaysia
Authors: Saparin Muhammad Aqqid , Ismail Mohd Suhaili
Published: January 2023

Graptolites from the latest Ordovician to the earliest Silurian rocks of northwest Peninsular Malaysia are described and reviewed. The fossils were collected previously by C. R. Jones and presently by the authors inside the black mudstones from the basal section of Tanjung Dendang Formation in Pulau Langgun, Langkawi, which comprises assemblages from the Hirnantian Metabolograptus extraordinarius Biozone to the Rhuddanian Akidograptus ascensus–Parakidograptus acuminatus Biozone. The latest Ordovician strata also include a Hirnantia fauna bed between the Metabolograptus extraordinarius and Metabolograptus persculptus biozones, in which shelly fossils such as Mucronaspis sp. could be recovered. A revised graptolite biozonation is proposed for the latest Ordovician to the earliest Silurian succession of northwest Peninsular Malaysia. This interval is significant for understanding the extent of mass extinction events happening right at the end of the Ordovician period and subsequent faunal change in the region.
Religious Authority beyond Domination and Discipline: Epistemic Authority and Its Vernacular Uses in the Shi‘i Diaspora
Authors: Bhojani Ali-Reza , Clarke Morgan
Published: January 2023

“Religious authority” remains a ubiquitous but controversial term of comparative analysis. In Islamic studies, authority is generally personified in the form of the ulama and most often viewed through Weber’s lens of charismatic, legal-rational, and traditional types of legitimate domination. Our particular interest, Twelver Shi‘i Islam, seems a paradigmatic case, where the relationship between “the Ayatollahs” and state power has dominated academic discussion since Khomeini. Through ethnography of a Shi‘i diaspora community in the UK, we argue for a radical shift in perspective: away from forms of clerical power and towards non-specialist uses of clerical authority as expert opinion. Far from such “epistemic” authority being opposed to ordinary agency, here they are inextricably linked. Inspirational work in the anthropology of Islam has understood ordinary Muslim experiences of authority in non-liberal ways, as (Foucauldian) ethical discipline and self-care. We maintain the need to transcend not only domination but discipline too, refocusing the comparison between (Shi‘i) Islamic legal and liberal thought, in the form of Raz’s classic “service conception” of authority. Both stress the rationality of following authoritative opinion and its role as reason and justification for individual action. Our ethnography of ordinary practice then shows the sheer diversity of ways that such epistemic authority can be taken up, including, but not limited to, projects of personal piety and adversarial community politics. In our context, as surely also in others, domination and discipline should thus be seen as potential uses of “religious” epistemic authority, rather than as its privileged form.
Ghana and Nkrumah Revisited: Lenin, State Capitalism, and Black Marxist Orbits
Authors: Osei-Opare Nana
Published: January 2023

This paper reexamines African socialism, the Ghanaian political economy under Kwame Nkrumah (1957–1966), Nkrumah’s intellectual genealogical heritage, and African intellectual history as a genre that transcends the bounds of the Atlantic world. First, I sketch the lives of Black Marxists—Nkrumah, C.L.R. James, George Padmore, and Bankole Awoonor-Renner—from Africa and the Americas, to the Soviet Union, to England and Ghana, to rethink Black bodies not merely as theorists of racial and decolonial questions but also as sites, carriers, and manipulators of political-economic theories. In constructing connected and overlapping histories, I demonstrate how controversial and contested Soviet ideas became key sites of interrogation among global Black Marxists. By reframing travel as an intellectual process, I reconceptualize the movements of Black Marxists to the USSR, the United States, England, and Ghana as critical intellectual and historical processes in their understandings of Lenin’s state capitalist ideas. Second, I revisit the Ghanaian political economy under Nkrumah to argue that combining socialist and capitalist development paths was not a contradictory Marxian policy but was embedded within Black Marxist understandings of Lenin’s state capitalist ideas. In so doing, I argue that we must situate African political ideologies not solely within a romanticized Afrocentric origin but as ideas that emerge out of contemporaneous global political and ideological struggles. I draw on global Black Marxists’ correspondence; newspaper and magazine articles; British and American espionage files; and Ghanaian, American, and British state and inter-state departmental documents in imperial, colonial, and postcolonial British, Ghanaian, American, and Russian archives.
Rethinking Political Agency in the Russian Revolution: A View from the Russian Empire's Borderlands
Authors: Shtakser Inna
Published: January 2023

The four books under review challenge the revolutionary leadership-centered view of the Russian Revolution from various perspectives. Specifically, they highlight the influence on revolutionary politics of seemingly peripheral groups such as workers and Jewish revolutionary activists. Each of the authors claims that the agendas of these groups were considerably more important than the agendas of the revolutionary leadership in ensuring the success or the failure of revolutionary policies.
Review: bioavailability and efficacy of ‘free’ curcuminoids from curcumagalactomannoside (CGM) curcumin formulation
Authors: Matthewman Cristina , Krishnakumar I.M. , Swick Andrew G.
Published: January 2023

The golden spice turmeric with its main bioactive component curcumin is one of the most popular and extensively studied nutraceuticals. Despite numerous pre-clinical studies reporting positive pharmacodynamics of turmeric extracts and curcumin, the main issues in translating the pharmacological effects to clinical efficacy have been to overcome its poor pharmacokinetics and to deliver significant amounts of the biologically relevant forms of the actives to various tissues. This review is aimed at providing a first critical evaluation of the current published literature with the novel curcumagalactomannoside (CGM) formulation of curcumin using fenugreek galactomannan dietary fibre, specifically designed to address curcumin poor pharmacokinetics. We describe CGM and its technology as a food-grade formulation to deliver ‘free’ unconjugated curcuminoids with enhanced bioavailability and improved pharmacokinetic properties. The therapeutic relevance of improving bioavailability of ‘free’ curcuminoids and some of the technical challenges in the measurement of the ‘free’ form of curcuminoids in plasma and tissues are also discussed. A total of twenty-six manuscripts are reviewed here, including fourteen pre-clinical and twelve clinical studies that have investigated CGM pharmacokinetics, safety and efficacy in various animal models and human conditions. Overall current scientific evidence suggests CGM formulation has improved bioavailability and tissue distribution of the biologically relevant unconjugated forms of turmeric actives called ‘free’ curcuminoids that may be responsible for the superior clinical outcomes reported with CGM treatments in comparison with unformulated standard curcumin across multiple studies.
Immediate results of primary balloon dilation for congenital aortic valve stenosis predict the mid-term outcome
Authors: Pavlovic Andrija , Parezanovic Vojislav , Stefanovic Igor , Dähnert Ingo , Tzifa Aphrodite , Djordjevic Stefan A. , Ilic Slobodan , Milovanovic Vladimir , Bijelic Maja , Bisenic Dejan , Kalanj Jasna , Djukic Milan
Published: January 2023

Background:

Balloon valvuloplasty is the primary treatment for congenital aortic valve stenosis in our centre. We sought to determine independent predictors of reintervention (surgical repair or repeated balloon dilation) after primary valvuloplasty.

Methods:

We retrospectively studied patients with congenital aortic valve stenosis who underwent balloon valvuloplasty during 2004–2018. The following risk factors were analysed: aortic valve insufficiency after balloon valvuloplasty >+1/4, post-procedural gradient across the aortic valve ≥35 mmHg, pre-interventional gradient across the valve, annulus size, use of rapid pacing, and balloon/annulus ratio. Primary outcome was aortic valve reintervention.

Results:

In total, 99 patients (median age 4 years, range 1 day to 26 years) underwent balloon valvuloplasty for congenital aortic valve stenosis. After a mean follow-up of 4.0 years, 30% had reintervention. Adjusted risks for reintervention were significantly increased in patients with post-procedural aortic insufficiency grade >+1/4 and/or residual gradient ≥35 mmHg (HR 2.55, 95% CI 1.13–5.75, p = 0.024). Pre-interventional gradient, annulus size, rapid pacing, and balloon/annulus ratio were not associated with outcome.

Conclusion:

Post-procedural aortic valve insufficiency grade >+1/4 and/or residual gradient ≥35 mmHg in patients undergoing balloon valvuloplasty for congenital aortic valve stenosis confers an increased risk for reintervention in mid-term follow-up.
The impact of SNAP-Ed interventions on California students’ diet and physical activity during COVID-19
Authors: Linares Amanda , Plank Kaela , Hewawitharana Sridharshi C , Woodward-Lopez Gail
Published: January 2023

Objective:

School-based CalFresh Healthy Living (CFHL) (California’s SNAP-Ed) interventions adapted to new learning environments necessitated by COVID-19. We examined the impact of these interventions on student diet and physical activity (PA) outcomes.

Design:

Quasi-experimental, two-group, pre-post.

Setting:

California public schools with ≥50 % of students Free and Reduced Price Meal-eligible (nintervention= 47;ncomparison= 17).

Participants:

Fourth- and fifth-grade students who completed the online Eating and Activity Tool for Students at pre and post (nintervention= 1087;ncomparison= 846 students).

Results:

Intervention students reported a significantly greater increase in consumption frequency of total fruit (by 0·16 times/d;P= 0·032), driven primarily by a greater increase in 100 % fruit juice (by 0·11 times/d;P= 0·007). Intervention students reported a significantly greater increase in total vegetable consumption frequency (by 0·45 times/d;P< 0·001) than comparison students. Specifically, intervention students reported increased, whereas comparison students reported decreased, consumption frequencies for starchy vegetables (0·05v. −0·10 times/d,P< 0·001), salad/green vegetables (0·01v. −0·11 times/d,P= 0·005) and beans (0·04v. −0·03 times/d,P= 0·025). Consumption frequency of other vegetables decreased in both groups (−0·01v. −0·09 times/d) but decreased more among comparison students (P= 0·048). No differences in pre-post change in PA outcomes were detected.

Conclusions:

Findings suggest that despite COVID-19-related challenges necessitating programme modifications, CFHL interventions played a role in protecting student consumption of fruit and vegetables during the 2020–2021 school year. Therefore, it appears that school-based CFHL interventions can be a viable means of safeguarding student nutrition at a time when access to nutritious food and PA opportunities are hindered.
Multiple Group Membership, Optimistic Bias, and Infection Risk in the	Context of Emerging Infectious Diseases
Authors: Frings Daniel , Wills Jane , Sykes Susie , Wood Kerry V. , Albery Ian P.
Published: January 2023

Abstract: Background: Understanding psychosocial factors which impact responses to emerging infectious diseases (EIDs) is vital in managing epidemics and pandemics. Two under-researched areas in this field are the interactive roles of optimistic bias (underestimation of the likelihood of negative events occurring to the self, relative to others) and group membership (a factor observed to be psychologically protective, but infection risk enhancing). Aims: The current study aimed to test the relationships between optimistic bias and membership of multiple groups upon EID-related emotional and psychological responses and behavioral intentions. Methods: Participants from the UK and US ( N = 360) rated how they would evaluate and respond to a fictitious EID immediately before the 2020 COVID-19 lockdowns in a correlational study. Results: Negative relationships were observed between optimistic bias and perceived infection vulnerability, infection prevention strategies, and perceived EID severity. Multiple group membership correlated negatively with germ avoidance, but positively with emotional responses such as disgust and increased perceived vulnerability to infection – factors linked to avoiding infection. Multiple group memberships and optimistic bias were unrelated. Limitations: The study focussed on a fictitious disease and relies on cross-sectional data and behavioral intentions. Conclusions: These findings build upon the small evidence base on the role of optimistic bias in EID management and suggest that multiple group membership is unlikely to increase optimistic bias. The theoretical and practical implications of the findings for EID management are discussed.
Effect of Plankton Composition Shifts in the North Atlantic on Atmospheric pCO2
Authors: Boot A. , von der Heydt A. S. , Dijkstra H. A.
Published: January 2023

Marine carbon cycle processes are important for taking up atmospheric CO2 thereby reducing climate change. Net primary and export production are important pathways of carbon from the surface to the deep ocean where it is stored for millennia. Climate change can interact with marine ecosystems via changes in the ocean stratification and ocean circulation. In this study we use results from the Community Earth System Model version 2 (CESM2) to assess the effect of a changing climate on biological production and phytoplankton composition in the high latitude North Atlantic Ocean. We find a shift in phytoplankton type dominance from diatoms to small phytoplankton which reduces net primary and export productivity. Using a conceptual carbon‐cycle model forced with CESM2 results, we give a rough estimate of a positive phytoplankton composition‐atmospheric CO2 feedback of approximately 60 GtCO2/°C warming in the North Atlantic which lowers the 1.5° and 2.0°C warming safe carbon budgets.
Fast Spin‐Up of Geochemical Tracers in Ocean Circulation and Climate Models
Authors: Khatiwala Samar
Published: January 2023

Ocean geochemical tracers such as radiocarbon, protactinium and thorium isotopes, and noble gases are widely used to constrain a range of physical and biogeochemical processes in the ocean. However, their routine simulation in global ocean circulation and climate models is hindered by the computational expense of integrating them to a steady state. Here, a new approach to this long‐standing “spin‐up” problem is introduced to efficiently compute equilibrium distributions of such tracers in seasonally‐forced models. Based on “Anderson Acceleration,” a sequence acceleration technique developed in the 1960s to solve nonlinear integral equations, the new method is entirely “black box” and offers significant speed‐up over conventional direct time integration. Moreover, it requires no preconditioning, ensures tracer conservation and is fully consistent with the numerical time‐stepping scheme of the underlying model. It thus circumvents some of the drawbacks of other schemes such as matrix‐free Newton Krylov that have been proposed to address this problem. An implementation specifically tailored for the batch HPC systems on which ocean and climate models are typically run is described, and the method illustrated by applying it to a variety of geochemical tracer problems. The new method, which provides speed‐ups by over an order of magnitude, should make simulations of such tracers more feasible and enable their inclusion in climate change assessments such as IPCC.
Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia
Authors: Ryan Sarra L. , Peden John F. , Kingsbury Zoya , Schwab Claire J. , James Terena , Polonen Petri , Mijuskovic Martina , Becq Jenn , Yim Richard , Cranston Ruth E. , Hedges Dale J. , Roberts Kathryn G. , Mullighan Charles G. , Vora Ajay , Russell Lisa J. , Bain Robert , Moorman Anthony V. , Bentley David R. , Harrison Christine J. , Ross Mark T.
Published: January 2023

Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by recurrent genetic abnormalities that drive risk-directed treatment strategies. Using current techniques, accurate detection of such aberrations can be challenging, due to the rapidly expanding list of key genetic abnormalities. Whole genome sequencing (WGS) has the potential to improve genetic testing, but requires comprehensive validation. We performed WGS on 210 childhood B-ALL samples annotated with clinical and genetic data. We devised a molecular classification system to subtype these patients based on identification of key genetic changes in tumour-normal and tumour-only analyses. This approach detected 294 subtype-defining genetic abnormalities in 96% (202/210) patients. Novel genetic variants, including fusions involving genes in the MAP kinase pathway, were identified. WGS results were concordant with standard-of-care methods and whole transcriptome sequencing (WTS). We expanded the catalogue of genetic profiles that reliably classify PAX5alt and ETV6::RUNX1-like subtypes. Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r): a good-risk B-ALL subtype with high survival rates. Overall, we have validated that WGS provides a standalone, reliable genetic test to detect all subtype-defining genetic abnormalities in B-ALL, accurately classifying patients for the risk-directed treatment stratification, while simultaneously performing as a research tool to identify novel disease biomarkers.
Plexin-A2 enables the proliferation and the development of tumors from glioblastoma derived cells
Authors: Toledano Shira , Sabag Adi D. , Ilan Neta , Liburkin-Dan Tanya , Kessler Ofra , Neufeld Gera
Published: January 2023

The semaphorin guidance factors receptor plexin-A2 transduces sema6A and sema6B signals and may mediate, along with plexin-A4, the anti-angiogenic effects of sema6A. When associated with neuropilins plexin-A2 also transduces the anti-angiogenic signals of sema3B. Here we show that inhibition of plexin-A2 expression in glioblastoma derived cells that express wild type p53 such as U87MG and A172 cells, or in primary human endothelial cells, strongly inhibits cell proliferation. Inhibition of plexin-A2 expression in U87MG cells also results in strong inhibition of their tumor forming ability. Knock-out of the plexin-A2 gene in U87MG cells using CRISPR/Cas9 inhibits cell proliferation which is rescued following plexin-A2 re-expression, or expression of a truncated plexin-A2 lacking its extracellular domain. Inhibition of plexin-A2 expression results in cell cycle arrest at the G2/M stage, and is accompanied by changes in cytoskeletal organization, cell flattening, and enhanced expression of senescence associated β-galactosidase. It is also associated with reduced AKT phosphorylation and enhanced phosphorylation of p38MAPK. We find that the pro-proliferative effects of plexin-A2 are mediated by FARP2 and FYN and by the GTPase activating (GAP) domain located in the intracellular domain of plexin-A2. Point mutations in these locations inhibit the rescue of cell proliferation upon re-expression of the mutated intracellular domain in the knock-out cells. In contrast re-expression of a plexin-A2 cDNA containing a point mutation in the semaphorin binding domain failed to inhibit the rescue. Our results suggest that plexin-A2 may represent a novel target for the development of anti-tumorigenic therapeutics.
Increased endogenous PKG I activity attenuates EGF-induced proliferation and migration of epithelial ovarian cancer via the MAPK/ERK pathway
Authors: Lan Ting , Li Ying , Wang Yue , Wang Zhong-Cheng , Mu Chun-Yan , Tao Ai-Bin , Gong Jian-Li , Zhou Yuan , Xu Hao , Li Shi-Bao , Gu Bing , Ma Ping , Luo Lan
Published: January 2023

The type I cGMP-dependent protein kinase (PKG I) is recognized as a tumor suppressor, but its role in EGFR regulated epithelial ovarian cancer (EOC) progression remains unclear. We evaluated the in vivo and in vitro effects of activated PKG I in EGF-induced EOC cell proliferation, migration, and invasion. The expressions of EGFR and PKG I were elevated, but the activated PKG I was decreased in EOC tissues of patients and cells lines. The addition of 8-Br-cGMP, a specific PKG I activator, attenuated the EGF-induced EOC cell proliferation, migration, and invasion in vitro. Similarly, activated PKG I also attenuated EOC progression in vivo using an EOC xenograft nude mouse model. The activated PKG I interacted with EGFR, causing increased threonine (693) phosphorylation and decreased tyrosine (1068) phosphorylation of EGFR, which resulted in disrupted EGFR-SOS1-Grb2 combination. Subsequently, the cytoplasmic phosphorylation of downstream proteins (c-Raf, MEK1/2, and ERK1/2) were declined, impeding the phosphorylated ERK1/2’s nucleus translocation, and this reduction of phosphorylated tyrosine (1068) EGFR and ERK1/2 were also abolished by Rp-8-Br-cGMPS. Our results suggest that the activation of PKG I attenuates EGF-induced EOC progression, and the 8-Br-cGMP-PKG I-EGFR/MEK/ERK axis might be a potential target for EOC therapy.
Hepatocyte growth factor-mediated apoptosis mechanisms of cytotoxic CD8+ T cells in normal and cirrhotic livers
Authors: Chen Quanyu , Yan Min , Lin Heng , Lai Jiejuan , Yang Zhiqing , Hu Deyu , Deng Yuanyu , Shi Saiyu , Shuai Ling , Zhang Leida , Zhang Hongyu , Bai Lianhua
Published: January 2023

Intrahepatic stem/progenitor cells and cytotoxic CD8+ T cells (CD8+ T cells) in the cirrhotic liver undergo apoptosis, which potentially facilitates progression to cancer. Here, we report that hepatocyte growth factor (HGF) signaling plays an important role in promoting normal and damaged liver CD8+ T cell Fas-mediated apoptosis through its only receptor, c-Met. In addition to binding with HGF, c-Met also binds to Fas to form a complex. Using a diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis mouse model, immunostaining, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, we found that HGF secretion was significantly higher at 10 weeks post-DEN, the liver cirrhotic phase (LCP), than at 3 weeks post-DEN, the liver fibrotic phase (LFP). Correspondingly, differences in CD8+ T cell proliferation and apoptosis were noted between the two phases. Interestingly, staining and TUNEL assays revealed lower smooth muscle actin (α-SMA)+ cell apoptosis, a marker for hepatic stellate cells (HSCs), in the LFP group than in the LCP group, which suggested a beneficial correlation among HGF, CD8+ T cells and HSCs in improving the fibrotic load during damaged liver repair. In cultures, when met different concentrations of recombinant HGF (rHGF), phytohemagglutinin (PHA)-stimulated naive mouse splenic CD8+ T cells (pn-msCD8+ T cells) responded differently; as increases in rHGF increased were associated with decreases in the clonal numbers of pn-msCD8+ T cells, and when the rHGF dose was greater than 200 ng/mL, the clonal numbers significantly decreased. In the presence of 400 ng/mL rHGF, the death-inducing signaling complex (DISC) can be directly activated in both nsCD8+ T cells and healthy human peripheral blood CD8+ T cells (hp-CD8+ T cells), as indicated by recruitment of FADD and caspase-8 because DISC forms via the recruitment of FADD and caspase-8, among others. These findings suggest that Fas-mediated apoptosis, may also indicate a regulatory role of HGF signaling in hepatic homeostasis.
Relationship between clinical parameters and quality of life in primary Sjögren’s Syndrome: a prospective study
Authors: Greenan E. , Pilson Q. , Ní Gabhann-Dromgoole J. , Murphy C. C.
Published: January 2023

Objectives

To quantify the impact of dry eye disease (DED) on health and vision related quality of life (HR-QOL, VR-QOL) in patients with Primary Sjögren’s Syndrome (pSS).

Methods

Thirty-four participants with a confirmed diagnosis of pSS as per the 2016 ACR EULAR criteria participated. Main outcome measures included ocular surface parameters and HR-QOL and VR-QOL questionnaires. Clinical examination included visual acuity, Schirmer I testing, ocular surface staining (OSS) and measurement of tear film breakup time. The questionnaires included Ocular Surface Disease Index, National Eye Institute Visual Function Questionnaire-25, Short Form-36 (SF-36) and EULAR Sjogren’s Syndrome Patient Reported Index.

Results

Despite the majority of participants (28 female, 6 male, mean age 61.3 years) having attained LogMAR 0.3 or better visual acuity, participants scored low on VR-QOL measures, representing DED related fluctuation in functional vision. All participants suffered from moderate to severe DED. OSS did not correlate with DED symptoms or QOL parameters. Lubricant usage and symptom severity had a statistically moderate to strong negative correlation with VR-QOL and HR-QOL. This was most evident in relation to physical and physiological wellbeing. Compared with normative data, participants had a lower HR-QOL in all scales of the SF-36 ((MD = 9.91 ± 5.16); t(7) = 5.43, p = 0.001).

Conclusions

Participants with pSS have a lower perceived QOL especially in relation to physical and mental wellbeing, correlating to severity of DED symptoms and treatment burden. Clinical signs do not align with symptoms. Therefore, clinicians should remain cognisant, adjusting treatment in accordance with patient reported perceptions.
DNA methylation is associated with codon degeneracy in a species of bumblebee
Authors: Marshall H. , Nicholas M. T. , van Zweden J. S. , Wäckers F. , Ross L. , Wenseleers T. , Mallon E. B.
Published: January 2023

Social insects display extreme phenotypic differences between sexes and castes even though the underlying genome can be almost identical. Epigenetic processes have been proposed as a possible mechanism for mediating these phenotypic differences. Using whole genome bisulfite sequencing of queens, males, and reproductive female workers we have characterised the sex- and caste-specific methylome of the bumblebeeBombus terrestris. We have identified a potential role for DNA methylation in histone modification processes which may influence sex and caste phenotypic differences. We also find differentially methylated genes generally show low levels of DNA methylation which may suggest a separate function for lowly methylated genes in mediating transcriptional plasticity, unlike highly methylated genes which are usually involved in housekeeping functions. We also examined the relationship between the underlying genome and the methylome using whole genome re-sequencing of the same queens and males. We find DNA methylation is enriched at zero-fold degenerate sites. We suggest DNA methylation may be acting as a targeted mutagen at these sites, providing substrate for selection via non-synonymous changes in the underlying genome. However, we did not see any relationship between DNA methylation and rates of positive selection in our samples. In order to fully assess a possible role for DNA methylation in adaptive processes a specifically designed study using natural population data is needed.
Bioprinting microporous functional living materials from protein-based core-shell microgels
Authors: Ou Yangteng , Cao Shixiang , Zhang Yang , Zhu Hongjia , Guo Chengzhi , Yan Wei , Xin Fengxue , Dong Weiliang , Zhang Yanli , Narita Masashi , Yu Ziyi , Knowles Tuomas P. J.
Published: January 2023

Living materials bring together material science and biology to allow the engineering and augmenting of living systems with novel functionalities. Bioprinting promises accurate control over the formation of such complex materials through programmable deposition of cells in soft materials, but current approaches had limited success in fine-tuning cell microenvironments while generating robust macroscopic morphologies. Here, we address this challenge through the use of core-shell microgel ink to decouple cell microenvironments from the structural shell for further processing. Cells are microfluidically immobilized in the viscous core that can promote the formation of both microbial populations and mammalian cellular spheroids, followed by interparticle annealing to give covalently stabilized functional scaffolds with controlled microporosity. The results show that the core-shell strategy mitigates cell leakage while affording a favorable environment for cell culture. Furthermore, we demonstrate that different microbial consortia can be printed into scaffolds for a range of applications. By compartmentalizing microbial consortia in separate microgels, the collective bioprocessing capability of the scaffold is significantly enhanced, shedding light on strategies to augment living materials with bioprocessing capabilities.
Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis
Authors: Moon Jae-Seung , Younis Shady , Ramadoss Nitya S. , Iyer Radhika , Sheth Khushboo , Sharpe Orr , Rao Navin L. , Becart Stephane , Carman Julie A. , James Eddie A. , Buckner Jane H. , Deane Kevin D. , Holers V. Michael , Goodman Susan M. , Donlin Laura T. , Davis Mark M. , Robinson William H.
Published: January 2023

The immune mechanisms that mediate synovitis and joint destruction in rheumatoid arthritis (RA) remain poorly defined. Although increased levels of CD8+ T cells have been described in RA, their function in pathogenesis remains unclear. Here we perform single cell transcriptome and T cell receptor (TCR) sequencing of CD8+ T cells derived from anti-citrullinated protein antibodies (ACPA)+ RA blood. We identify GZMB+CD8+ subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMK+CD8+ memory subpopulation comprises smaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC class I activate RA blood-derived GZMB+CD8+ T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expanded GZMB+CD8+ cells are present in RA synovium. These findings suggest that cytotoxic CD8+ T cells targeting citrullinated antigens contribute to synovitis and joint tissue destruction in ACPA+ RA.
Annotation of natural product compound families using molecular networking topology and structural similarity fingerprinting
Authors: Morehouse Nicholas J. , Clark Trevor N. , McMann Emily J. , van Santen Jeffrey A. , Haeckl F. P. Jake , Gray Christopher A. , Linington Roger G.
Published: January 2023

Spectral matching of MS2 fragmentation spectra has become a popular method for characterizing natural products libraries but identification remains challenging due to differences in MS2 fragmentation properties between instruments and the low coverage of current spectral reference libraries. To address this bottleneck we present Structural similarity Network Annotation Platform for Mass Spectrometry (SNAP-MS) which matches chemical similarity grouping in the Natural Products Atlas to grouping of mass spectrometry features from molecular networking. This approach assigns compound families to molecular networking subnetworks without the need for experimental or calculated reference spectra. We demonstrate SNAP-MS can accurately annotate subnetworks built from both reference spectra and an in-house microbial extract library, and correctly predict compound families from published molecular networks acquired on a range of MS instrumentation. Compound family annotations for the microbial extract library are validated by co-injection of standards or isolation and spectroscopic analysis. SNAP-MS is freely available at www.npatlas.org/discover/snapms.
Uncovering the mechanism for aggregation in repeat expanded RNA reveals a reentrant transition
Authors: Kimchi Ofer , King Ella M. , Brenner Michael P.
Published: January 2023

RNA molecules aggregate under certain conditions. The resulting condensates are implicated in human neurological disorders, and can potentially be designed towards specified bulk properties in vitro. However, the mechanism for aggregation—including how aggregation properties change with sequence and environmental conditions—remains poorly understood. To address this challenge, we introduce an analytical framework based on multimer enumeration. Our approach reveals the driving force for aggregation to be the increased configurational entropy associated with the multiplicity of ways to form bonds in the aggregate. Our model uncovers rich phase behavior, including a sequence-dependent reentrant phase transition, and repeat parity-dependent aggregation. We validate our results by comparison to a complete computational enumeration of the landscape, and to previously published molecular dynamics simulations. Our work unifies and extends published results, both explaining the behavior of CAG-repeat RNA aggregates implicated in Huntington’s disease, and enabling the rational design of programmable RNA condensates.
Phylogeography and transmission of Mycobacterium tuberculosis spanning prisons and surrounding communities in Paraguay
Authors: Sanabria Gladys Estigarribia , Sequera Guillermo , Aguirre Sarita , Méndez Julieta , dos Santos Paulo César Pereira , Gustafson Natalie Weiler , Godoy Margarita , Ortiz Analía , Cespedes Cynthia , Martínez Gloria , García-Basteiro Alberto L. , Andrews Jason R. , Croda Julio , Walter Katharine S.
Published: January 2023

Recent rises in incident tuberculosis (TB) cases in Paraguay and the increasing concentration of TB within prisons highlight the urgency of targeting strategies to interrupt transmission and prevent new infections. However, whether specific cities or carceral institutions play a disproportionate role in transmission remains unknown. We conducted prospective genomic surveillance, sequencing 471 Mycobacterium tuberculosis complex genomes, from inside and outside prisons in Paraguay’s two largest urban areas, Asunción and Ciudad del Este, from 2016 to 2021. We found genomic evidence of frequent recent transmission within prisons and transmission linkages spanning prisons and surrounding populations. We identified a signal of frequent M. tuberculosis spread between urban areas and marked recent population size expansion of the three largest genomic transmission clusters. Together, our findings highlight the urgency of strengthening TB control programs to reduce transmission risk within prisons in Paraguay, where incidence was 70 times that outside prisons in 2021.