bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships between functional alpha and beta diversities of flea parasites and their small mammalian hosts
Authors: Krasnov Boris R. , Khokhlova Irina S. , López Berrizbeitia M. Fernanda , Matthee Sonja , Sanchez Juliana P. , Shenbrot Georgy I. , van der Mescht Luther
Published: March 2024

We studied the relationships between functional alpha and beta diversities of fleas and their small mammalian hosts in 4 biogeographic realms (the Afrotropics, the Nearctic, the Neotropics and the Palearctic), considering 3 components of alpha diversity (functional richness, divergence and regularity). We asked whether (a) flea alpha and beta diversities are driven by host alpha and beta diversities; (b) the variation in the off-host environment affects variation in flea alpha and beta diversities; and (c) the pattern of the relationship between flea and host alpha or beta diversities differs between geographic realms. We analysed alpha diversity using modified phylogenetic generalized least squares and beta diversity using modified phylogenetic generalized dissimilarity modelling. In all realms, flea functional richness and regularity increased with an increase in host functional richness and regularity, respectively, whereas flea functional divergence correlated positively with host functional divergence in the Nearctic only. Environmental effects on the components of flea alpha diversity were found only in the Holarctic realms. Host functional beta diversity was invariantly the best predictor of flea functional beta diversity in all realms, whereas the effects of environmental variables on flea functional beta diversity were much weaker and differed between realms. We conclude that flea functional diversity is mostly driven by host functional diversity, whereas the environmental effects on flea functional diversity vary (a) geographically and (b) between components of functional alpha diversity.
A case of Carvajal syndrome presenting with dilated cardiomyopathy
Authors: Arıcı Sule , Akalın Figen , Geckinli Bilgen Bilge
Published: March 2024

Objectives:

Carvajal syndrome is a very rare autosomal recessive cardiocutaneous disorder caused by a desmosomal mutation in exon 24 of the desmoplakin gene. It manifests with woolly hair, epidermolytic palmoplantar keratoderma, and arrhythmogenic right ventricular cardiomyopathy. We herein present a patient with heart failure and dilated cardiomyopathy who was diagnosed with Carvajal syndrome because of dermatologic manifestations.

Case Presentation:

A seven-year-old girl was referred to our clinic due to decompensated heart failure and clinical deterioration. The patient had severe weakness, tachycardia, and tachypnea. She had a complaint of getting tired quickly for three weeks, and she had shortness of breath and abdominal pain for the last two days. She had hepatomegaly and woolly hair. Mild keratoderma was present on the soles of her feet. Echocardiography demonstrated biventricular dilatation, significantly impaired left ventricular systolic function (ejection fraction 22%), and moderate to severe mitral and tricuspid regurgitation. Molecular genetic evaluation was performed because of cutaneous and cardiac findings, which demonstrated a desmoplakin gene mutation. Homozygous mutation c.4297C > T (p.Gln1433*) was identified in desmoplakin gene, and the diagnosis of Carvajal syndrome was confirmed.

Conclusions:

Syndromic types of arrhythmogenic right ventricular cardiomyopathy such as Carvajal syndrome are rare diseases. Awareness about cutaneous manifestations and genetic evaluation would help diagnosis and prevention of sudden death. Genetic counselling is needed in familial cases.
Fusion imaging for guidance of pulmonary arteriovenous malformation embolisation with minimal radiation and contrast exposure
Authors: Vargas-Acevedo Catalina , Mejia Ernesto , Zablah Jenny E. , Morgan Gareth J.
Published: March 2024

Hereditary haemorrhagic telangiectasia is an inherited disorder characterised by vascular dysplasia that leads to the development of arteriovenous malformations. Pulmonary arteriovenous malformations occur in approximately 30% of patients with haemorrhagic telangiectasia. Given the complex characteristics of haemorrhagic telangiectasia lesions, the application of three-dimensional fusion imaging holds significant promise for procedural guidance and decrease in contrast and radiation dosing. We reviewed all patients who underwent transcatheter approach for pulmonary arteriovenous malformation occlusion with fusion image guidance from June 2018 to September 2023 from a single centre. A total of nine cases with haemorrhagic telangiectasia and transcatheter occlusion of pulmonary arteriovenous malformations using fusion imaging were identified. Five (56%) were male, mean age at procedure was 15.7 years (10–28 years) and mean number of pulmonary arteriovenous malformations intervened was three per patient (1–7). Two of the cases were complex repeat embolisations. The mean fluoroscopy time was 40.6 min (10.7–68.8 min), with mean contrast dose of 28.8 mL (11–60 mL; mean of 0.51 mL/kg) and mean radiation dose of 66.3 mGy (25.6–140 mGy; mean of 40.5 mGy/m2). There were no complications reported during the procedures, with no additional interventions necessary. Fusion imaging in pulmonary arteriovenous malformations embolisation for patients with haemorrhagic telangiectasia is feasible and has the potential to reduce contrast and radiation doses. To our knowledge, we describe the lowest radiation and contrast doses per patient using fusion imaging technology reported in the literature to date.
Extended surface brightness modeling of three sources strongly lensed by an ultra-massive elliptical galaxy
Authors: Bolamperti Andrea
Published: March 2024

Rare systems with multiple sources strongly lensed by a single galaxy provide the most robust way to explore the geometry of the Universe and to study the inner mass structure of lens galaxies. We present here a study of the SDSS J0100+1818 deflector, analyzing its total and baryonic mass distributions. The system comprises an ultra-massive early-type galaxy, surrounded by ten multiple images of three background sources. Exploiting high-resolution HST photometry and VLT/X-shooter spectroscopy we conduct a strong lensing analysis with the software GLEE to reconstruct the complex surface brightness distributions of the background sources over approximately 7200 HST pixels. These results are presented in our recent paper, Bolamperti et al. (2023). Finally, we present some preliminary results from new VLT/MUSE observations, that will allow us to build a new strong lensing+dynamics joint model and measure the values of the total matter density and of the cosmological constant parameters, Ωm and ΩΛ.
Lens Discovery in the Era of Wide-area Surveys
Authors: Holloway Philip , Marshall Philip J , Verma Aprajita
Published: March 2024

Forthcoming data from the Vera Rubin Observatory, Euclid and Roman telescopes are expected to increase the number of strong lenses by two orders of magnitude. With current discovery methods these would be accompanied by an even greater number of false positives. In that context we find that using an ensemble of classifiers would provide a more complete sample of high-purity lenses and present methods to post-process the outputs of such classifiers to give reliable probabilities that a given image contains a lens.
Lensed radio arcs at milli-arcsecond resolution: Methods, science results, and current status
Authors: Powell Devon M.
Published: March 2024

Strong gravitational lensing by galaxies provides us with a powerful laboratory for testing dark matter models. Various particle models for dark matter give rise to different small-scale distributions of mass in the lens galaxy, which can be differentiated with sensitive observations. Th. The sensitivity of a gravitational lens observation to the presence (or absence) of low-mass dark structures in the lens galaxy is determined mainly by the angular resolution of the instrument and the spatial structure of the source. Here, I discuss results from the analysis of a global VLBI observation of a gravitationally lensed radio jet. With an angular resolution better than 5 milli-arcseconds and a highly extended, spatially resolved source, we are able to place competitive constraints on the particle mass in fuzzy dark matter models using this single observation. I also discuss preliminary results from our analysis of warm dark matter models using this lens system.
Angular structure and gravitational imaging
Authors: O’Riordan Conor M.
Published: March 2024

In gravitational imaging, the mass model for the main lensing galaxy is one of the main sources of systematic uncertainty. We use subhalo detection models with increasing levels of angular complexity in the lens mass model to analyse 100 HST mock observations. We find that perturbations of just 1% are enough to cause a 20% false positive subhalo detection rate, with order 3 multipoles having the strongest effect. The area in an observation where a substructure can be detected drops by a factor of 10 if multipoles up to 3 per cent amplitude are included in the lens model. The mass of the smallest detectable substructure however is not affected. We find a detection limit of M>108.2M⊙ at 5σ in all models. In order for strong lensing searches for dark matter objects to remain reliable in the future, angular structure beyond the elliptical power-law must be included.
Time Delay Cosmograpy of SDSSJ1433 with the 2.1m Wendelstein Telescope
Authors: Queirolo G.
Published: March 2024

Time delay cosmography is based on the study of multiply gravitationally lensed images of a variable source. Their time delay differences are linearly dependent on the Fermat potential differences at the images’ positions and the Hubble parameter, whose exact value is to this date strongly debated in the framework of the Hubble tension. In this paper we present the study of SDSSJ1433, a quadruply lensed QSO, the time delays of which have been obtained after a 3-year observational campaign from the 2.1m Wendelstein telescope in the optical ǵ filter, and the corresponding mass model was constrained from multi-band archival HST observations. The resulting H0 value is $$77.4\frac{{km}}{{s\,Mpc}}$$ with a precision of∼ 6 %.
Frequency reconfigurable circular microstrip G-slotted antenna with DGS for various wireless applications
Authors: Mamta  , Nath Vandana
Published: March 2024

A novel reconfigurable circular microstrip G-slotted antenna having a circularly defected ground structure (DGS) capable of switching its resonance frequency for several microwave applications is presented in this paper. Reconfigurability of the proposed G-slot antenna is obtained by incorporating three PIN diodes. One diode is embedded in the patch and two diodes are integrated into the DGS structure at appropriate places in the slot to achieve four different wireless applications such as aeronautical radio navigation (4.3 GHz with gain 3.6 dB), satellite communication (3.78 GHz with gain 3.7 dB), mobile communication (4.55 GHz with gain 4.0 dB), and WiMAX (3.35 GHz with gain 3.3 dB). These four bands are achieved depending on the different biasing conditions of the three PIN switches used. Antenna performance has been analyzed in ANSYS Electronics Desktop 2018.2 software. The equivalent circuit component of the switching element (PIN diode) has been considered and designed during the simulation. The creative structure lies in the way that it exhibits higher gain with compact size than the previously reported similar antenna. A prototype of the proposed patch antenna has been fabricated on a Roger substrate and its testing and measurement have been performed to demonstrate its desirable characteristics and features.
I think learning ancient Greek via video game is…’: An online survey to understand perceptions of Digital Game-Based Learning for ancient Greek
Authors: Di Gioia Irene
Published: March 2024

Playing is connected at a deep level to how we learn, participate in and create culture, as it is dynamic, complex and even unpredictable just as learning is (Reinhardt, 2019). Even Plato in his Theaetetus recognises the importance of such a component in experiencing culture and knowledge. Could playing (or gaming) therefore be a useful didactical approach in promoting the study of ancient Greek around the world? From 10th May 2023 at 1 pm. until 1st June 2023 at 1 pm., an internet survey was conducted online by the researcher Irene Di Gioia through the use of Google Forms questionnaires. This questionnaire was distributed via different social networks and communication tools. The survey aimed to understand if people around the world are interested in the idea of learning ancient Greek via a video game and if so, which video gaming activities learners prefer. The goal of the survey was therefore to understand if a ludic pedagogical approach using Digital Game-Based Learning could theoretically represent an interest experience for learners or potential learners, and furthermore to investigate their feelings, prejudices, and motivations regarding the study of ancient Greek. From the analysed data the researcher will therefore develop a video game to teach ancient Greek language and culture, which comprises the focus of her ongoing PhD dissertation at Georg-August University of Göttingen (Germany) and Alma Mater Studiorum University of Bologna (Italy).
Frictional Strength, Stability, and Potential Shear Heating on Icy Satellite Faults
Authors: Zaman Maheenuz , McCarthy Christine , Skarbek Rob M. , Savage Heather M.
Published: March 2024

We determined the frictional strength and stability of polycrystalline ice and ice‐ammonia to constrain fault behavior on icy satellites such as Enceladus and Europa. Friction experiments including velocity steps and slide‐hold‐slide tests were conducted to measure the steady‐state coefficient of friction, velocity dependence and healing between temperatures of 98 and 248 K at a normal stress of 100 kPa. Rate‐state friction parameters determined from velocity steps provide stability values. The friction results are used to infer fault strength and frictional heating of an icy crust with depth for both a pure ice crust and one containing ammonia. We find a reduced coefficient of friction for an ammonia‐bearing crust and stronger velocity dependence in the presence of partial melt. The temperature dependence of fault stability maps a seismogenic zone with depth analogous to the synoptic model for terrestrial fault stability, where we find instability between 0.7 and 3.9 km with a return to stability from 4.6 km if we assume a 6 km ice shell. We consider the role of sliding velocity and fault thickness on localized frictional heating in both systems and estimate the depth of melt generation in an ammonia‐bearing crust. Our results imply that faults at conditions similar to icy satellites can be seismogenic.
Earth System Model Analysis of How Astronomical Forcing Is Imprinted Onto the Marine Geological Record: The Role of the Inorganic (Carbonate) Carbon Cycle and Feedbacks
Authors: Vervoort P. , Kirtland Turner S. , Rochholz F. , Ridgwell A.
Published: March 2024

Astronomical cycles are strongly expressed in marine geological records, providing important insights into Earth system dynamics and an invaluable means of constructing age models. However, how various astronomical periods are filtered by the Earth system and the mechanisms by which carbon reservoirs and climate components respond, particularly in absence of dynamic ice sheets, is unclear. Using an Earth system model that includes feedbacks between climate, ocean circulation, and inorganic (carbonate) carbon cycling relevant to geological timescales, we systematically explore the impact of astronomically‐modulated insolation forcing and its expression in model variables most comparable to key paleoceanographic proxies (temperature, the δ13C of inorganic carbon, and sedimentary carbonate content). Temperature predominately responds to obliquity and is little influenced by the modeled carbon cycle feedbacks. In contrast, the cycling of nutrients and carbon in the ocean generates significant precession power in atmospheric CO2, benthic ocean δ13C, and sedimentary wt% CaCO3, while inclusion of marine sedimentary and weathering processes shifts power to the long eccentricity period. Our simulations produce reduced pCO2 and dissolved inorganic carbon δ13C at long eccentricity maxima and, contrary to early Cenozoic marine records, CaCO3 preservation in the model is enhanced during eccentricity modulated warmth. Additionally, the magnitude of δ13C variability simulated in our model underestimates marine proxy records. These model‐data discrepancies hint at the possibility that the Paleogene silicate weathering feedback was weaker than modeled here and that additional organic carbon cycle feedbacks are necessary to explain the full response of the Earth system to astronomical forcing.
A Multi‐Model Ensemble of Baseline and Process‐Based Models Improves the Predictive Skill of Near‐Term Lake Forecasts
Authors: Olsson Freya , Moore Tadhg N. , Carey Cayelan C. , Breef‐Pilz Adrienne , Thomas R. Quinn
Published: March 2024

Water temperature forecasting in lakes and reservoirs is a valuable tool to manage crucial freshwater resources in a changing and more variable climate, but previous efforts have yet to identify an optimal modeling approach. Here, we demonstrate the first multi‐model ensemble (MME) reservoir water temperature forecast, a forecasting method that combines individual model strengths in a single forecasting framework. We developed two MMEs: a three‐model process‐based MME and a five‐model MME that includes process‐based and empirical models to forecast water temperature profiles at a temperate drinking water reservoir. We found that the five‐model MME improved forecast performance by 8%–30% relative to individual models and the process‐based MME, as quantified using an aggregated probabilistic skill score. This increase in performance was due to large improvements in forecast bias in the five‐model MME, despite increases in forecast uncertainty. High correlation among the process‐based models resulted in little improvement in forecast performance in the process‐based MME relative to the individual process‐based models. The utility of MMEs is highlighted by two results: (a) no individual model performed best at every depth and horizon (days in the future), and (b) MMEs avoided poor performances by rarely producing the worst forecast for any single forecasted period (<6% of the worst ranked forecasts over time). This work presents an example of how existing models can be combined to improve water temperature forecasting in lakes and reservoirs and discusses the value of utilizing MMEs, rather than individual models, in operational forecasts.
BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer
Authors: Jenkins Laura J. , Luk Ian Y. , Chionh Fiona , Tan Tao , Needham Kristen , Ayton Jamieson , Reehorst Camilla M. , Vukelic Natalia , Sieber Oliver M. , Mouradov Dmitri , Gibbs Peter , Williams David S. , Tebbutt Niall C. , Desai Jayesh , Hollande Frédéric , Dhillon Amardeep S. , Lee Erinna F. , Merino Delphine , Fairlie W. Douglas , Mariadason John M.
Published: March 2024

Metastatic BRAFV600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAFV600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAFV600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-XL, and that combining encorafenib with a BCL-XL inhibitor significantly enhances apoptosis in BRAFV600E CRC cell lines. This effect was partially dependent on the induction of BIM, as BIM deletion markedly attenuated BRAF plus BCL-XL inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-XL inhibition, we also examined the effect of combining encorafenib with the BCL-XL -targeting PROTAC DT2216, and the novel BCL-2/BCL-XL inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAFV600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAFV600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.
Gasdermin E promotes translocation of p65 and c-jun into nucleus in keratinocytes for progression of psoriatic skin inflammation
Authors: Long Fangyuan , Wei Xuecui , Chen Yujie , Li Min , Lian Ni , Yu Shanshan , Chen Sihan , Yang Yong , Li Min , Gu Heng , Chen Xu
Published: March 2024

Gasdermin E (GSDME) has recently been identified as a critical executioner to mediate pyroptosis. While epidermal keratinocytes can initiate GSDME-mediated pyroptosis, the role of keratinocyte GSDME in psoriatic dermatitis remains poorly characterized. Through analysis of GEO datasets, we found elevated GSDME levels in psoriatic lesional skin. Additionally, GSDME levels correlated with both psoriasis severity and response to biologics treatments. Single-cell RNA sequencing (scRNA-seq) from a GEO dataset revealed GSDME upregulation in keratinocytes of psoriasis patients. In the imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model, both full-length and cleaved forms of caspase-3 and GSDME were elevated in the epidermis. Abnormal proliferation and differentiation of keratinocytes and dermatitis were attenuated in Gsdme-/- mice and keratinocyte-specific Gsdme conditional knockout mice after IMQ stimulation. Exposure of keratinocytes to mixed cytokines (M5), mimicking psoriatic conditions, led to GSDME cleavage. Moreover, the interaction between GSDME-FL and p65 or c-jun was significantly increased after M5 stimulation. GSDME knockdown inhibited nuclear translocation of p65 and c-jun and decreased upregulation of psoriatic inflammatory mediators such as IL1β, CCL20, CXCL1, CXCL8, S100A8, and S100A9 in M5-challenged keratinocytes. In conclusion, GSDME in keratinocytes contributes to the pathogenesis and progression of psoriasis, potentially in a pyroptosis-independent manner by interacting and promoting translocation of p65 and c-jun. These findings suggest that keratinocyte GSDME could serve as a potential therapeutic target for psoriasis treatment.
Heterozygous THBS2 pathogenic variant causes Ehlers–Danlos syndrome with prominent vascular features in humans and mice
Authors: Hadar Noam , Porgador Omri , Cohen Idan , Levi Hilla , Dolgin Vadim , Yogev Yuval , Sued-Hendrickson Sufa , Shelef Ilan , Didkovsky Elena , Eskin-Schwartz Marina , Birk Ohad S.
Published: March 2024

Ehlers–Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2Cys896Arg KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.
A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss
Authors: Schilder Anne G. M. , Wolpert Stephan , Saeed Shakeel , Middelink Leonie M. , Edge Albert S. B. , Blackshaw Helen ,   REGAIN Consortium, Schilder Anne , Middelink Leonie , Edge Albert , Bibas Athanasios , Arram Elizabeth , Bilhet Asger , Cooper Hannah , Dalhoff Ernst , van Diggelen Femke , Rutten Rolf Jan , van Es Helmuth , Hojgaard Karin , Iliadou Eleftheria , Yildirim Omursen , Khalil Sherif , Kikidis Dimitris , Lowenheim Hubert , Markatos Nikos , Mueller Marcus , Schade-Mann Thore , Schneider Fritz , Vardonikolaki Katerina , Wilke August , Pastiadis Kostas , Bibas Athanasios G.
Published: March 2024

Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proof-of-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I (N = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa (N = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change −0.87 dB; 95% CI −2.37 to 0.63; P = 0.252 and −0.46 dB; 95% CI −1.94 to 1.03; P = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial’s primary endpoint was not met.
On-surface cyclization of vinyl groups on poly-para-phenylene involving an unusual pentagon to hexagon transformation
Authors: Di Giovannantonio Marco , Qiu Zijie , Pignedoli Carlo A. , Asako Sobi , Ruffieux Pascal , Müllen Klaus , Narita Akimitsu , Fasel Roman
Published: March 2024

On-surface synthesis relies on carefully designed molecular precursors that are thermally activated to afford desired, covalently coupled architectures. Here, we study the intramolecular reactions of vinyl groups in a poly-para-phenylene-based model system and provide a comprehensive description of the reaction steps taking place on the Au(111) surface under ultrahigh vacuum conditions. We find that vinyl groups successfully cyclize with the phenylene rings in the ortho positions, forming a dimethyl-dihydroindenofluorene as the repeating unit, which can be further dehydrogenated to a dimethylene-dihydroindenofluorene structure. Interestingly, the obtained polymer can be transformed cleanly into thermodynamically stable polybenzo[k]tetraphene at higher temperature, involving a previously elusive pentagon-to-hexagon transformation via ring opening and rearrangement on a metal surface. Our insights into the reaction cascade unveil fundamental chemical processes involving vinyl groups on surfaces. Because the formation of specific products is highly temperature-dependent, this innovative approach offers a valuable tool for fabricating complex, low-dimensional nanostructures with high precision and yield.
Nonpathogenic Pseudomonas syringae derivatives and its metabolites trigger the plant “cry for help” response to assemble disease suppressing and growth promoting rhizomicrobiome
Authors: Liu Yunpeng , Zhang Huihui , Wang Jing , Gao Wenting , Sun Xiting , Xiong Qin , Shu Xia , Miao Youzhi , Shen Qirong , Xun Weibing , Zhang Ruifu
Published: March 2024

Plants are capable of assembling beneficial rhizomicrobiomes through a “cry for help” mechanism upon pathogen infestation; however, it remains unknown whether we can use nonpathogenic strains to induce plants to assemble a rhizomicrobiome against pathogen invasion. Here, we used a series of derivatives of Pseudomonas syringae pv. tomato DC3000 to elicit different levels of the immune response to Arabidopsis and revealed that two nonpathogenic DC3000 derivatives induced the beneficial soil-borne legacy, demonstrating a similar “cry for help” triggering effect as the wild-type DC3000. In addition, an increase in the abundance of Devosia in the rhizosphere induced by the decreased root exudation of myristic acid was confirmed to be responsible for growth promotion and disease suppression of the soil-borne legacy. Furthermore, the “cry for help” response could be induced by heat-killed DC3000 and flg22 and blocked by an effector triggered immunity (ETI) -eliciting derivative of DC3000. In conclusion, we demonstrate the potential of nonpathogenic bacteria and bacterial elicitors to promote the generation of disease-suppressive soils.
G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage
Authors: Pena Nicholas , Richbourg Tara , Gonzalez-Hunt Claudia P. , Qi Rui , Wren Paul , Barlow Carrolee , Shanks Natalie F. , Carlisle Holly J. , Sanders Laurie H.
Published: March 2024

Pathogenic mutations in LRRK2 cause Parkinson’s disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis. The Mito DNADX assay, which allows for the accurate real-time quantification of mtDNA damage in a 96-well platform, was performed in parallel. We confirmed that EB-42168 selectively inhibits LRRK2 phosphorylation on G2019S LRRK2 relative to wild-type LRRK2. On the other hand, MLi-2 was equipotent for wild-type and G2019S LRRK2. Acute treatment with EB-42168 inhibited LRRK2 phosphorylation and also restored mtDNA damage to healthy control levels. We further investigated the relationship between LRRK2 kinase activity, mtDNA damage and mitophagy. Levels of mtDNA damage caused by G2019S LRRK2 were fully re-established within 2 h of a LRRK2 inhibitor wash out and recovery experiment, indicating the mtDNA damage phenotype is highly dynamic. G2019S LRRK2 mitophagy defects were not alleviated with LRRK2 kinase inhibition, suggesting that mitophagy is not mechanistically regulating LRRK2 kinase-mediated reversal of mtDNA damage in this acute timeframe. Abrogation of mtDNA damage with the mutant selective tool inhibitor EB-42168 demonstrates the potential of a precision medicine approach for LRRK2 G2019S PD. Levels of mtDNA damage may serve as a potential pharmacodynamic biomarker of altered kinase activity that could be useful for small molecule development and clinical trials.
Global emergent responses of stream microbial metabolism to glacier shrinkage
Authors: Kohler Tyler J. , Bourquin Massimo , Peter Hannes , Yvon-Durocher Gabriel , Sinsabaugh Robert L. , Deluigi Nicola , Styllas Michael ,   Vanishing Glaciers Field Team, Styllas Michael , Schön Martina , Tolosano Matteo , de Staercke Vincent , Battin Tom J.
Published: March 2024

Most cryospheric ecosystems are energy limited. How their energetics will respond to climate change remains largely unknown. This is particularly true for glacier-fed streams, which interface with the cryosphere and initiate some of Earth’s largest river systems. Here, by studying resource stoichiometry and microbial energetics in 154 glacier-fed streams sampled by the Vanishing Glaciers project across Earth’s major mountain ranges, we show that these ecosystems and their benthic microbiome are overall carbon and phosphorus limited. Threshold elemental ratios and low carbon use efficiencies (median: 0.15) modelled from extracellular enzymatic activities corroborate resource limitation in agreement with maintenance metabolism of benthic microorganisms. Space-for-time substitution analyses suggest that glacier shrinkage will stimulate benthic primary production in glacier-fed streams, thereby relieving microbial metabolism from carbon limitation. Concomitantly, we find that increasing streamwater temperature will probably stimulate microbial growth (temperature sensitivity: 0.62 eV). Consequently, elevated microbial demands for phosphorus, but diminishing inputs from subglacial sources, may intensify phosphorus limitation as glaciers shrink. Our study thus unveils a ‘green transition’ towards autotrophy in the world’s glacier-fed streams, entailing shifts in the energetics of their microorganisms.
A dataset for multi-faceted analysis of electric vehicle charging transactions
Authors: Baek Keon , Lee Eunjung , Kim Jinho
Published: March 2024

This study discloses a dataset of electric vehicles’ (EVs’) charging transactions at a scale for multi-faceted analysis from both EV charger and user perspectives. The data comprises whole sessions that occurred during a charging operation company’s annual commercial operation period, specifically including identifiers and charger location categories. For data acquisition, machine-to-machine wireless communication system with proper retransmission for interruption is utilised. The entire dataset is newly collected and is available with 72,856 sessions from 2,337 EV users and 2,119 chargers. The dataset can be used in a variety of ways for the functioning of power systems and markets, including EV charging service businesses, charger installation siting, demand transaction market design, and long-term investment planning of EV-related infrastructure.
Association between body mass index and three-year outcome of acute myocardial infarction
Authors: Park Soyoon , Kim Dae-Won , Lee Kyusup , Park Mahn-Won , Chang Kiyuk , Jeong Myung Ho , Ahn Young Keun , Chae Sung Chull , Ahn Tae Hoon , Rha Seung Woon , Kim Hyo-Soo , Gwon Hyeon Cheol , Seong In Whan , Hwang Kyung Kuk , Kim Kwon-Bae , Cha Kwang Soo , Oh Seok Kyu , Chae Jei Keon
Published: March 2024

Body mass index (BMI), as an important risk factor related to metabolic disease. However, in some studies higher BMI was emphasized as a beneficial factor in the clinical course of patients after acute myocardial infarction (AMI) in a concept known as the “BMI paradox.” The purpose of this study was to investigate how clinical outcomes of patients treated for AMI differed according to BMI levels. A total of 10,566 patients in the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) from May 2010 to June 2015 were divided into three BMI groups (group 1: BMI < 22 kg/m2, group 2: ≥ 22 and < 26 kg/m2, and group 3: ≥ 26 kg/m2). The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) at 3 years of follow-up. At 1 year of follow-up, the incidence of MACCE in group 1 was 10.1% of that in group 3, with a hazard ratio (HR) of 2.27, and 6.5% in group 2, with an HR of 1.415. This tendency continued up to 3 years of follow-up. The study demonstrated that lower incidence of MACCE in the high BMI group of Asians during the 3-year follow-up period compared to the low BMI group. The results implied higher BMI could exert a positive effect on the long-term clinical outcomes of patients with AMI undergoing percutaneous coronary intervention (PCI).
High-precision regressors for particle physics
Authors: Bishara Fady , Paul Ayan , Dy Jennifer
Published: March 2024

Monte Carlo simulations of physics processes at particle colliders like the Large Hadron Collider at CERN take up a major fraction of the computational budget. For some simulations, a single data point takes seconds, minutes, or even hours to compute from first principles. Since the necessary number of data points per simulation is on the order of $$10^9$$

10
9

–$$10^{12}$$

10
12

, machine learning regressors can be used in place of physics simulators to significantly reduce this computational burden. However, this task requires high-precision regressors that can deliver data with relative errors of less than 1% or even 0.1% over the entire domain of the function. In this paper, we develop optimal training strategies and tune various machine learning regressors to satisfy the high-precision requirement. We leverage symmetry arguments from particle physics to optimize the performance of the regressors. Inspired by ResNets, we design a Deep Neural Network with skip connections that outperform fully connected Deep Neural Networks. We find that at lower dimensions, boosted decision trees far outperform neural networks while at higher dimensions neural networks perform significantly better. We show that these regressors can speed up simulations by a factor of $$10^3$$

10
3

–$$10^6$$

10
6

over the first-principles computations currently used in Monte Carlo simulations. Additionally, using symmetry arguments derived from particle physics, we reduce the number of regressors necessary for each simulation by an order of magnitude. Our work can significantly reduce the training and storage burden of Monte Carlo simulations at current and future collider experiments.
Eye-tracking does not reveal early attention processing of sexual copulatory movement in heterosexual men and women
Authors: Vaníček Ondřej , Krejčová Lucie , Hůla Martin , Potyszová Kateřina , Klapilová Kateřina , Bártová Klára
Published: March 2024

Men and women respond differently when presented with sexual stimuli. Men's reaction is gender-specific, and women's reaction is gender-nonspecific. This might be a result of differential cognitive processing of sexual cues, namely copulatory movement (CM), which is present in almost every dynamic erotic stimulus. A novelty eye-tracking procedure was developed to assess the saliency of short film clips containing CM or non-CM sexual activities. Results from 29 gynephilic men and 31 androphilic women showed only small and insignificant effects in attention bias and no effects in attentional capture. Our results suggest that CM is not processed differently in men and women and, therefore, is not the reason behind gender-nonspecific sexual responses in women.
Hierarchical graph contrastive learning of local and global presentation for multimodal sentiment analysis
Authors: Du Jun , Jin Jianhang , Zhuang Jian , Zhang Cheng
Published: March 2024

Multi-modal sentiment analysis (MSA) aims to regress or classify the overall sentiment of utterances through acoustic, visual, and textual cues. However, most of the existing efforts have focused on developing the expressive ability of neural networks to learn the representation of multi-modal information within a single utterance, without considering the global co-occurrence characteristics of the dataset. To alleviate the above issue, in this paper, we propose a novel hierarchical graph contrastive learning framework for MSA, aiming to explore the local and global representations of a single utterance for multimodal sentiment extraction and the intricate relations between them. Specifically, regarding to each modality, we extract the discrete embedding representation of each modality, which includes the global co-occurrence features of each modality. Based on it, for each utterance, we build two graphs: local level graph and global level graph to account for the level-specific sentiment implications. Then, two graph contrastive learning strategies is adopted to explore the different potential presentations based on graph augmentations respectively. Furthermore, we design a cross-level comparative learning for learning local and global potential representations of complex relationships.
The first mitochondrial genome of Calophyllum soulattri Burm.f.
Authors: Cadorna Charles Anthon E. , Pahayo Dexter G. , Rey Jessica D.
Published: March 2024

Calophyllum soulattri Burm.f. is traditionally used to treat skin infections and reduce rheumatic pain, yet genetic and genomic studies are still limited. Here, we present the first complete mitochondrial genome of C. soulattri. It is 378,262 bp long with 43.97% GC content, containing 55 genes (30 protein-coding, 5 rRNA, and 20 tRNA). Repeat analysis of the mitochondrial genome revealed 194 SSRs, mostly mononucleotides, and 266 pairs of dispersed repeats ($$\ge $$
≥
30 bp) that were predominantly palindromic. There were 23 homologous fragments found between the mitochondrial and plastome genomes. We also predicted 345 C-to-U RNA editing sites from 30 protein-coding genes (PCGs) of the C. soulatrii mitochondrial genome. These RNA editing events created the start codon of nad1 and the stop codon of ccmFc. Most PCGs of the C. soulattri mitochondrial genome underwent negative selection, but atp4 and ccmB experienced positive selection. Phylogenetic analyses showed C. soulattri is a sister taxon of Garcinia mangostana. This study has shed light on C. soulattri’s evolution and Malpighiales’ phylogeny. As the first complete mitochondrial genome in Calophyllaceae, it can be used as a reference genome for other medicinal plant species within the family for future genetic studies.
Delineating immune variation between adult and children COVID-19 cases and associations with disease severity
Authors: Cevirgel Alper , Vos Martijn , Holtrop Anne Floor , Beckers Lisa , Reukers Daphne F. M. , Meijer Adam , Rots Nynke , van Beek Josine , van Baarle Debbie , de Wit Jelle
Published: March 2024

The SARS-CoV-2 pandemic has emphasized the need to explore how variations in the immune system relate to the severity of the disease. This study aimed to explore inter-individual variation in response to SARS-CoV-2 infection by comparing T cell, B cell, and innate cell immune subsets among primary infected children and adults (i.e., those who had never experienced SARS-CoV-2 infection nor received vaccination previously), with varying disease severity after infection. We also examined immune subset kinetics in convalescent individuals compared to those with persistent infection to identify possible markers of immune dysfunction. Distinct immune subset differences were observed between infected adults and children, as well as among adult cases with mild, moderate, and severe disease. IgM memory B cells were absent in moderate and severe cases whereas frequencies of B cells with a lack of surface immunoglobulin expression were significantly higher in severe cases. Interestingly, these immune subsets remained stable during recovery implying that these subsets could be associated with underlying baseline immune variation. Our results offer insights into the potential immune markers associated with severe COVID-19 and provide a foundation for future research in this area.
Exposure and risk assessment for agricultural workers during chlorothalonil and flubendiamide treatments in pepper fields
Authors: Lee Deuk-Yeong , Song Jong-Wook , An Ji-Young , Kim Yeong-Jin , Seo Jong-Su , Kim Jong-Hwan
Published: March 2024

Pesticides are indispensable tools in modern agriculture for enhancing crop productivity. However, the inherent toxicity of pesticides raises significant concerns regarding human exposure, particularly among agricultural workers. This study investigated the exposure and associated risks of two commonly used pesticides in open-field pepper cultivation, namely, chlorothalonil and flubendiamide, in the Republic of Korea. We used a comprehensive approach, encompassing dermal and inhalation exposure measurements in agricultural workers during two critical scenarios: mixing/loading and application. Results revealed that during mixing/loading, dermal exposure to chlorothalonil was 3.33 mg (0.0002% of the total active ingredient [a.i.]), while flubendiamide exposure amounted to 0.173 mg (0.0001% of the a.i.). Conversely, dermal exposure increased significantly during application to 648 mg (chlorothalonil) and 93.1 mg (flubendiamide), representing 0.037% and 0.065% of the total a.i., respectively. Inhalation exposure was also evident, with chlorothalonil and flubendiamide exposure levels varying across scenarios. Notably, the risk assessment using the Risk Index (RI) indicated acceptable risk of exposure during mixing/loading but raised concerns during application, where all RIs exceeded 1, signifying potential risk. We suggest implementing additional personal protective equipment (PPE) during pesticide application, such as gowns and lower-body PPE, to mitigate these risks.
ImmunoPET imaging of TIGIT in the glioma microenvironment
Authors: Vincze Sarah R. , Jaswal Ambika P. , Frederico Stephen C. , Nisnboym Michal , Li Bo , Xiong Zujian , Sever ReidAnn E. , Sneiderman Chaim T. , Rodgers Mikayla , Day Kathryn E. , Latoche Joseph D. , Foley Lesley M. , Hitchens T. Kevin , Frederick Robin , Patel Ravi B. , Hadjipanayis Costas G. , Raphael Itay , Nedrow Jessie R. , Edwards W. Barry , Kohanbash Gary
Published: March 2024

Glioblastoma (GBM) is the most common primary malignant brain tumor. Currently, there are few effective treatment options for GBM beyond surgery and chemo-radiation, and even with these interventions, median patient survival remains poor. While immune checkpoint inhibitors (ICIs) have demonstrated therapeutic efficacy against non-central nervous system cancers, ICI trials for GBM have typically had poor outcomes. TIGIT is an immune checkpoint receptor that is expressed on activated T-cells and has a role in the suppression of T-cell and Natural Killer (NK) cell function. As TIGIT expression is reported as both prognostic and a biomarker for anti-TIGIT therapy, we constructed a molecular imaging agent, [89Zr]Zr-DFO-anti-TIGIT (89Zr-αTIGIT), to visualize TIGIT in preclinical GBM by immunoPET imaging. PET imaging and biodistribution analysis of 89Zr-αTIGIT demonstrated uptake in the tumor microenvironment of GBM-bearing mice. Blocking antibody and irrelevant antibody tracer studies demonstrated specificity of 89Zr-αTIGIT with significance at a late time point post-tracer injection. However, the magnitude of 89Zr-αTIGIT uptake in tumor, relative to the IgG tracer was minimal. These findings highlight the features and limitations of using 89Zr-αTIGIT to visualize TIGIT in the GBM microenvironment.