bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural basis of Cdk7 activation by dual T-loop phosphorylation
Authors: Düster Robert , Anand Kanchan , Binder Sophie C. , Schmitz Maximilian , Gatterdam Karl , Fisher Robert P. , Geyer Matthias
Published: August 2024

Cyclin-dependent kinase 7 (Cdk7) is required in cell-cycle and transcriptional regulation owing to its function as both a CDK-activating kinase (CAK) and part of transcription factor TFIIH. Cdk7 forms active complexes by associating with Cyclin H and Mat1, and is regulated by two phosphorylations in the activation segment (T loop): the canonical activating modification at T170 and another at S164. Here we report the crystal structure of the human Cdk7/Cyclin H/Mat1 complex containing both T-loop phosphorylations. Whereas pT170 coordinates basic residues conserved in other CDKs, pS164 nucleates an arginine network unique to the ternary Cdk7 complex, involving all three subunits. We identify differential dependencies of kinase activity and substrate recognition on the individual phosphorylations. CAK function is unaffected by T-loop phosphorylation, whereas activity towards non-CDK substrates is increased several-fold by T170 phosphorylation. Moreover, dual T-loop phosphorylation stimulates multisite phosphorylation of the RNA polymerase II (RNAPII) carboxy-terminal domain (CTD) and SPT5 carboxy-terminal repeat (CTR) region. In human cells, Cdk7 activation is a two-step process wherein S164 phosphorylation precedes, and may prime, T170 phosphorylation. Thus, dual T-loop phosphorylation can regulate Cdk7 through multiple mechanisms, with pS164 supporting tripartite complex formation and possibly influencing processivity, while pT170 enhances activity towards key transcriptional substrates.
A unified model for interpretable latent embedding of multi-sample, multi-condition single-cell data
Authors: Madrigal Ariel , Lu Tianyuan , Soto Larisa M. , Najafabadi Hamed S.
Published: August 2024

Single-cell analysis across multiple samples and conditions requires quantitative modeling of the interplay between the continuum of cell states and the technical and biological sources of sample-to-sample variability. We introduce GEDI, a generative model that identifies latent space variations in multi-sample, multi-condition single-cell datasets and attributes them to sample-level covariates. GEDI enables cross-sample cell state mapping on par with state-of-the-art integration methods, cluster-free differential gene expression analysis along the continuum of cell states, and machine learning-based prediction of sample characteristics from single-cell data. GEDI can also incorporate gene-level prior knowledge to infer pathway and regulatory network activities in single cells. Finally, GEDI extends all these concepts to previously unexplored modalities that require joint consideration of dual measurements, such as the joint analysis of exon inclusion/exclusion reads to model alternative cassette exon splicing, or spliced/unspliced reads to model the mRNA stability landscapes of single cells.
Machine-learned interatomic potentials for transition metal dichalcogenide Mo1−xWxS2−2ySe2y alloys
Authors: Siddiqui Anas , Hine Nicholas D. M.
Published: August 2024

Machine Learned Interatomic Potentials (MLIPs) combine the predictive power of Density Functional Theory (DFT) with the speed and scaling of interatomic potentials, enabling theoretical spectroscopy to be applied to larger and more complex systems than is possible with DFT. In this work, we train an MLIP for quaternary Transition Metal Dichalcogenide (TMD) alloy systems of the form Mo1−xWxS2−2ySe2y, using the equivariant Neural Network (NN) MACE. We demonstrate the ability of this potential to calculate vibrational properties of alloy TMDs including phonon spectra for pure monolayers, and Vibrational Density of States (VDOS) and first-order Raman spectra for alloys across the range of x and y. We show that we retain DFT level accuracy while greatly extending feasible system size and extent of sampling over alloy configurations. We are able to characterize the first-order Raman active modes across the whole range of concentration, particularly for the “disorder-induced” modes.
Transcriptomics and weighted protein network analyses of the LRRK2 protein interactome reveal distinct molecular signatures for sporadic and LRRK2 Parkinson’s Disease
Authors: Zhao Yibo , Bracher-Smith Matthew , Li Yuelin , Harvey Kirsten , Escott-Price Valentina , Lewis Patrick A. , Manzoni Claudia
Published: August 2024

Mutations in the LRRK2 gene are the most common genetic cause of familial Parkinson’s Disease (LRRK2-PD) and an important risk factor for sporadic PD (sPD). Multiple clinical trials are ongoing to evaluate the benefits associated with the therapeutical reduction of LRRK2 kinase activity. In this study, we described the changes of transcriptomic profiles (whole blood mRNA levels) of LRRK2 protein interactors in sPD and LRRK2-PD cases as compared to healthy controls with the aim of comparing the two PD conditions. We went on to model the protein-protein interaction (PPI) network centred on LRRK2, which was weighted to reflect the transcriptomic changes on expression and co-expression levels of LRRK2 protein interactors. Our results showed that LRRK2 interactors present both similar and distinct alterations in expression levels and co-expression behaviours in the sPD and LRRK2-PD cases; suggesting that, albeit being classified as the same disease based on clinical features, LRRK2-PD and sPD display significant differences from a molecular perspective. Interestingly, the similar changes across the two PD conditions result in decreased connectivity within a topological cluster of the LRRK2 PPI network associated with protein metabolism/biosynthesis and ribosomal metabolism suggesting protein homoeostasis and ribosomal dynamics might be affected in both sporadic and familial PD in comparison with controls.
A comprehensive overview of liquid biopsy applications in pediatric solid tumors
Authors: Janssen Ferdinand W. , Lak Nathalie S. M. , Janda Claudia Y. , Kester Lennart A. , Meister Michael T. , Merks Johannes H. M. , van den Heuvel-Eibrink Marry M. , van Noesel Max M. , Zsiros Jozsef , Tytgat Godelieve A. M. , Looijenga Leendert H. J.
Published: August 2024

Liquid biopsies are emerging as an alternative source for pediatric cancer biomarkers with potential applications during all stages of patient care, from diagnosis to long-term follow-up. While developments within this field are reported, these mainly focus on dedicated items such as a specific liquid biopsy matrix, analyte, and/or single tumor type. To the best of our knowledge, a comprehensive overview is lacking. Here, we review the current state of liquid biopsy research for the most common non-central nervous system pediatric solid tumors. These include neuroblastoma, renal tumors, germ cell tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and other soft tissue sarcomas, and liver tumors. Within this selection, we discuss the most important or recent studies involving liquid biopsy-based biomarkers, anticipated clinical applications, and the current challenges for success. Furthermore, we provide an overview of liquid biopsy-based biomarker publication output for each tumor type based on a comprehensive literature search between 1989 and 2023. Per study identified, we list the relevant liquid biopsy-based biomarkers, matrices (e.g., peripheral blood, bone marrow, or cerebrospinal fluid), analytes (e.g., circulating cell-free and tumor DNA, microRNAs, and circulating tumor cells), methods (e.g., digital droplet PCR and next-generation sequencing), the involved pediatric patient cohort, and proposed applications. As such, we identified 344 unique publications. Taken together, while the liquid biopsy field in pediatric oncology is still behind adult oncology, potentially relevant publications have increased over the last decade. Importantly, steps towards clinical implementation are rapidly gaining ground, notably through validation of liquid biopsy-based biomarkers in pediatric clinical trials.
The METRIC-framework for assessing data quality for trustworthy AI in medicine: a systematic review
Authors: Schwabe Daniel , Becker Katinka , Seyferth Martin , Klaß Andreas , Schaeffter Tobias
Published: August 2024

The adoption of machine learning (ML) and, more specifically, deep learning (DL) applications into all major areas of our lives is underway. The development of trustworthy AI is especially important in medicine due to the large implications for patients’ lives. While trustworthiness concerns various aspects including ethical, transparency and safety requirements, we focus on the importance of data quality (training/test) in DL. Since data quality dictates the behaviour of ML products, evaluating data quality will play a key part in the regulatory approval of medical ML products. We perform a systematic review following PRISMA guidelines using the databases Web of Science, PubMed and ACM Digital Library. We identify 5408 studies, out of which 120 records fulfil our eligibility criteria. From this literature, we synthesise the existing knowledge on data quality frameworks and combine it with the perspective of ML applications in medicine. As a result, we propose the METRIC-framework, a specialised data quality framework for medical training data comprising 15 awareness dimensions, along which developers of medical ML applications should investigate the content of a dataset. This knowledge helps to reduce biases as a major source of unfairness, increase robustness, facilitate interpretability and thus lays the foundation for trustworthy AI in medicine. The METRIC-framework may serve as a base for systematically assessing training datasets, establishing reference datasets, and designing test datasets which has the potential to accelerate the approval of medical ML products.
Optimizing green and gray infrastructure planning for sustainable urban development
Authors: van Oorschot Janneke , Slootweg Mike , Remme Roy P. , Sprecher Benjamin , van der Voet Ester
Published: August 2024

The anticipated increase in urban population of 2.5 billion people by 2050 poses significant environmental challenges. While the various environmental impacts of urbanisation have been studied individually, integrated approaches are rare. This study introduces a spatially explicit model to assess urbanization’s effects on ecosystem services (green infrastructure availability, cooling, stormwater retention) and the environmental impact of building construction (material demand, greenhouse gas emissions, land use). Applied to the Netherlands from 2018 to 2050, our results show that integrating green infrastructure development with building construction could increase green areas by up to 5% and stabilize or increase ecosystem service provisioning. Dense building construction with green infrastructure development is generally more beneficial across the Netherlands, reducing resource use and enhancing ecosystem services. Conversely, sparse construction with green infrastructure is more advantageous for newly built areas. These findings offer insights into the environmental consequences of urbanization, guiding sustainable urban planning practices.
The increase of an allelopathic and unpalatable plant undermines reindeer pasture quality and current management in the Norwegian tundra
Authors: Tuomi Maria W. , Utsi Tove Aagnes , Yoccoz Nigel Gilles , Armstrong Claire W. , Gonzalez Victoria , Hagen Snorre B. , Jónsdóttir I. S. , Pugnaire Francisco I. , Shea Katriona , Wardle David A. , Zielosko Sophia , Bråthen Kari Anne
Published: August 2024

Ongoing Arctic greening can increase productivity and reindeer pasture quality in the tundra. However, greening may also entail proliferation of unpalatable species, with consequences for pastoral social-ecological systems. Here we show extensive greening across 20 reindeer districts in Norway between 2003 and 2020, which has reduced pasture diversity. The allelopathic, evergreen dwarf-shrub crowberry increased its biomass by 60%, with smaller increases of deciduous shrubs and no increase in forbs and graminoids, the most species rich growth forms. There was no evidence for higher reindeer densities promoting crowberry. The current management decision-making process aims at sustainable pasture management but does not explicitly account for pasture changes and reduced diversity. Large-scale shifts towards evergreening and increased allelopathy may thus undermine the resource base for this key Arctic herbivore and the pastoral social-ecological system. Management that is sensitive to changes in pasture diversity could avoid mismanagement of a social-ecological system in transition.
Synergistic atmosphere-ocean-ice influences have driven the 2023 all-time Antarctic sea-ice record low
Authors: Wang Jinfei , Massonnet François , Goosse Hugues , Luo Hao , Barthélemy Antoine , Yang Qinghua
Published: August 2024

Antarctic sea ice extent (SIE) reached a new record low in February 2023. Here we examine the evolution of the coupled ocean-atmosphere-sea ice system during the 12 months preceding the record. The impact of preceding conditions is assessed with observations, reanalyses, and output from the regional ocean-sea ice coupled model NEMO3.6-LIM3. We find that the 2022-2023 sea ice annual cycle was characterized by consistently low SIE throughout the year, anomalously rapid sea ice retreat in December 2022, and nearly circumpolar negative SIE anomalies in February 2023. While advection-induced positive air temperature anomalies inhibited the sea ice growth in most regions, strong southerly winds in the Amundsen-Ross Sea caused by an anomalously deep Amundsen Sea Low in spring transported notable volumes of sea ice northward, triggering an unusually active ice-albedo feedback onshore and favoring accelerated melt towards the minimum. This study highlights the impacts of multifactorial processes during the preceding seasons to explain the recent summer sea ice minima.
Interlayer ionic diffusion driven in situ QD-deposition in the Co9S8–LDH hybrid supercapacitor electrode
Authors: Zhang Yanan , Xu Nuo , Xu Jipeng , Shan Chi , Chen Junlei , Guo Liyuan , Qin Long , Wu Fan , Huang Wenhuan
Published: August 2024

QDs-Co9S8/CoNi-LDH was assembled by selective sulfurization derived from 2D MOF with the loading of Co9S8 quantum dots into layered double hydroxides. The constructed hybrid supercapacitor shown energy density of 33.3 Wh kg−1 at 820.0 W kg−1.
Selective binding of nitrate by a neutral bis(calix[4]pyrrole) [2]rotaxane
Authors: Li Yifan , Molina-Muriel Ricardo , Aragay Gemma , Ballester Pablo
Published: August 2024

Remarkable selectivity for nitrate by a neutral [2]rotaxane based on a bis(calix[4]pyrrole) macrocycle.
Early emission lines in SN 2024ggi revealed by high-resolution spectroscopy
Authors: Pessi Thallis , Cartier Régis , Hueichapan Emilio , de Brito Silva Danielle , Prieto Jose L. , Muñoz Ricardo R. , Medina Gustavo E. , Diaz Paula , Li Ting S.
Published: August 2024

Context. We present an analysis of very early high-resolution spectroscopic observations of the Type II supernova (SN) 2024ggi, a nearby SN that occurred in the galaxy NGC 3621 at a distance of 7.24 Mpc (z ≈ 0.002435). These observations represent the earliest high-resolution spectra of a Type II SN ever made.

Aims. We analyzed the very early-phase spectroscopic evolution of SN 2024ggi obtained in a short interval at 20.6 and 27.8 h after its discovery, or 26.6 and 33.8 h after the SN first light. Observations were obtained with the high-resolution spectrograph MIKE (R ≈ 22 600 − 28 000) at the 6.5 m Magellan Clay Telescope, located at the Las Campanas Observatory, on the night of April 12, 2024 UT.

Methods. The emission lines were identified and studied in detail during the first hours of SN 2024ggi. We analyzed the evolution of ions of H I, He I, He II, N III, C III, Si IV, N IV, and C IV detected across the spectra. We modeled these features with multiple Gaussian and Lorentzian profiles, and estimated their velocities and full widths at half maximum (FWHMs).

Results. The spectra show asymmetric emission lines of H I, He II, C IV, and N IV that can be described by narrow Gaussian cores (FWHM ≤ 200 km s−1) with broader Lorentzian wings, and symmetric narrow emission lines of He I, N III, and C III. The emission lines of He I are detected only in the first spectrum, indicating the rapid ionization of He I to He II. The narrow components of the emission lines show a systematic blueshift relative to their zero-velocity position, with an increase of ∼18 km s−1 in the average velocity between the two epochs. The broad Lorentzian components show a blueshift in velocity relative to the narrow components, and a significant increase in the average velocity of ∼103 km s−1. Such a rapid evolution and significant ionization changes in a short period of time were never observed before, and are probably a consequence of the radiative acceleration generated in the SN explosion.
Charting the Lyman-α escape fraction in the range 2.9 < z < 6.7 and consequences for the LAE reionisation contribution
Authors: Goovaerts I. , Thai T. T. , Pello R. , Tuan-Anh P. , Laporte N. , Matthee J. , Nanayakkara T. , Pharo J.
Published: August 2024

Context. The escape of Lyman-α photons at redshifts greater than two is an ongoing subject of study and an important quantity to further understanding of Lyman-α emitters (LAEs), the transmission of Lyman-α photons through the interstellar medium and intergalactic medium, and the impact these LAEs have on cosmic reionisation.

Aims. This study aims to assess the Lyman-α escape fraction, fesc, Lyα, over the redshift range 2.9 < z < 6.7, focusing on Very Large Telescope/Multi Unit Spectroscopic Explorer (VLT/MUSE) selected, gravitationally lensed, intrinsically faint LAEs. These galaxies are of particular interest as the potential drivers of cosmic reionisation.

Methods. We assessed fesc, Lyα in two ways: through an individual study of 96 LAEs behind the A2744 lensing cluster, with James Webb Space Telescope/Near-Infrared Camera (JWST/NIRCam) and HST data, and through a study of the global evolution of fesc, Lyα using the state-of-the-art luminosity functions for LAEs and the UV-selected ‘parent’ population (dust-corrected). We compared these studies to those in the literature based on brighter samples.

Results. We find a negligible redshift evolution of fesc, Lyα for our individual galaxies; it is likely that it was washed out by significant intrinsic scatter. We observed a more significant evolution towards higher escape fractions with decreasing UV magnitude and fit this relation. When comparing the two luminosity functions to derive fesc, Lyα in a global sense, we saw agreement with previous literature when integrating the luminosity functions to a bright limit. However, when integrating using a faint limit equivalent to the observational limits of our samples, we observed enhanced values of fesc, Lyα, particularly around z ∼ 6, where fesc, Lyα becomes consistent with 100% escape. This indicates for the faint regimes we sampled that galaxies towards reionisation tend to allow very large fractions of Lyman-α photons to escape. We interpret this as evidence of a lack of any significant dust in these populations; our sample is likely dominated by young, highly star-forming chemically unevolved galaxies. Finally, we assessed the contribution of the LAE population to reionisation using our latest values for fesc, Lyα and the LAE luminosity density. The dependence on the escape fraction of Lyman continuum photons is strong, but for values similar to those observed recently in z ∼ 3 LAEs and high-redshift analogues, LAEs could provide all the ionising emissivity necessary for reionisation.
Corporate governance and the internationalisation of African firms: An institutional investor perspective
Authors: Anderhofstadt Dominik , Wesson Nicolene , Viviers Suzette
Published: August 2024

The aim of this study was to investigate the impact of corporate governance on the internationalisation of African firms from the perspective of institutional investors. While African firms have significantly expanded their international operations over the past two decades, international business literature has not given the related corporate governance aspects enough attention. In particular, the complex interaction between firm-level corporate governance mechanisms and country-level corporate governance systems has considerable implications for the value creation of internationalisation strategies. To address this research gap, semi-structured interviews were conducted with 24 senior decision-makers of institutional investors operating in South Africa, Botswana, Zambia, Mauritius, Ghana, and Nigeria to gain an unprecedented view of the internationalisation of African firms. Based on the findings of the thematic analysis, this study developed a theoretical framework of high practical relevance that combines the concepts of corporate governance and internationalisation in the dynamic and diverse African context. The study further provides novel insights into the cultural dimension of corporate governance by demonstrating that the outcome of corporate governance practices depends on cultural norms and values across a multinational firm’s international operations.
Paternal exposure: two patients’ perspectives in an evolving landscape of therapeutics. Can we now provide reassurance?
Authors: Narayan Bhaskar , Asfour Leila
Published: August 2024

There is now substantial evidence of safety in pregnancy for several newer medications, particularly biologic disease-modifying antirheumatic drugs, although clinician confidence varies. There is much less information available regarding paternal exposure. This article provides insight from two patients who describe the impact of family planning on their therapeutic decision making.
Early Modern Histories of Fire on the Australian Continent
Authors: Broomhall Susan
Published: August 2024

This essay explores early modern European records of fire behaviours on the Australian continent. In particular, it analyses the perspectives provided in hitherto relatively unexplored records of the Dutch East India Company (VOC) and situates these in relation to contemporary English and later French and British accounts of fire practices. It argues that knowledge, use and textual record of fire practices constituted a key form of power for Europeans, a site of invasion and a tool of violence. Fire produced knowledge of people, of their resources and of their technologies, particularly their weaponry. Fire could be harnessed for European possession. Fire communicated distinctiveness in these records, marking a boundary between Aboriginal peoples and Europeans, and, on some occasions, interactions around fire with Indigenous people aimed to transition local peoples to new technologies and to presumed civilisation. In their own practices, in their perceptions of Aboriginal fire behaviours and in the written accounts that they produced from their experiences, Europeans form part of the story of early modern histories of Antipodean fire. Understanding what such sources reveal and what they obscure can assist in situating them appropriately in modern discussions about historic fire behaviours on the Australian continent.
Niche differentiation within bacterial key-taxa in stratified surface waters of the Southern Pacific Gyre
Authors: Oggerin Monike , Viver Tomeu , Brüwer Jan , Voß Daniela , García-Llorca Marina , Zielinski Oliver , Orellana Luis H , Fuchs Bernhard M
Published: August 2024

One of the most hostile marine habitats on Earth is the surface of the South Pacific Gyre (SPG), characterized by high solar radiation, extreme nutrient depletion, and low productivity. During the SO-245 “UltraPac” cruise through the center of the ultra-oligotrophic SPG, the marine alphaproteobacterial group AEGEAN169 was detected by fluorescence in situ hybridization at relative abundances up to 6% of the total microbial community in the uppermost water layer, with two distinct populations (Candidatus Nemonibacter and Ca. Indicimonas). The high frequency of dividing cells combined with high transcript levels suggests that both clades may be highly metabolically active. Comparative metagenomic and metatranscriptomic analyses of AEGEAN169 revealed that they encoded subtle but distinct metabolic adaptions to this extreme environment in comparison to their competitors SAR11, SAR86, SAR116, and Prochlorococcus. Both AEGEAN169 clades had the highest percentage of transporters per predicted proteins (9.5% and 10.6%, respectively). In particular, the high expression of ABC transporters in combination with proteorhodopsins and the catabolic pathways detected suggest a potential scavenging lifestyle for both AEGEAN169 clades. Although both AEGEAN169 clades may share the genomic potential to utilize phosphonates as a phosphorus source, they differ in their metabolic pathways for carbon and nitrogen. Ca. Nemonibacter potentially use glycine-betaine, whereas Ca. Indicimonas may catabolize urea, creatine, and fucose. In conclusion, the different potential metabolic strategies of both clades suggest that both are well adapted to thrive resource-limited conditions and compete well with other dominant microbial clades in the uppermost layers of SPG surface waters.
Administering the maternal bovine appeasing substance improves overall productivity and health in high-risk cattle during a 60-d feedlot receiving period
Authors: Pickett Autumn T , Cooke Reinaldo F , de Souza Izadora S , Mackey Shea J
Published: August 2024

This experiment evaluated health, physiological, and performance responses of high-risk cattle administered the maternal bovine appeasing substance (mBAS) during feedlot receiving. Angus-influenced, newly weaned male calves (n = 120) were purchased from an auction facility. Calves arrived at the research feedyard on day −1 and body weight (BW) was recorded upon arrival (199 ± 1 kg). Calves were ranked by arrival BW and received 1 of 2 treatments prior to initial processing (day 0): (1) 10 mL of an mBAS (Ferappease; FERA Diagnostics and Biologicals; College Station, TX) or (2) 10 mL of mineral oil (CON; placebo). Treatments were applied topically to the nuchal skin area (5 mL) and above the muzzle (5 mL). Calves were vaccinated against Clostridium and respiratory pathogens, dewormed, implanted, band-castrated, and received metaphylaxis at initial processing, and then distributed into 10 drylot pens according to arrival BW and treatment (n = 12 calves/pen, 5 pens/treatment). Calves were reapplied treatments (mBAS or CON) concurrently with booster vaccination on d 14. Feed intake and incidence of bovine respiratory disease (BRD) were recorded daily. Blood and hair samples from the tail-switch were collected on days 0, 14, 28, 42, and 60 for analysis of physiological variables. Calves were sampled for nasal microbiota analysis via swab on days 0, 14, and 28. Final shrunk BW was recorded on day 61 after 16 h of feed and water restriction. Calf BW gain and final BW did not differ between treatments (P ≥ 0.40). Incidence of BRD was similar (P = 0.99) between mBAS and CON (56.7% for both treatments; SEM = 6.45). A greater (P = 0.04) proportion of mBAS calves diagnosed with BRD required a single antibiotic treatment to regain health (70.6 vs. 47.0%; SEM = 8.32), and mortality was greater (P = 0.03) in CON calves diagnosed with BRD (17.6 vs. 2.94%; SEM = 5.133). Relative abundance of Mycoplasma in nasal microbiota was reduced (P = 0.04) in mBAS calves compared with CON (34.7 vs. 27.4%; SEM = 2.35). Cortisol concentration in hair from the tail-switch was less (P = 0.01) on day 28 for mBAS calves compared with CON. Administering mBAS improved (P = 0.04) total pen-based liveweight change during the experiment (498 vs. 309 kg/pen; SEM = 65.2) and final pen-based total liveweight (2,676 vs. 2,484 kg/pen; SEM = 65.4). Administration of mBAS to high-risk cattle decreased physiological stress markers, reduced mortality, and increased pen-based productivity during a 60-d receiving period.
Methodological Considerations in Evaluating Breast Cancer Screening Studies
Authors: Narayan Anand K , Miles Randy C , Woods Ryan W , Spalluto Lucy B , Burnside Elizabeth S
Published: August 2024

In evidence-based medicine frameworks, the highest level of evidence is derived from quantitative synthesis of double-masked, high-quality, randomly assigned controlled trials. Meta-analyses of randomly assigned controlled trials have demonstrated that screening mammography reduces breast cancer deaths. In the United States, every major guideline-producing organization has recommended screening mammography in average-risk women; however, there are controversies about age and frequency. Carefully controlled observational research studies and statistical modeling studies can address evidence gaps and inform evidence-based, contemporary screening practices. As breast imaging radiologists develop and evaluate existing and new screening tests and technologies, they will need to understand the key methodological considerations and scientific criteria used by policy makers and health service researchers to support dissemination and implementation of evidence-based screening tests. The Wilson and Jungner principles and the U.S. Preventive Services Task Force general analytic framework provide structured evaluations of the effectiveness of screening tests. Key considerations in both frameworks include public health significance, natural history of disease, cost-effectiveness, and characteristics of screening tests and treatments. Rigorous evaluation of screening tests using analytic frameworks can maximize the benefits of screening tests while reducing potential harms. The purpose of this article is to review key methodological considerations and analytic frameworks used to evaluate screening studies and develop evidence-based recommendations.
SNX10 regulates osteoclastogenic cell fusion and osteoclast size in mice
Authors: Barnea-Zohar Maayan , Stein Merle , Reuven Nina , Winograd-Katz Sabina , Lee Sooyeon , Addadi Yoseph , Arman Esther , Tuckermann Jan , Geiger Benjamin , Elson Ari
Published: August 2024

Bone-resorbing osteoclasts (OCLs) are formed by differentiation and fusion of monocyte precursor cells, generating large multinucleated cells. Tightly regulated cell fusion during osteoclastogenesis leads to formation of resorption-competent OCLs, whose sizes fall within a predictable physiological range. The molecular mechanisms that regulate the onset of OCL fusion and its subsequent arrest are, however, largely unknown. We have previously shown that OCLs cultured from mice homozygous for the R51Q mutation in the vesicle trafficking-associated protein sorting nexin 10, a mutation that induces autosomal recessive osteopetrosis in humans and in mice, display deregulated and continuous fusion that generates gigantic, inactive OCLs. Fusion of mature OCLs is therefore arrested by an active, genetically encoded, cell-autonomous, and SNX10-dependent mechanism. To directly examine whether SNX10 performs a similar role in vivo, we generated SNX10-deficient (SKO) mice and demonstrated that they display massive osteopetrosis and that their OCLs fuse uncontrollably in culture, as do homozygous R51Q SNX10 (RQ/RQ) mice. OCLs that lack SNX10 exhibit persistent presence of DC-STAMP protein at their periphery, which may contribute to their uncontrolled fusion. To visualize endogenous SNX10-mutant OCLs in their native bone environment, we genetically labeled the OCLs of WT, SKO, and RQ/RQ mice with enhanced Green Fluorescent Protein (EGFP), and then visualized the 3D organization of resident OCLs and the pericellular bone matrix by 2-photon, confocal, and second harmonics generation microscopy. We show that the volumes, surface areas and, in particular, the numbers of nuclei in the OCLs of both mutant strains were on average 2–6-fold larger than those of OCLs from WT mice, indicating that deregulated, excessive fusion occurs in the mutant mice. We conclude that the fusion of OCLs, and consequently their size, is regulated in vivo by SNX10-dependent arrest of fusion of mature OCLs.
A post in an internet forum led to a discovery of an invasive drywood termite in Korea,Cryptotermes domesticus(Haviland) (Blattodea: Kalotermitidae)
Authors: Lee Sang-Bin , Lee Heejo , Song Jongwon , Jang Beom-jun , Cho Sang Moon , Yum Jinwhoa , Ahn Neung-Ho , Kim Jungae , Lee Hyunjik , Choi Yong-Seok , Lee Hyun Mi , Seo Min Seok , Lee Hyobin , Son Seokyoung , Bergbower Hunter , Lim Kukhyun , Su Nan-Yao , Lee Wonhoon
Published: August 2024

Invasive drywood termites are one of the most challenging species to detect in the early invasion process as they can infest a small piece of wood and be transported by human activity. Cryptotermes domesticus (Haviland, 1898) is native to south Asia and Australia and has been introduced into many other Asian countries and pacific islands, where they cause damage to furniture and wooden structures. Recently, an established colony of C. domesticus has been found in the Seoul metropolitan area, Republic of Korea, where drywood termites were not thought to be able to establish due to low winter temperatures. The discovery of C. domesticus was initiated from a post on an internet forum in which an anonymous homeowner collected alates in an apartment and asked for pest identification. This information was readily delivered to professional entomologists, and a task force was formed for inspection. During the thorough inspection, an infested sliding door frame was identified and a colony of C. domesticus was found. Instead of fumigation and localized pesticide treatment, the door and frame were removed and replaced, which was the most cost-effective control measure as the colony was only found there. Since the potential spread of C. domesticus is uncertain, the task force collaborated with the media, including newspapers and broadcasting news, to disseminate information to help recognize any additional unreported infestations. This study provides insights on how to cooperate with the media and citizens when a new invasive species is found.
Prediction of birthdates based on fetal development in Bighorn Sheep (Ovis canadensis)
Authors: Argov Jonathan R , Michaels Nesha B , Smiley Rachel A , Wagler Brittany L , Gavin Jack N , Courtemanch Alyson B , Clause Dean , Kaiser Rusty C , Lutz Daryl , Scurlock Brandon , Monteith Kevin L
Published: August 2024

Reproductive phenology is a critical element of how animals persist in their environment and affects survival of young, especially in seasonal environments. We investigated the correlation between fetal eye diameter and birth timing to determine if birthdates could be predicted by a prenatal metric. We used ultrasonography to measure eye diameters of fetuses and vaginal implant transmitters to determine birthdates of Rocky Mountain Bighorn Sheep (Ovis canadensis canadensis) in Wyoming, United States, from 2019 to 2023. Fetal eye diameter strongly predicted days until birth (β = −2.8; pseudo-R2 = 0.88). Effective prediction of birthdates via ultrasonography can yield opportunities for logistical planning in neonatal studies, monitoring changes in reproductive phenology, and evaluating questions of resource allocation relative to reproductive processes.
The association of the US–Mexico border wall extension on deaths from harsh land conditions
Authors: Tenorio Alexander , McCann Carson P , Young Janine , Hill Linda L , Doucet Jay J , Levy Michael
Published: August 2024

Utilizing data from the Missing Migrants Project, we compared deaths due to harsh conditions before the wall fortification vs after. Texas had a modest increase in deaths while Arizona and California had significant increases. Although multifaceted, this change in deaths due to harsh land conditions raises concerns about migration patterns.
Dust rings trap protoplanets on eccentric orbits and get consumed by them
Authors: Velasco-Romero David A , Masset Frédéric S , Morbidelli Alessandro , Benítez-Llambay Pablo , Krapp Leonardo , Lega Elena
Published: August 2024

We study the orbital evolution and mass growth of protoplanets with masses $M \in [0.1{\!-\!}8]$ M$_{{\oplus }}$ in the vicinity of a dusty ring, using three-dimensional numerical simulations with a two-fluid model and nested-meshes. We find two stable, eccentric orbits that lock the planet in the ring vicinity, thereby inhibiting its migration and allowing it to accrete dust from the ring. One of these orbits has an eccentricity comparable to the aspect ratio of the gaseous disc and has its periastron within the ring, enabling intermittent accretion during each pass. The other orbit has a smaller eccentricity and an apoastron slightly inside the ring. A planet locked at the outer orbit efficiently accretes from the ring and can reach the critical mass for runaway gas accretion on time-scales $\gtrsim 10^5$ yr (for a 10 M$_{{\oplus }}$ dust ring at 10 au), while a planet locked at the inner orbit has a slower growth and might not supersede the super-Earth stage over the disc lifetime. While in our runs a low-mass embryo forming within the ring eventually joins the outer orbit, it is likely that the path taken depends on the specific details of the ring. The trapping on the outer orbit arises from an intermittent, strong thermal force at each passage through the ring, where the accretion rate spikes. It is insensitive to uncertainties that plague models considering planets trapped on circular orbits in rings. It is highly robust and could allow a growing planet to follow an expanding ring over large distances.
Multicentric reticulohistiocytosis with oral and laryngeal involvement in association with autoimmune/inflammatory syndrome induced by adjuvants: Expanding the spectrum of two uncommon entities
Authors: Girolami Ilaria , Kluge Reinhard Walter , Gallmetzer Lorenz , Albi Cecilia , Sorgi Paola , Dejaco Christian , Tauber Martina , Hanspeter Esther , Matzneller Peter
Published: August 2024

Multicentric reticulohistiocytosis (MRH) is the most frequent entity in the group of reticulohistiocytoses. It is usually accompanied by symmetrical erosive polyarthritis and is frequently associated with cancer and autoimmune disorders. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is an inflammatory syndrome triggered by adjuvants such as those contained in vaccines or by silicone implants. Here, we report the case of a 71-year-old woman with a history of breast cancer treated with surgery and subsequent prosthesis who developed a systemic hyperinflammatory syndrome including seronegative symmetric polyarthritis, multiple skin lesions, and two large nodular lesions in the oral cavity and larynx. The clinical picture was consistent with a clinical diagnosis of ASIA, with breast implant rupture and/or vaccination against severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) as possible triggers. Histopathology of skin, oral nodules, and laryngeal nodules revealed cutaneous/mucous and submucosal infiltration of large epithelioid mononuclear or binucleated cells with fine granular ground glass-like cytoplasm and round to kidney-shaped nuclei with prominent nucleoli, without atypical features or relevant pleomorphism, accompanied by sparse giant cells and lymphocytes. These cells stained positive for CD68 and CD45 and negative for S100, CD1a, and markers of epithelial or neural/melanocytic differentiation, altogether consistent with a diagnosis of reticulohistiocytosis. Clinicopathological correlation allowed the final diagnosis of MRH. To our knowledge, this is the first report of a co-occurrence of MRH with ASIA, and this is relevant to broaden the spectrum of both these rare diseases.
Arthroscopic treatment of septic arthritis of the ankle joint caused by streptococcus in patients with chronic inflammatory diseases: Two case reports
Authors: Okamura Gensuke , Hirao Makoto , Noguchi Takaaki , Etani Yuki , Ebina Kosuke , Miura Taihei , Tsuboi Hideki , Goshima Atsushi , Okada Seiji , Hashimoto Jun
Published: August 2024

This report describes the arthroscopic treatment of septic arthritis of the ankle joint in two patients with inflammatory diseases, including rheumatoid arthritis and nail psoriasis. We treated both the ankle joints with antibiotic administration and urgent arthroscopic synovectomy and irrigation, although the procedure was performed several days (4 and 6 days) after the time at which the infection would have occurred. Fortunately, no recurrence has been seen for >18 and 20 months, respectively, after surgery, without antibiotic administration. Although septic arthritis of the ankle joint accounts for a small proportion of joint arthritis cases, diagnosis as early as possible is important. Our experience suggests that arthroscopic synovectomy and irrigation are effective for septic ankle arthritis even in chronic inflammatory disease cases.
BSBM-04 THE MULTI-OMIC LANDSCAPE OF SOMATIC VARIATION ACROSS A PAN-CANCER COHORT OF BRAIN METASTASES
Authors: Hall Grace , Campbell Bethany , Stylli Stanley , Jung Chol-Hee , Pope Bernard , Park Daniel , Molania Ramyar , Bedo Justin , Ureta Jennifer , Rodrigues Silvia , Fidalgo-Ribeiro Caroline , Loda Massimo , McCoy Patrick , Gray Clint , Tan Swee , Wickremesekera Agadha , Saunders Christobel , Drummond Kate , Corcoran Niall , Dimou James , Papenfuss Tony , Hovens Christopher
Published: August 2024

INTRODUCTION

Brain metastases pose a significant and growing challenge in clinical practice, yet the molecular variants of this tumor type has not previously been examined comprehensively across multiple cancer types. In particular, there has been limited focus on contrasting the genetic profiles of common brain metastases originating from primary sites like lung, breast, melanoma, colorectal, and renal cancers, with those arising infrequently such as prostate and others.

METHODS

We have prospectively collected over 125 fresh frozen brain metastases and matching germline reference samples from 14 different primary tumor types and to date have performed WGS, RNA-Seq and Epic 850k methylation profiling on 60 of these samples spanning both common and rare brain metastases. We have employed machine learning algorithms, network analysis techniques, and integrative bioinformatics pipelines to extract meaningful insights into the biological underpinnings of brain metastasis formation.

RESULTS

We conducted an in-depth investigation into the genomic, transcriptomic, and epigenomic profiles of brain metastases, spanning both common and rare types. By merging these diverse datasets, we identified distinct molecular modifications linked to brain metastases with low incidence rates compared to those more frequently observed. Notably, we observed heightened alterations in the regulation of Golgi dynamics, sensing of lipid species, chromatin remodeling factors, and cytoskeletal remodeling in rare brain metastases. These changes likely influence cell migration and invasion dynamics, elucidating the potential for unique characteristics of less common brain metastasis types.

CONCLUSIONS

This research indicates that the molecular mechanisms driving the formation of brain metastases may vary depending on whether the primary malignancy frequently or infrequently spreads to the brain. Studies such as these, will aid in eventually driving innovations in precision oncology and ultimately improving patient outcomes.
BSBM-09 ASTROCYTES MEDIATE PARACRINE ACTIVATION OF FGFR1 TO ER+ BREAST CANCER BRAIN METASTASES
Authors: Jaramillo-Gómez Jenny A , Fox Morgan , Cittelly María J Contreras-Zárate Diana M
Published: August 2024

ER+ breast cancer (BC) accounts for ~50% of all BC brain metastases (BCBM) and is severely understudied. By contrast to BM from triple-negative and Her2+ BC, ER+ BCBM occurs mostly in post-menopausal women due to aging or endocrine therapy. Thus, specific interactions with cells within the aged/estrogen-depleted brain tumor microenvironment (TME) may promote ER+ BCBM. Amplification of FGFR1 (a TK receptor that binds canonically to FGF2) is the only genetic alteration shown to predict late recurrence of ER+ BC following anti-estrogen-therapies. Astrocytes promote BM by secreting growth factors that in a paracrine manner activate TK receptors in cancer cells that drive colonization. Thus, we hypothesize that paracrine activation of FGFR1 by astrocytes contributes to estrogen-independent ER+ BCBM outgrowth, and changes in FGFR1 ligand-expression in the brain TME may influence the ability of ER+ BC to colonize the brain niche. Using in vitro co-culture systems, we demonstrate that conditioned media from astrocytes (CMAst) promotes estrogen-independent proliferation and tumor-initiating capability of ER+ FGFR1-amplified PDX-derived cell lines (UCD65). CMAst activated FGFR1 and downstream signaling in ER+ cells, but FGFR1 inhibitors had modest ability to block this signaling, suggesting astrocytes activate FGFR1 dependent and independent pathways. FGFR1 KD impaired the growth of ER+ cells when cultured with CMAst but abolished their growth when co-cultured directly on astrocytes, suggesting FGFR1 is critical for cancer cell-astrocyte direct interactions. Young astrocytes promoted cancer cells proliferation more effectively than aged astrocytes and FGF2 decreased in astrocytes from aged mice compared to young mice, suggesting that FGF2/FGFR1 interactions promote ER+ growth in the young but not the old brain TME. Moreover, ER+ BC cells were able to invade in brain slices from old but not young mice, suggesting that loss of canonical FGF2/FGFR1 signaling (and possibly activation of non-canonical FGFR1 functions) promote metastases in the older brain TME.
BSBM-12 TARGETING OSIMERTINIB-RESISTANT BRAIN METASTASIS USING RAR ANTAGONISTS
Authors: Biswas Anup , Acharyya Swarnali
Published: August 2024

It is estimated that one-third of EGFR-mutant lung cancer patients develop brain metastasis during the course of their disease. Brain metastasis is associated with a significant decline in cognitive and motor function, daily functioning, and accelerated mortality. Brain metastasis is a severe complication for 45% of patients with EGFR-mutant lung cancer that drastically reduces their quality of life and survival. Fortunately, EGFR-tyrosine kinase inhibitors (TKIs) such as osimertinib showed excellent blood-brain-barrier permeability and resulted in dramatic responses in patients with brain metastases. However, despite a striking initial response, osimertinib-treated patients eventually develop relapse, often to the brain, and succumb to death. With this fatal malignancy, it is important to understand underlying mechanisms of brain metastasis to improve treatment outcomes, which is an unmet need in the field. To study mechanisms of brain relapse, we generated osimertinib treatment-response-and-relapse mouse models using human lung cancer cells harboring osimertinib-sensitive EGFR-activating mutations. Using these new brain relapse models of EGFR-mutant lung cancer, we identified that a S100A9-ALDH1A1-RA signaling axis endows cancer cells with the ability to thrive in the brain despite on-target inhibition of EGFR activity by osimertinib. Mechanistically, we show that S100A9 upregulates ALDH1A1 expression and activate the retinoic acid (RA) signaling pathway in cancer cells, which promotes brain relapse. We demonstrate that the genetic repression of S100A9, ALDH1A1, or retinoic acid receptor (RAR) in cancer cells, or treatment with a pan-retinoic-acid-receptor antagonist, dramatically reduces brain metastasis in independent preclinical models of brain relapse. Importantly, S100A9 expression in cancer cells correlates with poor PFS in patients on osimertinib. Based on these preclinical findings, we propose that RAR antagonist treatment can be tested in patients to target osimertinib-resistant brain metastases. Notably, intracellular S100A9 expression in cancer cells can be used as a biomarker to stratify patients who might benefit from this combination treatment.