bluuebunny/crossref_metadata_2025 huggingface dataset:
Faster steroid-free remission with tocilizumab compared to methotrexate in giant cell arteritis: a real-life experience in two reference centres
Authors: Quartuccio Luca , Treppo Elena , De Martino Maria , Pillon Maria , Perniola Simone , Bruno Dario , Isola Miriam , Gremese Elisa
Published: August 2024

Glucocorticoids (GCs) are still the mainstay of treatment of giant cell arteritis (GCA). Although GCs are highly effective in GCA, the high burden of toxicity of GCs as well as the disease relapse during GC tapering is well documented. To compare the efficacy and rapidity of TCZ and MTX as steroid-sparing agents in a real-life cohort of GCA patients. A retrospective analysis was conducted including patients with newly diagnosed GCA from the Rheumatology Units of Udine and Rome. The inclusion criterion was the treatment with TCZ or MTX as first steroid-sparing drug. 112 GCA patients (81 females) with a median age of 70 (IQ 65–75) years were collected. Thirty-one out of 112 (27.7%) patients were treated with TCZ (162 mg/week), while 81/112 (72.3%) patients received MTX (up to 20 mg/week) as a GC-sparing agent. At month 6 after GCA onset, 5/31 (16.1%) patients in TCZ group and none in MTX group were in GC-free sustained remission (p value = 0.001). Similarly, at month 12, 64.5% (20/31) and 11.1% (9/81) of patients were in sustained GC-free remission in TCZ and MTX group, respectively (p value <0.001). At month 24 of follow-up, at least one relapse of the disease occurred in 7/31 (22.6%) in TCZ-treated and 28/81 (34.6%) in MTX-treated patients, respectively (p value = 0.22). TCZ allowed a faster discontinuation of steroid therapy than MTX in GCA patients, without increasing the risk of relapse.
Effect of physical activity on patients of NSCLC
Authors: Min Qi , Xianru Shao , Gengyun Sun
Published: August 2024

Objective

The purpose of this study is to assess the impact of physical activity on both therapeutic efficacy and immune-related adverse events (irAEs) during immunotherapy for non-small cell lung cancer (NSCLC).

Methods

Physical activity was divided into three groups: light physical activity (LPA), moderate physical activity (MPA), and vigorous physical activity (VPA) for laboratory indexes, efficacy, and irAEs. A multivariate logistic regression was employed to analyze the relationship between sedentary behavior with efficacy and irAEs.

Results

The study included 121 patients. The three levels of physical activity were not significantly associated with efficacy or irAEs. However, noteworthy disparities were observed in base-hemoglobin levels (F = 3.4, P = 0.037) and base-lymphocyte levels (χ2 = 6.13, P = 0.047) among the three groups. After treatment, we identified statistically significant variations in albumin levels (P = 0.012) and lymphocyte counts (P = 0.035). Furthermore, a negative correlation emerged between pre-treatment sedentary behavior duration and immune-efficacy (β: −0.005, P = 0.027).

Conclusions

In summary, within the cohort of NSCLC patients undergoing single immunotherapy or a combination of immunotherapy and chemotherapy, physical activity is closely related to immune and inflammatory indicators in patients, and prolonged sitting will reduce the therapeutic effect.
Influence of confining pressure on rock fracture propagation under particle impact
Authors: Li Dong , Li Xing , Liu Huaiqian , Liu Yong
Published: August 2024

Revealing the influence of confining pressure on the propagation and formation mechanism of rock cracks under particle impact is significant to deep rock excavation. In this study, the three-dimensional fracture reconstruction of the rock after particle impact was carried out by CT scanning, and the stress and crack field evolution of the rock under particle impact were analyzed by PFC2D discrete element numerical simulation. The results demonstrate that after particles impact, a fracture zone and intergranular main crack propagation zone are formed in the rock. The shear stress and tensile stress caused by compressive stress are the main reasons for the formation of the fracture zone, while the formation of the intergranular main crack propagation zone is mainly due to tangential derived tensile stress. The confining pressure induces prestress between rock particles such that the derived tensile stress needs to overcome the initial compressive stress between the particles to form tensile fractures. And the increase in the confining pressure leads to increases in the proportion of shear cracks and friction effects between rock particles, resulting in an increase in energy consumption for the same number of cracks. From a macroscopic perspective, the confining pressure can effectively inhibit the generation of cracks.
Rising potentials of epigallocatechin gallate (EGCG) loaded lipid-based delivery platforms for breast cancer
Authors: Nag Sagnik , Bhunia Adrija , Mohanto Sourav , Ahmed Mohammed Gulzar , Subramaniyan Vetriselvan
Published: August 2024

Breast cancer is a major global health concern that requires the development of innovative treatment strategies. Epigallocatechin gallate (EGCG), a polyphenolic phytocompound found abundantly in green tea, has exhibited potential anti-cancer properties, including anti-inflammatory, anti-oxidant, anti-angiogenic, and anti-proliferative effects. However, the clinical translation of EGCG is hindered by its poor bioavailability and stability. Lipid-based nanocarriers have materialized as an optimistic platform for encapsulating various therapeutics due to their high drug-loading capacity, stability, biocompatibility, and versatility. The rationale for encapsulating EGCG-loaded lipid nanoparticles is to enhance the therapeutic efficacy, bioavailability, and targeted delivery of EGCG for breast cancer treatment. This targeted delivery minimizes off-target effects and enhances the accumulation of EGCG within tumors or diseased tissues in a controlled or sustained manner, reducing systemic toxicity. In addition, co-delivery of EGCG with synergistic agents can enhance therapeutic efficacy through complementary mechanisms of action, overcome biological barriers, and can be combined with other treatment modalities, i.e., radiation therapy, immunotherapy, chemotherapy, etc., to achieve synergistic effectiveness and overcome resistance mechanisms. The advancement of EGCG-loaded lipid nanoparticles exhibits the potential effectiveness of EGCG-based treatments, can overcome the challenges of administering EGCG, and can transform cancer therapy and other biomedical applications.

Graphical abstract

Understanding the potential role of Epigallocatechin gallate (EGCG) in breast cancer treatment through various signaling pathways and further loaded into the lipid-based delivery system for the improvement of mechanical and biological characteristics of the EGCG.
Acceptability and feasibility of integrating psychosocial stimulation interventions in the inpatient care of children with severe acute malnutrition in resource-poor settings: a qualitative study
Authors: Tessema Tesfalem Teshome , Alamdo Andamlak Gizaw , Mekonnen Eyoel B. , Yirtaw Tewodros G. , Debele Fanna A. , Gemechu Teklu , Belachew Tefera
Published: August 2024

Children with Severe Acute Malnutrition (SAM) are at risk of developmental problems. Psychosocial stimulation can improve the developmental outcomes of hospitalised children with SAM. However, the intervention has remained underutilised in health facilities in resource-poor settings. Moreover, there is limited evidence on the acceptability and feasibility of the intervention. We conducted a qualitative study to explore the acceptability and feasibility of integrating psychosocial stimulation interventions in the inpatient care of children with SAM in selected areas in the Silti Zone, Central Ethiopia. Nine focus group discussions and 15 key informant interviews were conducted with parents, health workers, and other stakeholders. The data were transcribed, translated, and analysed using a thematic approach. Caregivers and health workers had positive attitudes toward the intervention and perceived it beneficial for the children’s development, recovery, and bonding with the mothers. Health workers reported barriers such as lack of materials, time, and space, capacity building training, and supervision for the effective implementation of the intervention. At the household level, gendered factors such as the housework burden of mothers and the inadequate engagement of fathers in childcare were the main challenges to the implementation of the intervention. Overall, psychosocial stimulation intervention was found to be acceptable and feasible for routine implementation with inpatient care provided for children with SAM. The study recommends supporting health facilities, health workers, and partners with the necessary resources and skills to promote the implementation of stimulation interventions along with the existing care provided in health facilities in resource-poor settings.
Do Local Roots Impact Washington Behaviors? District Connections and Representation in the U.S. Congress
Authors: CROSSON JESSE , KASLOVSKY JACLYN
Published: August 2024

Although commentators often point to the political value of legislators’ geographic ties, less is known about the influence of such connections once in office. Given recent scholarship underscoring the importance of geography as a dimension of identity, we argue that local legislators should behave as descriptive representatives. We collect the hometowns of all members of Congress with known birth locations from 1789 to 2020 to analyze how being born near one’s district impacts legislator behavior. We connect these data to information on a series of behaviors, finding that local legislators emphasize constituency work over policymaking and party-building. Moreover, while local legislators do not demonstrate substantively less partisan unity in roll-call voting, they attract a higher percentage of out-party cosponsors to their bills. Together, our results point to important representational implications regarding the geographic roots of legislators and the role of local connections in the contemporary Congress.
The American Viewer: Political Consequences of Entertainment Media
Authors: KIM EUNJI , PATTERSON SHAWN
Published: August 2024

American voters consume an astounding amount of entertainment media, yet its political consequences are often neglected. We argue that this ostensibly apolitical content can create unique opportunities for politicians to build parasocial ties with voters. We study this question in the context of Donald Trump’s unconventional political trajectory and investigate the electoral consequences of The Apprentice. Using an array of data—content analysis, surveys, Twitter data, open-ended answers—we investigate how this TV program helped Trump brand himself as a competent leader and foster viewers’ trust in him. Exploiting the geographic variation in NBC channel inertia, we find that exposure to The Apprentice increased Donald Trump’s electoral performance in the 2016 Republican primary. We discuss the implications of these findings in light of the rise of nonconventional politicians in this golden age of entertainment.
Racial Tropes in the Foreign Policy Bureaucracy: A Computational Text Analysis
Authors: Carson Austin , Min Eric , Van Nuys Maya
Published: August 2024

How do racial stereotypes affect perceptions in foreign policy? Race and racism as topics have long been marginalized in the study of international relations but are receiving renewed attention. In this article we assess the role of implicit racial bias in internal, originally classified assessments by the US foreign policy bureaucracy during the Cold War. We use a combination of dictionary-based and supervised machine learning techniques to identify the presence of four racial tropes in a unique corpus of intelligence documents: almost 5,000 President's Daily Briefs given to Kennedy, Johnson, Nixon, and Ford. We argue and find that entries about countries that the US deemed “racialized Others”—specifically, countries in the Global South, newly independent states, and some specific regional groupings—feature an especially large number of racial tropes. Entries about foreign developments in these places are more likely to feature interpretations that infantilize, invoke animal-based analogies, or imply irrationality or belligerence. This association holds even when accounting for the presence of conflict, the regime type of the country being analyzed, the invocation of leaders, and the topics being discussed. The article makes two primary contributions. First, it adds to the revival of attention to race but gives special emphasis to implicit racialized thinking and its appearance in bureaucratic settings. Second, we show the promise of new tools for identifying racial and other forms of implicit bias in foreign policy texts.
Recent Emerging Shifts in Precipitation Intensity and Frequency in the Global Tropics Observed by Satellite Precipitation Data Sets
Authors: Fu Yuxia , Wu Qiaoyan
Published: August 2024

Climate models indicate that a warmer environment will increase low‐level moisture, potentially intensify extreme precipitation. However, its impact on different rainfall types remains unclear. Using satellite data, we examined changes in light (0‐95th percentile, ≤5.28 mm hr−1) and heavy (95‐100th percentile, >5.28 mm hr−1) precipitation in the tropics from 1998 to 2019. Our findings show a −9 ± 2% (23 ± 2%) change in heavy (light) rain intensity and a 13 ± 2% (−24 ± 1%) change in heavy (light) rain frequency. These changes link to warmer sea surface temperatures, increased atmospheric stability and water vapor, and weakened upward velocity. These insights shed light on how heavy and light precipitation patterns respond to changing climate, emphasizing the complexities within the hydrological cycle.
Fully Developed Open Channel Flow Over Clusters of Freshwater Mussels Partially Buried in a Gravel Bed
Authors: Lazzarin T. , Constantinescu G. , Wu H. , Viero D. P.
Published: August 2024

The present study uses results of eddy‐resolving numerical simulations to investigate the open channel flow over large clusters of freshwater mussels (Unio elongatulus) partially buried in a rough, gravel bed. The density of the mussels forming the array varies from 26 to 500 mussels/m2. The flow structure is analyzed at large distances from the leading edge of the mussel bed, where the flow can be considered fully developed. The effects of changing the mussel bed density, the filtering discharge, the burial level and the roughness of the bed surface in which mussels are burrowed, are investigated in terms of flow field, turbulent structures, drag forces, and bed shear stresses. It is found that strong interactions occur between energetic eddies generated by the larger gravels on the exposed bed surface and by the mussel shells. Simulations results show that for a burial depth close to 50% and a ratio between the average gravel size and the mussel protruding height of 0.13, the shell induced turbulence becomes dominant for mussel bed densities around 50 mussels/m2. The influence of the bed roughness becomes less relevant with increasing mussel density, as the generation of energetic eddies is mostly controlled by mussel‐to‐mussel interactions. For fixed bed roughness, burial level and filtering velocity, the mean streamwise drag force and the associated drag coefficient for the exposed part of each mussel decrease with increasing mussel density, even if strong variations are observed for individual mussels. For constant mussel bed density and burial level, the mean streamwise drag force and the mean drag coefficient decrease slightly with increasing bed roughness. Increasing the burial level decreases not only the drag forces but also the drag coefficients because of the more streamlined shape of the top of the mussels. Strong active filtering acts toward decreasing the mean streamwise force and the mean drag coefficient. The spanwise drag forces contribute significantly to the total drag force, especially for high mussel bed densities. Based on smooth bed calculations, bed‐averaged shear stresses are reduced in highly dense clusters.
Interaction of Cosmic Rays With Magnetic Flux Ropes
Authors: Lara Alejandro , Borgazzi A. , Guennam Eduardo , Niembro Tatiana , Arunbabu K. P.
Published: August 2024

The heliosphere is full of galactic cosmic rays (GCR), high‐energy charged particles coming isotropically from the galaxy. The GCR interact with the solar wind blown by the Sun carrying out plasma, magnetic fields and transient structures such as interplanetary coronal mass ejections (ICMEs) and their associated magnetic flux ropes (MFR). The GCR interaction with ICMEs has been extensively studied particularly the GCR flux attenuation (known as Forbush decreases) as a result of interacting with the ICME sheath and magnetic field. In this work, we investigate the opposite effect: the MFR's ability to generate GCR anisotropies which an observer may detect as an increase in the GCR flux. To achieve this, we simulated a flux of protons with energies in the 10–160 GeV range arriving from all directions to a cylindrical MFR (with and without sheath) with plasma, magnetic field, and spatial dimensions found in average ICMEs observed at 1 au. By following the individual trajectories of the injected particles we found that the MFR deviates the charged particles preferentially in one direction parallel to the MFR–axis. We also found that the peak of this anisotropic GCR flux depends on: the angle between the MFR and ambient magnetic fields; the presence or not of the sheath region; the energy of the incident particles and the observer location inside the MFR.
Hypotheses Concerning Global Magnetospheric Convection, Magnetosphere‐Ionosphere Coupling, and Auroral Activity at Uranus
Authors: Turner Drew L. , Cohen Ian J. , Clark George , Kollmann Peter , Regoli Leonardo , Caggiano Joe , McNutt Ralph , Mauk Barry
Published: August 2024

We investigate the unique magnetosphere of Uranus and its interaction with the solar wind. Following the work of Masters (2014), https://doi.org/10.1002/2014ja020077 and others, we developed and validated a simple yet valuable and illustrative model of Uranus' offset, tilted, and rapidly‐spinning magnetic field and magnetopause (nominal and fit to the Voyager‐2 inbound crossing point) in three‐dimensional space. With this model, we investigated details of the seasonal and interplanetary magnetic field (IMF) orientation dependencies of dayside and flank reconnection along the Uranian magnetopause. We found that anti‐parallel (magnetic field shear angle greater than 170°) reconnection occurs nearly continuously along the Uranian dayside and/or flank magnetopause under all seasons of the 84 (Earth) year Uranian orbit and the most likely IMF orientations. Such active and continuous driving of the Uranian magnetosphere should result in constant loading and unloading of the Uranian magnetotail, which may be further complicated and destabilized by sudden changes in the IMF orientation and solar wind conditions plus the reconfigurations from the rotation of Uranus itself. We demonstrate that unlike the other magnetospheric systems that are Dungey‐cycle driven (i.e., Mercury and Earth) or rotationally driven (Jupiter and Saturn), global magnetospheric convection of plasma, magnetic flux, and energy flow may occur via three distinct cycles, two of which are unique to Uranus (and possibly also Neptune). Our simple model is also used to map signatures of dayside and flank reconnection down to the Uranian ionosphere, as a function of planetary latitude and longitude. Such mapping demonstrates that “spot‐like” auroral features should be very common on the Uranian dayside, consistent with observations from Hubble Space Telescope. We further detail how the combination of Uranus' rapid rotation and unique and very active global magnetospheric convection should be consistent with fueling of the surprisingly intense trapped radiation environment observed by Voyager‐2 during its single flyby. Summarizing, Uranus is a very interesting magnetosphere that offers new insights on the nature, complexity, and diversity of planetary magnetospheric systems and the acceleration of particles in space plasmas, which might have important analogs to exoplanetary magnetospheric systems. Our hypotheses can be tested with further work involving more advanced models, new auroral observations, and unprecedented missions to explore the in situ environment from orbit around Uranus, which should include a complement of magnetospheric instruments in the payload.
Correlations of Plasma Properties Between the Upstream Magnetosheath and the Downstream Outflow Region of Magnetopause Reconnection
Authors: Han Yimin , Dai Lei , Ren Yong , Wang Chi , Gonzalez Walter , Zhu Minghui
Published: August 2024

The impact of upstream conditions on magnetopause reconnection has been an intriguing question in solar wind‐magnetosphere coupling. In this study, we conduct a statistical analysis of plasma properties in the reconnection outflow region and the associated upstream solar wind/magnetosheath. We observe that the normalized ion density (N/Nsw) decreases and the flow speed (V/Vsw) increases in the upstream magnetosheath with distance from the subsolar point, consistent with previous models and observations. The magnetic field strength (|B|), ion density (N), and ion bulk speed (|V|) in the upstream magnetosheath exhibit close correlations with those in the reconnection outflow region. This upstream‐downstream correlation likely arises from the process of forming reconnection outflows, where most upstream ions cross the separatrix and mix with ion outflow already accelerated near the X‐line. High‐speed part of reconnection outflow is mostly located on the magnetosphere side of the magnetopause current layer, with outflow velocities peaking close to the upstream magnetosheath Alfvén speed. The spatial extent of high‐speed outflow is greater in conditions of lower solar wind Alfvén Mach number (MA,sw). Additionally, the southward magnetic field in the magnetosheath and |B| of magnetopause current layer are larger in the cases of lower MA,sw. These findings indicate a close connection of plasma properties between the outflow region of magnetopause reconnection and the upstream magnetosheath.
Impact of systemic disease on CNS disease control after stereotactic radiosurgery to breast cancer brain metastases (The SYBRA Study)
Authors: Schick Alex , Hardy Sara , Strawderman Myla , Zheng Dandan , Cummings Michael , Milano Michael T. , Magnuson Allison , Behr Jacqueline , Sammons Sarah , Usuki Kenneth , Mohile Nimish , O’Regan Ruth , Anders Carey K. , Hicks David , Dhakal Ajay
Published: August 2024

The objective of the study is to assess impact of systemic disease (SD) status on overall survival and brain metastasis (BM) control, adopting a novel landmark approach to categorize SD among breast cancer (BC) patients. This single institution retrospective study included BCBM patients who have received stereotactic radiosurgery (SRS) to brain. Separate endpoints [CNS failure-free survival (cFFS), overall survival (OS)] were analyzed from each Landmark (LM): LM1 (3-months), LM2 (6-months). Patients were categorized into early and non-early progression (EP, NEP) groups depending on SD status before LMs. Median survivals from LM were assessed with Kaplan Meier plots, compared with Log-Rank test. EP was associated with worse median cFFS and OS vs NEP in both LM analyses (cFFS- LM1: 3.6 vs. 9.7 months, p = 0.0016; LM2: 2.3 vs. 12.5 months, p < 0.0001; OS- LM1: 3.6 vs. 24.3 months, p < 0.0001; LM2: 5.3 vs. 30.2 months, p < 0.0001). In multivariate analyses, EP was associated with shorter cFFS [LM1: Hazard Ratio (HR) with 95% confidence interval (CI) 3.16, 1.46–6.83, p = 0.0034; LM2: 5.32, 2.33–12.15, p = <0.0001] and shorter OS (LM1: HR with 95% CI 4.28, 1.98–9.12, p = 0.0002; LM2: 7.40, 3.10–17.63, p = <0.0001) vs NEP. Early systemic disease progressions after 1st SRS to brain is associated with worse cFFS and OS in patients with BCBM.
Phenotype prediction using biologically interpretable neural networks on multi-cohort multi-omics data
Authors: van Hilten Arno , van Rooij Jeroen ,   BIOS consortium, Heijmans Bastiaan T. , ’t Hoen Peter A. C. , Meurs Joyce van , Jansen Rick , Franke Lude , Boomsma Dorret I. , Pool René , van Dongen Jenny , Hottenga Jouke J. , van Greevenbroek Marleen M. J. , Stehouwer Coen D. A. , van der Kallen Carla J. H. , Schalkwijk Casper G. , Wijmenga Cisca , Zhernakova Sasha , Tigchelaar Ettje F. , Slagboom P. Eline , Beekman Marian , Deelen Joris , van Heemst Diana , Veldink Jan H. , van den Berg Leonard H. , van Duijn Cornelia M. , Hofman Bert A. , Isaacs Aaron , Uitterlinden André G. , Jhamai P. Mila , Verbiest Michael , Suchiman H. Eka D. , Verkerk Marijn , van der Breggen Ruud , van Rooij Jeroen , Lakenberg Nico , Mei Hailiang , van Iterson Maarten , van Galen Michiel , Bot Jan , van ’t Hof Peter , Deelen Patrick , Nooren Irene , Moed Matthijs , Vermaat Martijn , Luijk René , Jan Bonder Marc , van Dijk Freerk , Arindrarto Wibowo , Kielbasa Szymon M. , Swertz Morris A. , van Zwet Erik. W. , Ikram M. Arfan , Niessen Wiro J. , van Meurs Joyce. B. J. , Roshchupkin Gennady V.
Published: August 2024

Integrating multi-omics data into predictive models has the potential to enhance accuracy, which is essential for precision medicine. In this study, we developed interpretable predictive models for multi-omics data by employing neural networks informed by prior biological knowledge, referred to as visible networks. These neural networks offer insights into the decision-making process and can unveil novel perspectives on the underlying biological mechanisms associated with traits and complex diseases. We tested the performance, interpretability and generalizability for inferring smoking status, subject age and LDL levels using genome-wide RNA expression and CpG methylation data from the blood of the BIOS consortium (four population cohorts, Ntotal = 2940). In a cohort-wise cross-validation setting, the consistency of the diagnostic performance and interpretation was assessed. Performance was consistently high for predicting smoking status with an overall mean AUC of 0.95 (95% CI: 0.90–1.00) and interpretation revealed the involvement of well-replicated genes such as AHRR, GPR15 and LRRN3. LDL-level predictions were only generalized in a single cohort with an R2 of 0.07 (95% CI: 0.05–0.08). Age was inferred with a mean error of 5.16 (95% CI: 3.97–6.35) years with the genes COL11A2, AFAP1, OTUD7A, PTPRN2, ADARB2 and CD34 consistently predictive. For both regression tasks, we found that using multi-omics networks improved performance, stability and generalizability compared to interpretable single omic networks. We believe that visible neural networks have great potential for multi-omics analysis; they combine multi-omic data elegantly, are interpretable, and generalize well to data from different cohorts.
CFTIlandslides, Italian database of historical earthquake-induced landslides
Authors: Zei Caterina , Tarabusi Gabriele , Ciuccarelli Cecilia , Burrato Pierfrancesco , Sgattoni Giulia , Taccone Rita Chiara , Mariotti Dante
Published: August 2024

Knowing the location, the extent and the characteristics of any earthquake-induced environmental phenomenon is becoming an increasingly pressing need for civil protection agencies and local administrations. In particular, earthquake-triggered landslides are known for being among the most important sources of secondary hazard, as they may cause significant losses and may delay rescue operations across large areas. The combination of the relatively frequent seismic release with a very high landslide susceptibility makes the Italian territory especially prone to the occurrence of earthquake-induced landslides. The CFTIlandslides dataset features over 1,000 landslides triggered by historical Italian earthquakes (up to 1997). The landslides effects are subdivided into classes based on location accuracy and type of movement. Knowing the distribution of the past earthquake-induced landslides provides the input information for assessing the related hazard. This dataset is addressed to a large audience of potential users, including researchers and scholars, administrators and technicians belonging to local institutions, and civil protection authorities.
Computational studies on the catalytic potential of the double active site for enzyme engineering
Authors: Krishna Naveen Banchallihundi , Roopa Lalitha , Pravin Kumar R. , S Gopenath T
Published: August 2024

Proteins possessing double active sites have the potential to revolutionise enzyme design strategies. This study extensively explored an enzyme that contains both a natural active site (NAS) and an engineered active site (EAS), focusing on understanding its structural and functional properties. Metadynamics simulations were employed to investigate how substrates interacted with their respective active sites. The results revealed that both the NAS and EAS exhibited similar minimum energy states, indicating comparable binding affinities. However, it became apparent that the EAS had a weaker binding site for the substrate due to its smaller pocket and constrained conformation. Interestingly, the EAS also displayed dynamic behaviour, with the substrate observed to move outside the pocket, suggesting the possibility of substrate translocation. To gain further insights, steered molecular dynamics (SMD) simulations were conducted to study the conformational changes of the substrate and its interactions with catalytic residues. Notably, the substrate adopted distinct conformations, including near-attack conformations, in both the EAS and NAS. Nevertheless, the NAS demonstrated superior binding minima for the substrate compared to the EAS, reinforcing the observation that the engineered active site was less favourable for substrate binding due to its limitations. The QM/MM (Quantum mechanics and molecular mechanics) analyses highlight the energy disparity between NAS and EAS. Specifically, EAS exhibited elevated energy levels due to its engineered active site being located on the surface. This positioning exposes the substrate to solvents and water molecules, adding to the energy challenge. Consequently, the engineered enzyme did not provide a significant advantage in substrate binding over the single active site protein. Further, the investigation of internal channels and tunnels within the protein shed light on the pathways facilitating transport between the two active sites. By unravelling the complex dynamics and functional characteristics of this double-active site protein, this study offers valuable insights into novel strategies of enzyme engineering. These findings establish a solid foundation for future research endeavours aimed at harnessing the potential of double-active site proteins in diverse biotechnological applications.
Enhanced strength of ultrasonically-welded austenitic stainless steels joints by introducing dynamic recrystallization of interlayers
Authors: Chung Yun-Ta , Chu Hue-En , Juan Yu-Hsuan , Yang Yo-Lun , Lin Jhe-Yu
Published: August 2024

This study investigated the role of interfacial deformability in bond integrity and strength, particularly in the production of robust joints between harder austenitic stainless steels (SS) during ultrasonic welding. The specimen without the interlayer experienced limited strength enhancement owing to internal cracking from continuous sliding at interfacial temperatures below 0.6 times the melting point (Tm), which is attributed to the limited deformability of the austenitic SS. In contrast, introducing Fe and Ni interlayers between the substrates resulted in a notable increase in the interfacial strength, surpassing 2500 N in the peak load within a reduced welding duration. The correlation between the interfacial strength and the peak temperature suggests that a substantial decrease in hardness below 0.4 Tm is sufficient for extensive bond formation. Moreover, dynamic recrystallization (DRX) led to grain refinement in the Fe interlayer owing to shorter weld durations, whereas grain growth was observed in the Ni interlayer due to higher peak temperatures. Both the Fe and Ni interlayers significantly improved the bonding integrity by accommodating plasticity through the above phenomena without severe damage to the substrates, leading to increase of interfacial strength by 24% (2050 N to 2500 N) and reduction of weld duration by 40% (1.5 s in Fe interlayer). In addition, the fracture position after the lap shear test shifted from the edge of the weld area to the SS substrate.
The influence of biotic and abiotic factors on the bacterial microbiome of gentoo penguins (Pygoscelis papua) in their natural environment
Authors: Kaczvinsky Chloe , Levy Hila , Preston Stephen , Youngflesh Casey , Clucas Gemma , Lynch Heather J. , Hart Tom , Smith Adrian L.
Published: August 2024

The microbiome is a key factor in the health, well-being, and success of vertebrates, contributing to the adaptive capacity of the host. However, the impact of geographic and biotic factors that may affect the microbiome of wild birds in polar environments is not well defined. To address this, we determined the bacterial 16S rRNA gene sequence profiles in faecal samples from pygoscelid penguin populations in the Scotia Arc, focusing on gentoo penguins. This mesopredatory group breeds in defined colonies across a wide geographic range. Since diet could influence microbiome structure, we extracted dietary profiles from a eukaryotic 18S rRNA gene sequence profile. The bacterial microbiome profiles were considered in the context of a diverse set of environmental and ecological measures. Integrating wide geographic sampling with bacterial 16S and eukaryotic 18S rRNA gene sequencing of over 350 faecal samples identified associations between the microbiome profile and a suite of geographic and ecological factors. Microbiome profiles differed according to host species, colony identity, distance between colonies, and diet. Interestingly there was also a relationship between the proportion of host DNA (in relation to total 18S rRNA gene signal) and the microbiome, which may reflect gut passage time. Colony identity provided the strongest association with differences in microbiome profiles indicating that local factors play a key role in the microbiome structure of these polar seabirds. This may reflect the influence of local transfer of microbes either via faecal-oral routes, during chick feeding or other close contact events. Other factors including diet and host species also associate with variation in microbiome profile, and in at least some locations, the microbiome composition varies considerably between individuals. Given the variation in penguin microbiomes associated with diverse factors there is potential for disruption of microbiome associations at a local scale that could influence host health, productivity, and immunological competence. The microbiome represents a sensitive indicator of changing conditions, and the implications of any changes need to be considered in the wider context of environmental change and other stressors.
InSAR data for detection and modelling of overexploitation-induced subsidence: application in the industrial area of Prato (Italy)
Authors: Medici Camilla , Del Soldato Matteo , Fibbi Gabriele , Bini Lorenzo , Confuorto Pierluigi , Mannori Gaddo , Mucci Alessandra , Pellegrineschi Vania , Bianchini Silvia , Raspini Federico , Casagli Nicola
Published: August 2024

Spaceborne-based monitoring for environmental purposes has become a well-established practice. The recent progress of synthetic aperture radar (SAR) sensors, including through the European Space Agency’s (ESA) Sentinel-1 constellation, has enabled the scientific community to identify and monitor several geohazards, including subsidence ground deformations. A case study in the Tuscany Region, Italy, highlights the effectiveness of interferometric synthetic aperture radar (InSAR) in detecting abrupt increases in ground deformation rates in an industrial area of Montemurlo municipality. In this case, InSAR data enabled prompt identification of the phenomenon, supporting the authorities in charge of environmental management to thoroughly investigate the situation. First, an on-site validation was performed via field surveys confirming the presence of cracks and fissures on some edifices. Further analysis, including water pumping rates, settlement gauge and topographic levelling, corroborated the InSAR data's findings regarding vertical deformation. Integration of collected data allowed for spatial identification and assessment of the subsidence bowl and its source depth recognized by the remote sensing data. The Montemurlo case offers a procedural guideline for managing abrupt accelerations, identified by InSAR data in subsidence-prone areas due to fluid overexploitation. In fact, these data proved useful in helping local authorities responsible for hydrogeomorphological risk management. With the exacerbation of deformation issues in subsidence-prone regions due to climate change, early detection and monitoring of such phenomena are increasingly crucial, with InSAR data playing a central role in achieving this goal.
Association between polychlorinated biphenyl (PCB) and dioxin with metabolic syndrome (METS): a systematic review and meta-analysis
Authors: Mohd Efendy Goon Mohd Danial , Zulkifli Sarah , Abdullah Soheimi Siti Suhana , Ab. Rahim Sharaniza , Abd Latip Normala , Hashim Norbaya , Kerisnan Nirmala Devi , E. M. Yahaya Nasehir Khan , Mohamed Alias , Sheikh Abdul Kadir Siti Hamimah
Published: August 2024

Polychlorinated biphenyls (PCBs) and dioxin are persistent endocrine disrupting chemicals (EDCs) and have been associated with an increased risk of metabolic syndrome (MetS). The aim of this systematic review and meta-analysis was to assess the associations of PCBs and dioxin with MetS and its risk factors, including obesity, hypertriglyceridaemia (HTG), hypertension (HTN) and diabetes mellitus (DM). We searched three electronic databases for epidemiological studies concerning PCBs and dioxin with MetS published up to the end of 2023. Meta-analysis was performed for MetS itself and each of the MetS risks based on a random-effects meta-analysis model, and odds ratios (ORs) with 95% confidence intervals (CIs) were obtained. Publication bias was assessed based on Egger’s test. Eleven studies were included from three databases up to 2023. There were 40,528 participants aged 18–89, where 18–100% of them were males, included in our meta-analysis. The meta-analysis results showed a strong association between PCB exposure and DM (OR = 3.593, 95% CI 2.566, 5.031), while most of the risk factors for MetS, including obesity (OR = 1.875, 95% CI 0.883, 3.979), HTN (OR = 1.335, 95% CI 0.902, 1.976) and HTG (OR = 1.611, 95% CI 0.981, 2.643), were weakly associated with PCB. Furthermore, both PCBs (OR = 1.162, 95% CI 0.994, 1.357) and dioxin (OR = 2.742, 95% CI 1.936, 3.883) were found to be weakly and strongly associated with MetS, respectively. Meta-regression analysis showed that DM in the Asian population is associated with PCB exposure, while HTG in the Northern American population is associated with PCB exposure. Our meta-analysis has demonstrated a strong relationship between DM and PCBs, while the relationship between PCBs with MetS and other risk factors is less pronounced. Additionally, MetS is weakly associated with dioxin exposure. To improve primary care outcomes, healthcare providers should consider incorporating the assessment of patients' risk of exposure to PCBs and dioxins into their evaluation procedures for more targeted medical interventions.
Developing an optimised method for accurate wear testing of dental materials using the ‘Rub&Roll’ device
Authors: Maier Eva , Ruben Jan , Palin William M. , Bronkhorst Ewald , Olmos Manuel , Matta Ragai Edward , Loomans Bas
Published: August 2024

Dental materials are challenged by wear processes in the oral environment and should be evaluated in laboratory tests prior to clinical use. Many laboratory wear-testing devices are high-cost investments and not available for cross-centre comparisons. The ‘Rub&Roll’ wear machine enables controlled application of force, chemical and mechanical loading, but the initial design was not able to test against rigid antagonist materials. The current study aimed to probe the sensitivity of a new ‘Rub&Roll’ set-up by evaluating the effect of force and test solution parameters (deionized water; water + abrasive medium; acid + abrasive medium) on the wear behaviour of direct and indirect dental resin-based composites (RBCs) compared with human molars against 3D-printed rod antagonists. Molars exhibited greater height loss than RBCs in all test groups, with the largest differences recorded with acidic solutions. Direct RBCs showed significantly greater wear than indirect RBCs in the groups containing abrasive media. The acidic + abrasive medium did not result in increased wear of RBC materials. The developed method using the ‘Rub&Roll’ wear machine in the current investigation has provided a sensitive wear test method to allow initial screening of resin-based composite materials compared with extracted human molars under the influence of different mechanical and erosive challenges.
Task-dependent contribution to edge-based versus region-based texture perception
Authors: Gheorghiu Elena , Diggiss Cassandra , Kingdom Frederick A. A.
Published: August 2024

Texture segregation studies indicate that some types of textures are processed by edge-based and others by region-based mechanisms. However, studies employing nominally edge-based textures have found evidence for region-based processing mechanisms when the task was to detect rather than segregate the textures. Here we investigate directly whether the nature of the task determines if region-based or edge-based mechanisms are involved in texture perception. Stimuli consisted of randomly positioned Gabor micropattern texture arrays with five types of modulation: orientation modulation, orientation variance modulation, luminance modulation, contrast modulation and contrast variance modulation (CVM). There were four modulation frequencies: 0.1, 0.2, 0.4 and 0.8 cpd. Each modulation type was defined by three types of waveforms: sinewave (SN) with its smooth variations, square-wave (SQ) and cusp-wave (CS) with its sharp texture edges. The CS waveform was constructed by removing a sinewave from an equal amplitude square-wave. Participants performed two tasks: detection in which participants selected which of two stimuli contained the modulation and discrimination in which participants indicated which of two textures had a different modulation orientation. Our results indicate that threshold amplitudes in the detection task followed the ordering SQ < SN < CS across all spatial frequencies, consistent with detection being mediated by the overall energy in the stimulus and hence region based. With the discrimination task at low texture spatial frequencies and with CVM textures at all spatial frequencies the order was CS ≤ SQ with both < SN, consistent with being edge-based. We modeled the data by estimating the spatial frequency of a Difference of Gaussian filter that gave the largest peak amplitude response to the data. We found that the peak amplitude was lower for detection than discrimination across all texture types except for the CVM texture. We conclude that task requirements are critical to whether edges or regions underpin texture processing.
miR-182, miR-221 and miR-222 are potential urinary extracellular vesicle biomarkers for canine urothelial carcinoma
Authors: Karttunen Jenni , Kalmar Lajos , Grant Andrew , Ying Jun , Stewart Sarah E. , Wang Xiaonan , Frankl Fiona Karet , Williams Tim
Published: August 2024

Current diagnostic methods for canine urothelial carcinoma (UC) are technically challenging or can lack specificity, hence there is a need for novel biomarkers of UC. To this end, we analysed the microRNA (miRNA) cargo of extracellular vesicles (EVs) from urine samples of dogs with UC to identify candidate miRNA biomarkers. Urine was fractionated using ultrafiltration combined with size-exclusion chromatography and small RNA sequencing analysis was performed on both the EV enriched and (EV free) protein fractions. A greater number of candidate miRNA biomarkers were detected in the EV fraction than the protein fraction, and further validation using droplet digital PCR (ddPCR) was performed on the EV enriched fraction of a second cohort of dogs with UC which indicated that miR-182, miR-221 and miR-222 were significantly overrepresented in dogs with UC when compared with healthy dogs and dogs with urinary tract infections. Pathway analysis confirmed that these three miRNAs are involved in cancer. In addition, their potential downstream gene targets were predicted and PIK3R1, a well-known oncogene is likely to be a shared target between miRNA-182 and miRNA-221/222. In summary, this study highlights the potential of urinary EV-associated miRNAs as a source of biomarkers for the diagnosis of canine UC.
Increased imaging ligand hydrophilicity and improved pharmacokinetic properties provides enhanced in vivo targeting of fibroblast activation protein
Authors: Narain Radhika , Nessler Ian , Richardson Paul L. , Erickson Jamie E. , Wang Yuzhen , Ferri Jacqueline , Knight Heather L. , Bryant Shaughn H. , Phillips Lucy A. , Zhang Liang , Mitra Soumya
Published: August 2024

In this work, the impact of physicochemical modifications on pharmacokinetics and in vivo targeting of a small molecule fibroblast activation protein inhibitor (FAPI) imaging ligand in a murine model of rheumatoid arthritis was evaluated. While similar ligands have been well-reported in oncology for molecular imaging and radiotherapy, there are limited reports of FAPI derivatives in targeted applications in immunology. As inflammation may increase both specific and non-specific delivery of targeted agents in general, we sought to identify the optimal targeted molecular imaging probe characteristics for efficient cell surface engagement. A series of FAPI derivatives were synthesized and their physicochemical properties modified via conjugation of fluorescent dyes and/or an albumin-binding small molecule. The impact of these modifications on cell surface binding affinity was assessed using an overexpressing cell line. Additionally, a thorough mechanistic characterization of fibroblast activation protein (FAP) cell surface internalization was evaluated in both overexpressing and endogenously expressing cells. Lastly, the pharmacokinetics and in vivo uptake in inflamed arthritic paws were characterized via near-infrared (NIR) imaging. All targeted molecular imaging agents tested maintained strong nanomolar binding affinity to cell surface FAP independent of chemical modification. The murine fibroblast-like synoviocytes expressed lower absolute cell-surface FAP compared to a transfected line, and the net internalization half-life measured for the transfected cells via flow cytometry was 7.2 h. The unmodified FAPI ligand exhibited the poorest in vivo targeting, likely resulting from its large apparent volume of distribution (62.7 ml) and rapid systemic clearance (t1/2 = 0.5 h). Conjugation of a charged, hydrophilic AF647 fluorophore decreased systemic clearance (t1/2 = 2.1 h) and demonstrated a 2-fold improvement in blocking FAPI-800CW engagement of FAP in vivo when compared to blocking of FAPI-800CW with FAPI with up to 2.8-fold improvements noted for the equivalent albumin binding construct comparison.