bluuebunny/crossref_metadata_2025 huggingface dataset:
A Global Industry Survey on Post-Approval Change Management and Use of Reliance
Authors: Deavin Andrew , Hossain Aliyah , Colmagne-Poulard Isabelle , Wong Kum Cheun , Perea-Vélez Mónica , Cappellini Sonia , Ausborn Susanne , Meillerais Sylvie , Bourguignon Céline
Published: August 2024

Post-approval changes (PACs) to the control and manufacturing processes of medicines and vaccines are routinely undertaken and critical to enable both innovation and secure sustained supply. In a world of global supply chains, the existence of divergent national PAC requirements (with additional countries introducing new requirements with potential differences) and other factors including document preparation and response timelines, can lead to long delays in approval (of up to 3–5 years) increasing the risk of disruption and shortages.

We undertook an Industry survey in 2023 to assess implementation of ICH Q12, PAC procedures (change categorisation and review timelines) and use of reliance mechanisms across different countries (9 selected ICH Members and 19 Observers). Although this survey revealed limited implementation of Q12 in ICH Member countries, when comparing the data collected with those of a previous survey performed in 2020, we observed a broader adoption of risk-based approaches to variation categorisation (in all countries). This, however, was not reflected in improved timelines for approval.

With regards to ICH Q12 adoption, the uptake of Post-Approval Change Management Protocols (PACMPs) was unchanged (with only one country reporting in-use) and implementation gaps were evident for Established Conditions (EC) and the Product Life Cycle Management document (PLCM). The survey found greater awareness of ICH Q12 and its tools compared to 2020, potentially illustrating the positive impact of training efforts. This illustrates the challenges being faced to broaden its implementation and use globally.

In the same Industry survey, we also assessed PAC processes across different international countries. Long unpredictable timelines were the major concern across the countries surveyed together with limited capacity of the regulators. Four different CMC changes were selected and categorized by the respondents according to current knowledge of national classifications and timelines in the selected countries and compared with a reference classification and timeline from the European Medicines Agency and the World Health Organisation. This highlighted the lack of harmonisation of many countries with EU/WHO requirements, especially within the ICH Observer group.

Last, this survey showed that some use of unilateral forms of reliance to Reference Authorities for PACs is starting. This is a mechanism all countries can employ, regardless of convergence of requirements and expertise, to enhance capacity building and reduce duplication of reviews, streamline variations approval, whilst accelerating patient access to innovation and securing supply.
Reimagining Earth in the Earth System
Authors: Bonan Gordon B. , Lucier Oliver , Coen Deborah R. , Foster Adrianna C. , Shuman Jacquelyn K. , Laguë Marysa M. , Swann Abigail L. S. , Lombardozzi Danica L. , Wieder William R. , Dahlin Kyla M. , Rocha Adrian V. , SanClements Michael D.
Published: August 2024

Terrestrial, aquatic, and marine ecosystems regulate climate at local to global scales through exchanges of energy and matter with the atmosphere and assist with climate change mitigation through nature‐based climate solutions. Climate science is no longer a study of the physics of the atmosphere and oceans, but also the ecology of the biosphere. This is the promise of Earth system science: to transcend academic disciplines to enable study of the interacting physics, chemistry, and biology of the planet. However, long‐standing tension in protecting, restoring, and managing forest ecosystems to purposely improve climate evidences the difficulties of interdisciplinary science. For four centuries, forest management for climate betterment was argued, legislated, and ultimately dismissed, when nineteenth century atmospheric scientists narrowly defined climate science to the exclusion of ecology. Today's Earth system science, with its roots in global models of climate, unfolds in similar ways to the past. With Earth system models, geoscientists are again defining the ecology of the Earth system. Here we reframe Earth system science so that the biosphere and its ecology are equally integrated with the fluid Earth to enable Earth system prediction for planetary stewardship. Central to this is the need to overcome an intellectual heritage to the models that elevates geoscience and marginalizes ecology and local land knowledge. The call for kilometer‐scale atmospheric and ocean models, without concomitant scientific and computational investment in the land and biosphere, perpetuates the geophysical view of Earth and will not fully provide the comprehensive actionable information needed for a changing climate.
Remote Sensing Large‐Wood Storage Downstream of Reservoirs During and After Dam Removal: Elwha River, Washington, USA
Authors: Buscombe D. , Warrick J. A. , Ritchie A. , East A. E. , McHenry M. , McCoy R. , Foxgrover A. , Wohl E.
Published: August 2024

Large wood is an integral part of many rivers, often defining river‐corridor morphology and habitat, but its occurrence, magnitude, and evolution in a river system are much less well understood than the sedimentary and hydraulic components, and due to methodological limitations, have seldom previously been mapped in substantial detail. We present a new method for this, representing a substantial advance in automated deep‐learning‐based image segmentation. From these maps, we measured large wood and sediment deposits from high‐resolution orthoimages to explore the dynamics of large wood in two reaches of the Elwha River, Washington, USA, between 2012 and 2017 as it adjusted to upstream dam removals. The data set consists of a time series of orthoimages (12.5‐cm resolution) constructed using Structure‐from‐Motion photogrammetry on imagery from 14 aerial surveys. Model training was optimized to yield maximum accuracy for estimated wood areas, compared to manually digitized wood, therefore model development and intended application were coupled. These fully reproducible methods and model resulted in a maximum of 15% error between observed and estimated total wood areas and wood deposit size‐distributions over the full spatio‐temporal extent of the data. Areal extent of wood in the channel margin approximately doubled in the years following dam removal, with greatest increases in large wood in wider, lower‐gradient sections. Large‐wood deposition increased between the start of dam removal (2011) and winter 2013, then plateaued. Sediment bars continued to grow up until 2016/17, assisted by a partially static wood framework deposited predominantly during the period up to winter 2013.
To Identify the Forecast Skill Windows of MJO Based on the S2S Database
Authors: Liu Xiaolei , Peng Yihao , Su Jingzhi , Liu Xinli
Published: August 2024

As a practical reflection of the opportunity window of Madden‐Julian Oscillation (MJO), there are intermittent periods of relatively high forecasting skills, namely the forecast skill windows. Robust forecast skill windows are identified based on the subseasonal‐seasonal reforecast database, during which the majority of models show high forecast skills. A total of 15 MJO forecast skill windows during 1993–2020 have been identified. Most of the forecast skill windows are closely associated with active MJO events with high amplitude. Whether a high‐skill forecast window appears significantly depends on the magnitude of MJO intensity during the same period. The maintenance of active strong MJO events is potentially related with the warmer surface sea temperature anomalies in the western Pacific. Further research into such processes may unveil the MJO development mechanism and improve the MJO forecast skill.
Ion‐Acoustic Waves Associated With Interplanetary Shocks
Authors: Boldú J. J. , Graham D. B. , Morooka M. , André M. , Khotyaintsev Yu. V. , Dimmock A. , Píša D. , Souček J. , Maksimovic M. , Louarn P. , Fedorov A. , Nicolaou G. , Owen C.
Published: August 2024

Ion‐acoustic waves (IAWs) commonly occur near interplanetary (IP) shocks. These waves are important because of their potential role in the dissipation required for collisionless shocks to exist. We study IAW occurrence statistically at different heliocentric distances using Solar Orbiter to identify the processes responsible for IAW generation near IP shocks. We show that close to IP shocks the occurrence rate of IAW increases and peaks at the ramp. In the upstream region, the IAW activity is highly variable among different shocks and increases with decreasing distance from the Sun. We show that the observed currents near IP shocks are insufficient to reach the threshold for the current‐driven instability. We argue that two‐stream proton distributions and suprathermal electrons are likely sources of the waves.
Direct In‐Situ Estimates of Energy and Force Balance Associated With Magnetopause Reconnection
Authors: Dahani Souhail , Lavraud Benoit , Génot Vincent , Toledo‐Redondo Sergio , Kieokaew Rungployphan , Fargette Naïs , Roberts Owen W. , Gershman Daniel , Saito Yoshifumi , Giles Barbara , Torbert Roy , Burch James
Published: August 2024

Fundamental processes in plasmas act to convert energies into different forms, for example, electromagnetic, kinetic and thermal. Direct derivation from the Vlasov‐Maxwell equation yields sets of equations that describe the temporal evolution of magnetic, kinetic and internal energies in either the monofluid or multifluid frameworks. In this work, we focus on the main terms affecting the changes in kinetic energy. These are pressure‐gradient‐related terms and electromagnetic terms. The former account for plasma acceleration/deceleration from a pressure gradient, while the latter from an electric field. Although limited spatial and temporal deviations are expected, a statistical balance between these terms is fundamental to ensure the overall conservation of energy and momentum. We use in‐situ observations from the Magnetospheric MultiScale (MMS) mission to study the relationship between these terms. We perform a statistical analysis of those parameters in the context of magnetic reconnection by focusing on small‐scale Electron Diffusion Regions and large‐scale Flux Transfer Events. The analysis reveals a correlation between the two terms in the monofluid force balance, and in the ion force and energy balance. However, the expected relationship cannot be verified from electron measurements. Generally, the pressure‐gradient‐related terms are smaller than their electromagnetic counterparts. We perform an error analysis to quantify the expected underestimation of gradient values as a function of the spacecraft separation compared to the gradient scale. Our findings highlight that MMS is capable of capturing energy and force balance for the ion fluid, but that care should be taken for energy conversion terms based on electron pressure gradients.
A Prototype of a 900 MHz Band Integrated Rectenna by Using a Planar Monopole Antenna With Feeder
Authors: Nakashima N. , Sumiyoshi T.
Published: August 2024

A rectenna designed for wireless power transfer at 900 MHz focuses on conjugate impedance matching and image impedance matching for improved efficiency. To do them, a voltage doubler rectifier circuit (VD) and a planar monopole antenna (PMA) were engineered with the same pure resistance value and integrated into the rectenna. The input impedance of the VD with 30 Ω load resistance indicated a pure resistance of approximately 73 Ω. This value closely matches the input impedance of a dipole antenna operating as a pure resistor. Since the prototype rectifier circuit is unbalanced, the authors constructed a PMA, an unbalanced antenna similar to a dipole antenna, on a double‐sided circuit board. In this setup, a microstrip line was created by extending the radiating element, achieving the impedance matchings. Measurements indicated a voltage standing wave ratio of approximately 1.03. A rectenna efficiency of 37.4% was observed for a transmission distance of 50 cm. The rectification efficiency of the VD is nearly 0% when the input power is less than −20 dBm, and the received power of the PMA is less than −20 dBm when the transmission distance is 60 cm or more. It is predicted that the rectenna efficiency will be 0% when the transmission distance is 60 cm or more. However, the rectenna efficiency was 24.6% when the transmission distance was 60 cm. This over 20% improvement is due to the connection between the PMA and the VD using pure resistance.
Evaluate the Impact of Regional Ionospheric Data Assimilation Model on Precise Point Positioning
Authors: Chen Yan‐Shen , Chen Chia‐Hung , Yang Ming , Chu Feng‐Yu
Published: August 2024

This study presents an innovative approach to improving the accuracy and reducing the error convergence time of static Precise Point Positioning (PPP) in Global Positioning System (GPS) navigation. The research focuses on the impact of the high spatial and temporal resolution of a regional ionospheric data assimilation model on PPP over Taiwan. The study further evaluates the performance of both static PPP with the ionospheric information using commonly used models such as Klobuchar and International Reference Ionosphere (IRI), as well as a global ionospheric data assimilation model. Compared to the default IRI, the data assimilated IRI model can improve the overall ionospheric total electron content by approximately 83%. Additionally, it can significantly reduce horizontal positioning errors and shorten the error convergence time more than 52% for static PPP, even during geomagnetic storm events. The study concludes that the high resolution of a regional ionospheric data assimilation model can enhance the accuracy and reduce the error convergence time of PPP navigation and positioning. This research provides valuable insights for future studies in this field, especially in the development of more precise and efficient models for correcting ionospheric delay in GPS navigation.
Longitudinal Range of the Eastward‐Traveling Equatorial Plasma Bubble Inducing Ionospheric Scintillation
Authors: Abadi P. , Otsuka Y. , Saito S. , Yamamoto M. , Perwitasari S. , Muafiry I. N. , Putra A. Y. , Faturahman A.
Published: August 2024

Equatorial Plasma Bubbles (EPBs) can generate ionospheric scintillation at GHz frequencies used in the Global Navigation Satellite System (GNSS). Emerging at any longitude following sunset and typically moving eastward, monitoring the EPBs is essential for space weather services. Using three GNSS receivers positioned at the same latitude (∼0°N) but separated in longitudes (∼9°, ∼16°, and ∼25°) and the 47 MHz Equatorial Atmosphere Radar (EAR) in Indonesia, our study delineates the zonal extent of eastward‐traveling post‐sunset EPB inducing ionospheric GNSS scintillation. Typically, the scintillation occurrences detected by a ground receiver concentrate between 19 and 01 local time (LT), with a peak incidence observed at 21 LT. Furthermore, an experiment combining EAR observations with GNSS receiver data allowed for the determination of the linear change in the speed of eastward‐traveling EPB inducing scintillation during this time period. Interestingly, the longitudinal range of eastward‐traveling EPBs increased with higher solar flux (F10.7) levels. Our findings suggest that EPB can induce scintillation up to a longitudinal distance of approximately 25° from the onset location at sunset to the eastern midnight region, particularly in F10.7 ranging from 90 to 150 solar flux units. Moreover, experiments using longitudinally separated GNSS receivers indicated that scintillations during 19–01 LT originate from post‐sunset EPBs within a longitudinal range extending 25° to the west. In conclusion, our research provides valuable insight into the ability of eastward‐traveling EPB to induce GNSS scintillation within a longitudinal range of 25°, thereby enhancing EPB and scintillation monitoring and prediction in regional space weather services.
Healthy lifestyle practice correlates with decreased obesity prevalence in individuals with high polygenic risk: TMM CommCohort study
Authors: Sutoh Yoichi , Hachiya Tsuyoshi , Otsuka-Yamasaki Yayoi , Komaki Shohei , Minabe Shiori , Ohmomo Hideki , Sasaki Makoto , Shimizu Atsushi
Published: August 2024

Obesity and overweight, fundamental components of the metabolic syndrome, predispose individuals to lifestyle-related diseases. The extent to which adopting healthy lifestyles can reduce obesity risk, even in those with a high genetic risk, remains uncertain. Our aim was to assess the extent to which lifestyle modifications can improve outcomes in individuals with a high polygenic score (PGS) for obesity. We quantified the genetic risk of obesity using PGSs. Four datasets from the Tohoku Medical Megabank Community-Based Cohort (TMM CommCohort) were employed in the study. One dataset (n = 9958) was used to select the best model for calculating PGS. The remaining datasets (total n = 69,341) were used in a meta-analysis to validate the model and to evaluate associated risks. The odds ratio (OR) for obesity risk in the intermediate (11th–90th percentiles in the dataset) and high PGS categories (91st–100th) was 2.27 [95% confidence intervals: 2.12–2.44] and 4.83 [4.45–5.25], respectively, compared to that in the low PGS category (1st–10th). Trend analysis showed that an increase in leisure-time physical activity was significantly associated with reduced obesity risk across all genetic risk categories, representing an OR of 0.9 [0.87–0.94] even among individuals in the high PGS category. Similarly, sodium intake displayed a positive association with obesity across all genetic risk categories, yielding an OR of 1.24 [1.17–1.31] in the high PGS category. The risk of obesity was linked to the adoption of healthy lifestyles, even in individuals with high PGS. Our results may provide perspectives for integrating PGSs into preventive medicine.
Likely causal effects of insulin resistance and IGF-1 bioaction on childhood and adult adiposity: a Mendelian randomization study
Authors: Olwi Duaa I. , Kaisinger Lena R. , Kentistou Katherine A. , Vaudel Marc , Stankovic Stasa , Njølstad Pål R. , Johansson Stefan , Perry John R. B. , Day Felix R. , Ong Ken K.
Published: August 2024

Background

Circulating insulin and insulin-like growth factor-1 (IGF-1) concentrations are positively correlated with adiposity. However, the causal effects of insulin and IGF-1 on adiposity are unclear.

Methods

We performed two-sample Mendelian randomization analyses to estimate the likely causal effects of fasting insulin and IGF-1 on relative childhood adiposity and adult body mass index (BMI). To improve accuracy and biological interpretation, we applied Steiger filtering (to avoid reverse causality) and ‘biological effect’ filtering of fasting insulin and IGF-1 associated variants.

Results

Fasting insulin-increasing alleles (35 variants also associated with higher fasting glucose, indicative of insulin resistance) were associated with lower relative childhood adiposity (P = 3.8 × 10−3) and lower adult BMI (P = 1.4 × 10−5). IGF-1-increasing alleles also associated with taller childhood height (351 variants indicative of greater IGF-1 bioaction) showed no association with relative childhood adiposity (P = 0.077) or adult BMI (P = 0.562). Conversely, IGF-1-increasing alleles also associated with shorter childhood height (306 variants indicative of IGF-1 resistance) were associated with lower relative childhood adiposity (P = 6.7 × 10−3), but effects on adult BMI were inconclusive.

Conclusions

Genetic causal modelling indicates negative effects of insulin resistance on childhood and adult adiposity, and negative effects of IGF-1 resistance on childhood adiposity. Our findings demonstrate the need to distinguish between bioaction and resistance when modelling variants associated with biomarker concentrations.
Methodologic considerations in estimating racial disparity of mortality among very preterm infants
Authors: Jiang Siyuan , Rose Laura A. , Gould Jeffrey B. , Bennett Mihoko V. , Profit Jochen , Lee Henry C.
Published: August 2024

This review explores methodological considerations in estimating racial disparities in mortality among very preterm infants (VPIs). Significant methodological variations are evident across studies, potentially affecting the estimated mortality rates of VPIs across racial groups and influencing the perceived direction and magnitude of racial disparities. Key methodological approaches include the birth-based approach versus the fetuses-at-risk approach, with each offering distinct insights depending on the specific research questions posed. Cohort selection and the decision for crude versus adjusted comparison are also critical elements that shape the outcomes and interpretations of these studies. This review underscores the importance of careful methodological planning and highlights that no single approach is definitively superior; rather, each has its strengths and limitations depending on the research objectives. The findings suggest that adjusting the methodological approach to align with specific research questions and contexts is essential for accurately assessing and addressing racial disparities in neonatal mortality.

Impact

Elucidates the impact of methodological choices on perceived racial disparities in neonatal mortality.

Offers a comprehensive comparison of birth-based vs. fetuses-at-risk approaches in the context of racial disparity research.

Provides guidance on the cohort selection and adjustment criteria critical for interpreting studies on racial disparities in very preterm infant mortality.
Placental abruption and the risk of necrotizing enterocolitis in neonates with birth weight ≥1500 grams; US national database study
Authors: Abuelazm Somaya , Iben Sabine , Farghaly Mohsen , Mohamed Mohamed A. , Aly Hany
Published: August 2024

Background

The pathogenesis of necrotizing enterocolitis (NEC) is multifactorial, placental abruption is associated with serious neonatal complications attributed to disruption of the maternal-fetal vascular interface. This study aimed to investigate the association between placental abruption and NEC.

Methods

We analyzed the United States (US) National Inpatient Sample (NIS) dataset for the years 2016–2018. Using the logistic regression model, the adjusted odds ratios (aOR) were calculated to assess the risk of NEC in infants born to mothers with placental abruption after controlling for significant confounders. Analyses were repeated after stratifying the population into two birth weight (BW) categories: <1500 g and ≥1500 g.

Results

The study included 11,597,756 newborns. Placental abruption occurred in 0.16% of the population. NEC was diagnosed in 0.18% of infants, with a higher incidence (2.5%) in those born to mothers with placental abruption (aOR = 1.2, 95% CI: 1.1–1.3, p < 0.001). Placental abruption was associated with NEC only in infants with BW ≥ 1500 g (aOR = 1.34, 95% CI: 1.11–1.62, p 0.003).

Conclusion

Placental abruption is associated with an increased risk of NEC in neonates with BW ≥ 1500 g. Research is needed to explore the mechanisms behind this association and to develop targeted interventions to mitigate NEC risks in this population.

Impact

Placental abruption is associated with an increased risk of developing necrotizing enterocolitis (NEC) in neonates with a birth weight ≥1500 grams. This effect could be via direct in utero bowel injury or due to indirect postnatal compromise that occurs in these infants.

This is the first study to specifically address the association between placental abruption and NEC in neonates ≥1500 g.

The study used a national dataset that included all neonates delivered in the US, thereby allowing for the generalization of the findings after adjustment for multiple confounding factors.

This study lays the groundwork for subsequent studies aimed at modifying feeding strategies and other neonatal management for the prevention of NEC in infants delivered after placental abruption.
Mesothelin expression correlates with elevated inhibitory immune activity in patients with colorectal cancer
Authors: Malla Midhun , Deshmukh Sachin Kumar , Wu Sharon , Samec Timothy , Olevian Dane C. , El Naili Reima , El-Rayes Bassel , Xiu Joanne , Farrell Alex , Lenz Heinz-Josef , Lou Emil , Goel Sanjay , Spetzler David , Goldberg Richard M. , Hazlehurst Lori
Published: August 2024

The expression of the protein Mesothelin (MSLN) is highly variable in several malignancies, including colorectal cancer (CRC), and high levels are associated with aggressive clinicopathological features and worse patient survival. Colorectal cancer is both a common and deadly cancer; being the third most common in incidence and second most common cause of cancer-related death. While systemic therapy remains the primary therapeutic option for most patients with stage IV (metastatic; m) CRC, their disease eventually becomes treatment refractory, and 85% succumb within 5 years. Microsatellite-stable (MSS) CRC tumors, which constitute more than 90% of patients with mCRC, are generally refractory to immunotherapeutic interventions. In our current work, we characterize MSLN levels in CRC, specifically correlating expression with clinical outcomes in relevant CRC subtypes, and explore how MSLN expression impacts the status of immune activation and suppression in the peritumoral microenvironment. Higher MSLN expression is prevalent in CMS1 and CMS4 CRC subtypes and correlates with higher gene mutation rates across the patient cohorts. Further, MSLN-high patients exhibit increased M1/M2 macrophage infiltration, PD-L1 staining, immune-inhibitory gene expression, enrichment in inflammatory, TGF-β, IL6/JAK/STAT3, IL2/STAT5 signaling pathways, and mutation in KRAS and FBXW7. Together, these results suggest that MSLN protein is a potential target for antigen-specific therapy and supports investigation into its tumorigenic effects to identify possible therapeutic interventions for patients with high MSLN expressing MSS CRC.
MiRNA-449 family is epigenetically repressed and sensitizes to doxorubicin through ACSL4 downregulation in triple-negative breast cancer
Authors: Torres-Ruiz Sandra , Garrido-Cano Iris , Lameirinhas Ana , Burgués Octavio , Hernando Cristina , Martínez María Teresa , Rojo Federico , Bermejo Begoña , Tapia Marta , Carbonell-Asins Juan Antonio , Peña Carlos Javier , Lluch Ana , Cejalvo Juan Miguel , Tormo Eduardo , Eroles Pilar
Published: August 2024

Despite progress in breast cancer treatment, a significant portion of patients still relapse because of drug resistance. The involvement of microRNAs in cancer progression and chemotherapy response is well established. Therefore, this study aimed to elucidate the dysregulation of the microRNA-449 family (specifically, microRNA-449a, microRNA-449b-5p, and microRNA-449c-5p) and its impact on resistance to doxorubicin, a commonly used chemotherapeutic drug for the treatment of triple-negative breast cancer. We found that the microRNA-449 family is downregulated in triple-negative breast cancer and demonstrated its potential as a diagnostic biomarker. Besides, our findings indicate that the downregulation of the microRNA-449 family is mediated by the microRNAs-449/SIRT1-HDAC1 negative feedback loop. Moreover, it was found that the microRNA-449 family dysregulates the fatty acid metabolism by targeting ACSL4, which is a potential prognostic biomarker that mediates doxorubicin response through regulation of the drug extrusion pump ABCG2. Altogether, our results suggest that the microRNA-449 family might be a potential therapeutic target for the treatment of triple-negative breast cancer since it is implicated in doxorubicin response through ACSL4/ABCG2 axis regulation. Ultimately, our results also highlight the value of microRNAs-449 and ACSL4 as diagnostic and prognostic biomarkers in triple-negative breast cancer.
High tolerance of the superconducting current to large grain boundary angles in potassium-doped BaFe2As2
Authors: Hatano Takafumi , Qin Dongyi , Iida Kazumasa , Gao Hongye , Guo Zimeng , Saito Hikaru , Hata Satoshi , Shimada Yusuke , Naito Michio , Yamamoto Akiyasu
Published: August 2024

Superconducting magnets based on high-temperature superconductors (HTSs) have become critical components in cutting-edge technologies such as advanced medical applications. In HTSs, weak links of superconductivity are inevitable at high-angle grain boundaries (GBs). Thus, two adjacent grains should be crystallographically aligned within the critical angle (θ
c), for which the intergrain critical current density (J
c) starts to decrease exponentially. The θ
c of several iron-based superconductors (IBSs) is larger than that of cuprates. However, the decreases in both θ
c and intergrain J
c under magnetic fields for IBSs are still substantial, hampering their applications in polycrystalline forms. Here, we report that potassium-doped BaFe2As2 (Ba122:K) exhibits superior GB performance to that of previously reported IBSs. A transport J
c of over 0.1 MA/cm2 across [001]-tilt GBs with misorientation angles up to θ
GB = 24° was recorded even at 28 K, which is a required level for practical applications. Additionally, even in an applied magnetic field, θ
c was unaltered, and the decay of the intergrain J
c was small. Our results highlight the exceptional potential of Ba122:K for polycrystalline applications and pave the way for next-generation superconducting magnets.
Multi-habitat landscapes are more diverse and stable with improved function
Authors: Hackett Talya D. , Sauve Alix M. C. , Maia Kate P. , Montoya Daniel , Davies Nancy , Archer Rose , Potts Simon G. , Tylianakis Jason M. , Vaughan Ian P. , Memmott Jane
Published: August 2024

Conservation, restoration and land management are increasingly implemented at landscape scales1,2. However, because species interaction data are typically habitat- and/or guild-specific, exactly how those interactions connect habitats and affect the stability and function of communities at landscape scales remains poorly understood. We combine multi-guild species interaction data (plant–pollinator and three plant–herbivore–parasitoid communities, collected from landscapes with one, two or three habitats), a field experiment and a modelling approach to show that multi-habitat landscapes support higher species and interaction evenness, more complementary species interactions and more consistent robustness to species loss. These emergent network properties drive improved pollination success in landscapes with more habitats and are not explained by simply summing component habitat webs. Linking landscape composition, through community structure, to ecosystem function, highlights mechanisms by which several contiguous habitats can support landscape-scale ecosystem services.
Visualizing chaperonin function in situ by cryo-electron tomography
Authors: Wagner Jonathan , Carvajal Alonso I. , Bracher Andreas , Beck Florian , Wan William , Bohn Stefan , Körner Roman , Baumeister Wolfgang , Fernandez-Busnadiego Ruben , Hartl F. Ulrich
Published: August 2024

Chaperonins are large barrel-shaped complexes that mediate ATP-dependent protein folding1–3. The bacterial chaperonin GroEL forms juxtaposed rings that bind unfolded protein and the lid-shaped cofactor GroES at their apertures. In vitro analyses of the chaperonin reaction have shown that substrate protein folds, unimpaired by aggregation, while transiently encapsulated in the GroEL central cavity by GroES4–6. To determine the functional stoichiometry of GroEL, GroES and client protein in situ, here we visualized chaperonin complexes in their natural cellular environment using cryo-electron tomography. We find that, under various growth conditions, around 55–70% of GroEL binds GroES asymmetrically on one ring, with the remainder populating symmetrical complexes. Bound substrate protein is detected on the free ring of the asymmetrical complex, defining the substrate acceptor state. In situ analysis of GroEL–GroES chambers, validated by high-resolution structures obtained in vitro, showed the presence of encapsulated substrate protein in a folded state before release into the cytosol. Based on a comprehensive quantification and conformational analysis of chaperonin complexes, we propose a GroEL–GroES reaction cycle that consists of linked asymmetrical and symmetrical subreactions mediating protein folding. Our findings illuminate the native conformational and functional chaperonin cycle directly within cells.
Thermal infrared directs host-seeking behaviour in Aedes aegypti mosquitoes
Authors: Chandel Avinash , DeBeaubien Nicolas A. , Ganguly Anindya , Meyerhof Geoff T. , Krumholz Andreas A. , Liu Jiangqu , Salgado Vincent L. , Montell Craig
Published: August 2024

Mosquito-borne diseases affect hundreds of millions of people annually and disproportionately impact the developing world1,2. One mosquito species, Aedesaegypti, is a primary vector of viruses that cause dengue, yellow fever and Zika. The attraction of Ae. aegypti female mosquitos to humans requires integrating multiple cues, including CO2 from breath, organic odours from skin and visual cues, all sensed at mid and long ranges, and other cues sensed at very close range3–6. Here we identify a cue that Ae. aegypti use as part of their sensory arsenal to find humans. We demonstrate that Ae. aegypti sense the infrared (IR) radiation emanating from their targets and use this information in combination with other cues for highly effective mid-range navigation. Detection of thermal IR requires the heat-activated channel TRPA1, which is expressed in neurons at the tip of the antenna. Two opsins are co-expressed with TRPA1 in these neurons and promote the detection of lower IR intensities. We propose that radiant energy causes local heating at the end of the antenna, thereby activating temperature-sensitive receptors in thermosensory neurons. The realization that thermal IR radiation is an outstanding mid-range directional cue expands our understanding as to how mosquitoes are exquisitely effective in locating hosts.
Oligodendrocytes and myelin limit neuronal plasticity in visual cortex
Authors: Xin Wendy , Kaneko Megumi , Roth Richard H. , Zhang Albert , Nocera Sonia , Ding Jun B. , Stryker Michael P. , Chan Jonah R.
Published: August 2024

Developmental myelination is a protracted process in the mammalian brain1. One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age2–4. We tested this theory in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity5. During adolescence, visual experience modulated the rate of oligodendrocyte maturation in visual cortex. To determine whether oligodendrocyte maturation in turn regulates neuronal plasticity, we genetically blocked oligodendrocyte differentiation and myelination in adolescent mice. In adult mice lacking adolescent oligodendrogenesis, a brief period of monocular deprivation led to a significant decrease in visual cortex responses to the deprived eye, reminiscent of the plasticity normally restricted to adolescence. This enhanced functional plasticity was accompanied by a greater turnover of dendritic spines and coordinated reductions in spine size following deprivation. Furthermore, inhibitory synaptic transmission, which gates experience-dependent plasticity at the circuit level, was diminished in the absence of adolescent oligodendrogenesis. These results establish a critical role for oligodendrocytes in shaping the maturation and stabilization of cortical circuits and support the concept of developmental myelination acting as a functional brake on neuronal plasticity.
Emission control of entangled electrons in photoionisation of a hydrogen molecule
Authors: Shobeiry Farshad , Fross Patrick , Srinivas Hemkumar , Pfeifer Thomas , Moshammer Robert , Harth Anne
Published: August 2024

For photo-dissociation of a single hydrogen molecule ($$H_2$$

H
2

) with combined XUV and IR laser pulses, we demonstrate optical control of the emission direction of the photoelectron with respect to the outgoing neutral fragment (the H-atom). Depending on the relative delay between the two laser fields, adjustable with sub-femtosecond time resolution, the photoelectron is emitted into the same hemisphere as the H-atom or opposite. This emission asymmetry is a result of entanglement of the two-electron final-state involving the spatially separated bound and emitted electron.
Renogrit selectively protects against cisplatin-induced injury in human renal tubular cells and in Caenorhabditis elegans by harmonizing apoptosis and mitophagy
Authors: Balkrishna Acharya , Gohel Vivek , Pathak Nishit , Joshi Monali , Singh Rani , Kumari Ankita , Dev Rishabh , Varshney Anurag
Published: August 2024

Cisplatin-induced nephrotoxicity restricts its clinical use against solid tumors. The present study elucidated the pharmacological effects of Renogrit, a plant-derived prescription medicine, using cisplatin-induced human renal proximal tubular (HK-2) cells and Caenorhabditis elegans. Quantification of phytochemicals in Renogrit was performed on HPTLC and UHPLC platforms. Renogrit was assessed in vitro in HK-2 cells post-exposure to clinically relevant concentration of cisplatin. It was observed that renoprotective properties of Renogrit against cisplatin-induced injury stem from its ability to regulate renal injury markers (KIM-1, NAG levels; NGAL mRNA expression), redox imbalance (ROS generation; GST levels), and mitochondrial dysfunction (mitochondrial membrane potential; SKN-1, HSP-60 expression). Renogrit was also found to modulate apoptosis (EGL-1 mRNA expression; protein levels of p-ERK, p-JNK, p-p38, c-PARP1), necroptosis (intracellular calcium accumulation; RIPK1, RIPK3, MLKL mRNA expression), mitophagy (lysosome population; mRNA expression of PINK1, PDR1; protein levels of p-PINK1, LC3B), and inflammation (IL-1β activity; protein levels of LXR-α). More importantly, Renogrit treatment did not hamper normal anti-proliferative effects of cisplatin as observed from cytotoxicity analysis on MCF-7, A549, SiHa, and T24 human cancer cells. Taken together, Renogrit could be a potential clinical candidate to mitigate cisplatin-induced nephrotoxicity without compromising the anti-neoplastic properties of cisplatin.
Spatial–temporal variations of sediment transport rate and driving factors in Shule River Basin, northwest China
Authors: Sun Dongyuan , Wang Yike , Niu Zuirong , Shu Heping , Wang Xingfan , Cui Yanqiang , Ma Yali , Wu Lanzhen
Published: August 2024

The sediment content and transport rate of rivers are crucial indicators reflecting soil erosion, water quality, and water resource management in a region. Studying changes in river sediment transport rates within a basin is essential for evaluating water quality, restoring water ecosystems, and implementing soil and water conservation measures. This study focused on the Shule River Basin and utilized various methods such as moving average, cumulative anomaly, Mann–Kendall mutation test, Mann–Kendall (M–K) trend test, Sen’s slope estimation, Correlation analysis, wavelet analysis, R/S analysis, ARCGIS10.7 interpolation, non-uniformity coefficient, and concentration to analyze data from hydrologic stations at Changmapu (CMP), Panjiazhuang (PJZ), and Dangchengwan (DCW). The research examined the temporal and spatial characteristics of sediment transport rates and identified key driving factors. Findings revealed significant increases in annual sediment transport rates at CMP and PJZ by 12.227 and 4.318 kg/s (10a)−1, respectively, while DCW experienced a decrease of 0.677 kg/s (10a)−1. The sediment transport rate of the three stations had a sudden change around 1994. The average annual sediment transport rates displayed distinct cycles, with CMP, PJZ, and DCW showing cycles of 51a, 53a, and 29a respectively. Additionally, while CMP and PJZ exhibited a continuous upward trend in sediment transport rates, DCW showed a consistent decline. The annual average sediment transport rates of CMP, PJZ, and DCW were 1305.43 kg/s, 810.06 kg/s, and 247.80 kg/s, respectively. These research findings contribute to enhancing the comprehension of sediment dynamics in the arid region of northwest China and offer a theoretical basis for the restoration and management of ecological environments in similar areas in the future.
Phytoplankton dynamics in a shellfish farming lagoon in a deltaic system threatened by ongoing climate change
Authors: Bolinesi Francesco , Rossetti Emanuele , Mangoni Olga
Published: August 2024

Global climate change has generated an increasing number of environmental problems, especially in Mediterranean coastal areas, such as the Po Delta (PD), where shellfish production has undergone an overall decline because of strong environmental changes. The present study is centred on assessing the fundamental ecological aspects in one of the most crucial European shellfish production lagoons, Sacca degli Scardovari (SC), addressing phytoplankton community parameters directly affecting shellfish production, namely, chemotaxonomic composition, size fractions, and total biomass, in relation to the physicochemical properties of the water column and mussel filtering activity. Our findings suggest that the phytoplankton community structure, its role within the lagoon food web and its production cycles depend on two distinct allogenic inputs, which shape the community differently and exert substantial control on shellfish production. At the same time, the suspended mussel biomass strongly controls the phytoplankton size composition, as their growth is largely supported by nanophytoplankton. As the Po River collects the drainage waters of the Italian side of the entire Alpine Arch, the phytoplankton dynamics reported here represent a useful baseline for further addressing issues of climatic changes affecting lagoon ecology. We believe that our study presents an innovative tool for the planning and management of interventions aimed at enhancing national mussel production without neglecting aspects of environmental protection or the integrity of the coastal system, with significant scientific implications.
Enhancing soil health, microbial count, and hydrophilic methomyl and hydrophobic lambda-cyhalothrin remediation with biochar and nano-biochar
Authors: Chandi Kanchana , Udomkun Patchimaporn , Boonupara Thirasant , Kaewlom Puangrat
Published: August 2024

Pesticide contamination and soil degradation present significant challenges in agricultural ecosystems, driving extensive exploration of biochar (BC) and nano-biochar (NBC) as potential solutions. This study examines their effects on soil properties, microbial communities, and the fate of two key pesticides: the hydrophilic methomyl (MET) and the hydrophobic lambda-cyhalothrin (LCT), at different concentrations (1%, 3%, and 5% w w−1) in agricultural soil. Through a carefully designed seven-week black bean pot experiment, the results indicated that the addition of BC/NBC significantly influenced soil dynamics. Soil pH and moisture content (MC) notably increased, accompanied by a general rise in soil organic carbon (SOC) content. However, in BC5/NBC5 treatments, SOC declined after the 2nd or 3rd week. Microbial populations, including total plate count (TPC), phosphate-solubilizing bacteria (PSB), and nitrogen-fixing bacteria (NFB), showed dynamic responses to BC/NBC applications. BC1/NBC1 and BC3/NBC3 applications led to a significant increase in microbial populations, whereas BC5/NBC5 treatments experienced a decline after the initial surge. Furthermore, the removal efficiency of both MET and LCT increased with higher BC/NBC concentrations, with NBC demonstrating greater efficacy than BC. Degradation kinetics, modeled by a first-order equation, revealed that MET degraded faster than LCT. These findings underscore the profound impact of BC/NBC on pesticide dynamics and microbial communities, highlighting their potential to transform sustainable agricultural practices.
Targeting SWI/SNF ATPases reduces neuroblastoma cell plasticity
Authors: Xu Man , Hong Jason J , Zhang Xiyuan , Sun Ming , Liu Xingyu , Kang Jeeyoun , Stack Hannah , Fang Wendy , Lei Haiyan , Lacoste Xavier , Okada Reona , Jung Raina , Nguyen Rosa , Shern Jack F , Thiele Carol J , Liu Zhihui
Published: August 2024

Tumor cell heterogeneity defines therapy responsiveness in neuroblastoma (NB), a cancer derived from neural crest cells. NB consists of two primary subtypes: adrenergic and mesenchymal. Adrenergic traits predominate in NB tumors, while mesenchymal features becomes enriched post-chemotherapy or after relapse. The interconversion between these subtypes contributes to NB lineage plasticity, but the underlying mechanisms driving this phenotypic switching remain unclear. Here, we demonstrate that SWI/SNF chromatin remodeling complex ATPases are essential in establishing an mesenchymal gene-permissive chromatin state in adrenergic-type NB, facilitating lineage plasticity. Targeting SWI/SNF ATPases with SMARCA2/4 dual degraders effectively inhibits NB cell proliferation, invasion, and notably, cellular plasticity, thereby preventing chemotherapy resistance. Mechanistically, depletion of SWI/SNF ATPases compacts cis-regulatory elements, diminishes enhancer activity, and displaces core transcription factors (MYCN, HAND2, PHOX2B, and GATA3) from DNA, thereby suppressing transcriptional programs associated with plasticity. These findings underscore the pivotal role of SWI/SNF ATPases in driving intrinsic plasticity and therapy resistance in neuroblastoma, highlighting an epigenetic target for combinational treatments in this cancer.
Combination of AID2 and BromoTag expands the utility of degron-based protein knockdowns
Authors: Hatoyama Yuki , Islam Moutushi , Bond Adam G , Hayashi Ken-ichiro , Ciulli Alessio , Kanemaki Masato T
Published: August 2024

Acute protein knockdown is a powerful approach to dissecting protein function in dynamic cellular processes. We previously reported an improved auxin-inducible degron system, AID2, but recently noted that its ability to induce degradation of some essential replication factors, such as ORC1 and CDC6, was not enough to induce lethality. Here, we present combinational degron technologies to control two proteins or enhance target depletion. For this purpose, we initially compare PROTAC-based degrons, dTAG and BromoTag, with AID2 to reveal their key features and then demonstrate control of cohesin and condensin with AID2 and BromoTag, respectively. We develop a double-degron system with AID2 and BromoTag to enhance target depletion and accelerate depletion kinetics and demonstrate that both ORC1 and CDC6 are pivotal for MCM loading. Finally, we show that co-depletion of ORC1 and CDC6 by the double-degron system completely suppresses DNA replication, and the cells enter mitosis with single-chromatid chromosomes, indicating that DNA replication is uncoupled from cell cycle control. Our combinational degron technologies will expand the application scope for functional analyses.
Topochemically synthesized Nb3VS6 as a stable anode for sodium-ion batteries
Authors: Pandey Harshit , Chithaiah Pallellappa , Vishwanathan Savithri , Ramakrishna Matte H. S. S. , Rao C. N. R.
Published: August 2024

Nb3VS6 is topochemically synthesized using Nb–V–HDA complex and H2S gas as the sulfidation agent. When used as an anode for SIBs it exhibits an excellent cyclic stability as high as 2500 cycles.
Enhancing CO2 electroreduction to ethylene via microenvironment regulation in boron–imidazolate frameworks
Authors: Lu Chen , Hong Qin-Long , Zhang Hai-Xia , Zhang Jian
Published: August 2024

The surrounding microenvironment regulation enhances the activity and selectivity towards C2H4 in electrochemical CO2 reduction reaction.
The synthesis of polydopamine nano- and microspheres in microdroplets
Authors: Zhang Jianze , Tian Shufang , Zhu Chenghui , Han Lifeng , Zhang Xinxing
Published: August 2024

Polydopamine nano- and microspheres, with aminochrome as the principal building block, were rapidly and controllably synthesized in microdroplets.