bluuebunny/crossref_metadata_2025 huggingface dataset:
Prosodic strength in Campidanese Sardinian as Substance-Free Phonology
Authors: Chabot Alex
Published: December 2024

The ambition of this article is to provide a phonological account of an intricate pattern of lenition and gemination in Campidanese Sardinian. The data show two things: that a model of phonology needs some way of showing strength and weakness as positional effects and that neither can be reliably understood in phonetic terms. In this analysis, the discovery procedure does not depend on raw phonetic facts, but rather on a rich model of abstract phonological representations. These representations are of two kinds, melodic and prosodic, and they allow for a substance-free phonological analysis of lenition and fortition in Campidanese that is not confronted by the difficulties inherent in surface-oriented approaches.
Continuities and disruptions in the National Council of Justice’s strategy of AI implementation in Brazil: the data-seafarers of Justice 4.0
Authors: Hedler Luisa
Published: December 2024

The introduction of algorithms in courts is currently the object of much scrutiny, attempting to find balance between increasing efficiency to the legal system and avoiding associated risks. This paper aims to explore how the judiciary organisations responsible for implementing algorithms describe the temporal demands of continuity and change, through a case-study of the Brazilian National Council of Justice (CNJ). Through its centralised, collaborative and open-access based platform, the CNJ views algorithms as a necessary step to deal with excessive case-load, and as a rationality-instituting mechanism for a currently dysfunctional situation. It attempts to deal with risks of disruption by placing itself in a supervisory role regarding all algorithms developed by courts across the country, ensuring the quality of the data and excluding the moment of judicial decision-making from automation, but this does not exclude the representation of the new technology as an instrument to implement specific doctrinal positions.
Black-box guided generalised linear model building with non-life pricing applications
Authors: Lindholm Mathias , Palmquist Johan
Published: December 2024

The paper introduces a method for creating a categorical generalized linear model (GLM) based on information extracted from a given black-box predictor. The procedure for creating the guided GLM is as follows: For each covariate, including interactions, a covariate partition is created using partial dependence functions calculated based on the given black-box predictor. In order to enhance the predictive performance, an auto-calibration step is used to determine which parts of each covariate partition should be kept, and which parts should be merged. Given the covariate and interaction partitions, a standard categorical GLM is fitted using a lasso penalty. The performance of the proposed method is illustrated using a number of real insurance data sets where gradient boosting machine (GBM) models are used as black-box reference models. From these examples, it is seen that the predictive performance of the guided GLMs is very close to that of the corresponding reference GBMs. Further, in the examples, the guided GLMs have few parameters, making the resulting models easy to interpret. In the numerical illustrations techniques are used to, e.g., identify important interactions both locally and globally, which is essential when, e.g., constructing a tariff.
The Impacts of Warming on Shallow and Deep‐Water Fisheries in New Zealand
Authors: Datta S. , Beran H. , Rogers A.
Published: December 2024

Climate change is already impacting ecosystem composition and species distributions. Here we study two different, but equally valuable New Zealand fisheries (Tasman Bay and Golden Bay, and Chatham Rise), and the potential impacts of climate change on ecosystem structure. We use mizer, a size‐based multispecies modeling package, to simulate interacting fish species in each ecosystem. Utilizing therMizer, an extension of mizer which incorporates temperature effects on species' metabolic rate and aerobic scope, we implement historical climate data from the Fisheries and Marine Ecosystem Model Intercomparison Project (FishMIP). This enables us to recreate the historical time period of 1961–2010, deriving reasonable steady state biomasses closely matching past observations. We then carry out a controlled warming simulation experiment, allowing for temperature to remain steady or to increase for both ecosystems, both with and without fishing pressure. The shallower ecosystem of Tasman and Golden Bay has more thermally tolerant species and experiences an overall increase in community biomass under warming, whilst the deeper ecosystem of Chatham Rise suffers an overall decline. In addition, fishing has a stronger negative impact on the Chatham Rise community. Smaller bodied animals also tend to be more resilient, both to warming and fishing impacts. Despite differences in community responses, the majority of important fisheries suffer reduced yields under warming in both ecosystems. Issues raised during the incorporation of temperature effects include species' thermal tolerances and model calibration to data. This study facilitates ecosystem intercomparisons under climate change and offers insight into drivers of ecosystem responses.
Spatial Variability of Dissolved Cobalt in the Indian Ocean Waters: Contrasting Behavior in the Arabian Sea, the Bay of Bengal and the Southern Sector of the Indian Ocean
Authors: Malla Nirmalya , Singh Sunil Kumar
Published: December 2024

The present study explored the dynamics of total dissolved Cobalt (dCo) in the Indian Ocean, revealing different distribution patterns in the different sub‐basins, nutrient‐type in the southern sector, hybrid‐type in the Arabian Sea to scavenged‐type in the Bay of Bengal (BoB). The dCo in the coastal water of the Arabian Sea displays elevated (0.12–0.13 nmol L−1) abundance and diminishes gradually toward the central Arabian Sea. Similarly, in the BoB, dCo concentrations are notably higher in the northern region (0.11 nmol L−1) and gradually decrease toward the south (0.03 nmol L−1 at 5°N). The Arabian Sea with higher biological uptake and remineralization in the oxycline supports a higher abundance of dCo in the intermediate oxygen minimum zone (OMZ), much a like the OMZs of the Atlantic and the Pacific Oceans. The influence of the phytoplankton community shift and uptake on the dCo distribution in the Indian Ocean could be inferred from the association between Co and phosphate in the photic waters. Our observation demonstrates a scavenging type dCo profile in the BoB due to its higher riverine as well as dust inputs in addition to its supply from continental shelf sediments. Such a higher concentration of dCo in the surface waters of the northern BoB masks the dCo signal associated with nitrite maxima. dCo gets removed by its scavenging with Mn oxides at deeper depths, as reflected by higher particulate Co in the BoB. Subduction fluids contribute significantly to the dCo inventory of the deep water in the Indian Ocean near the Java‐Sumatra subduction zone.
On the Advection–Diffusion Process With Developing Eddies in Karst Conduits
Authors: Li Zhongxia , Yang Yun , Zhan Hongbin , Wan Junwei , Cheng Jianmei , Feng Haibo , Yang Xianshuo
Published: December 2024

Understanding the fluid flow and solute transport in karst conduits is significant for preventing pollutants (treated as solutes) in karst areas. This study evaluates the evolution of eddies in semi‐circular rough conduits under different hydrodynamic conditions and their effects on solute transport. As inlet flow velocity increases, the non‐Fickian coefficient (a parameter used for qualifying the tailing of BTCs) increases first then decreases afterward. A critical equilibrium concentration is found when the concentration of the main flow stream and the concentration of the eddy zone reaches the same value, signaling the moment at which the mass transfer (due to diffusion) between the main flow stream and the eddy zone drops to zero. Such a critical equilibrium concentration and its corresponding moment of occurrence are found to follow two distinctive logarithmic functions of the inlet flow velocity. These findings provide crucial technical support for groundwater pollution control in karst areas.
Coupled Impact of Climate Change and Anthropogenic Activity on the Changes of Terrestrial Organic Carbon Accumulation in the River‐Dominated Coastal Margin
Authors: Jiang Li , Hu Limin , Bai Yazhi , Du Jiazong , Bi Naishuang , Wu Xiao , Sun Xueshi , Guo Zhigang , Wang Houjie , Yang Zuosheng
Published: December 2024

River‐dominated marginal seas play a crucial role in the global carbon cycle. However, the centennial burial record of organic carbon (OC) remains unclear. In this study, we conducted a comprehensive analysis of bulk OC, its isotopic composition (δ13C and Δ14C), biomarkers (lignin and n‐alkanes), and sedimentological evolution based on sediment core from the Yellow River‐dominated Bohai Sea (BS). We also compiled several published OC burial records from other river‐dominated coastal margins. Our findings indicated that since the 1950s, the accumulation of terrestrial OC in central BS has shown a concurrent decline, as evidenced by a ∼50% decrease in terrigenous/aquatic ratio of n‐alkanes (TAR), which accompanied by a significant reduction in sediment load due to the watershed human activities. More intense erosion and resuspension due to stronger hydrodynamic condition under the increasing frequency of winter storms could account for the observed sediment coarsening and concomitant increase of the degraded lignin and old‐OC since the 1980s, suggesting that delta erosion‐induced sediment redistribution could influence the selective transport and accumulation of the more woody allochthonous OC components. The temporal profiles of lignin records indicated a spatial heterogeneity of recent terrestrial OC burial among the large river‐dominated coastal margins under the enhanced global delta erosion. Compared to the fluvial input‐dominated OC burial in the Yangtze River, Pearl River and Mississippi River delta margins, a more hydrodynamic forcing impact on the terrestrial OC burial was discerned in the BS due to the coupled effect of recent climate change and substantial decline in sediment load.
Numerical Mixing Suppresses Submesoscale Baroclinic Instabilities Over Sloping Bathymetry
Authors: Schlichting Dylan , Hetland Robert , Jones C. Spencer
Published: December 2024

The impacts of spurious numerical salinity mixing on the larger‐scale flow and tracer fields are characterized using idealized simulations. The idealized model is motivated by realistic simulations of the Texas‐Louisiana shelf and features oscillatory near‐inertial wind forcing. can exceed the physical mixing from the turbulence closure in frontal zones and within the mixed layer. This suggests that simulated mixing processes in frontal zones are driven largely by . Near‐inertial alongshore wind stress amplitude is varied to identify a base case that maximizes the ratio of to in simulations with no prescribed horizontal mixing. We then test the sensitivity of the base case with three tracer advection schemes (MPDATA, U3HC4, and HSIMT) and conduct ensemble runs with perturbed bathymetry. Instability growth is evaluated using the volume‐integrated eddy kinetic energy and available potential energy . While all schemes have similar total mixing, the HSIMT simulations have over double the volume‐integrated and 20% less relative to other schemes, which suppresses the release of and reduces the by roughly 25%. This results in reduced isohaline variability and steeper isopycnals, evidence that enhanced suppresses instability growth. Differences in and between the MPDATA and U3HC4 simulations are marginal. However, the U3HC4 simulations have 25% more . Experiments with variable horizontal viscosity and diffusivity coefficients show that small amounts of prescribed horizontal mixing improve the representation of the ocean state for all advection schemes by reducing the and increasing the .
PyIRTAM: A New Module of PyIRI for IRTAM Coefficients
Authors: Forsythe Victoriya V. , Galkin Ivan , McDonald Sarah E. , Dymond Kenneth F. , Fritz Bruce A. , Burrell Angeline G. , Zawdie Katherine A. , Drob Douglas P.
Published: December 2024

A novel model called PyIRI was recently developed. It constructs the ionospheric electron density for the entire day and on the entire global grid in one computation, which has a very low computational overhead. PyIRI introduced a novel approach to the computation of the global and diurnal functions and their matrix multiplication with Consultative Committee on International Radio (CCIR) coefficients or the International Union of Radio Science (URSI) coefficients, that enabled this global approach for the density specification. Since the International Reference Ionosphere‐based Real‐Time Assimilative Model (IRTAM) produces coefficients in a similar format as CCIR/URSI coefficients, the PyIRI computational approach was extended to work with IRTAM coefficients. This technical note describes the PyIRTAM software and provides usage examples. The PyIRTAM tool is made publicly available through PyPI and GitHub.
Strain Partitioning and Strike‐Slip Faulting in the Nanjieshan, North Tibetan Foreland: Progressive Widening of the Altyn Tagh Fault System With Implications for Regional Earthquake Hazards
Authors: Yang Haibo , Lin Daoxiu , Yang Xiaoping , Cunningham Dickson , Hu Zongkai , Huang Xiongnan , Zhang Yingfeng , Li An
Published: December 2024

Large continental strike‐slip fault systems typically comprise a principal displacement zone and subordinate splay faults, exhibiting complex geometries, connectivity, and kinematics. Understanding the three‐dimensional arrangement of major and minor faults is important for determining strain distribution, landform development, and potential earthquake behavior. This study examines the Quaternary deformation, fault kinematics, and late Holocene ruptures along the Nanjieshan Fault system (NJSF), a major branch of the Altyn Tagh Fault (ATF) system in the North Tibetan Foreland. The E‐W‐trending NJSF comprises a principal strike‐slip fault flanked by two thrust faults, forming a regional, sinistral positive flower structure. Cosmogenic exposure dating, field data and remote sensing observations indicate that the strike‐slip rate of the main NJSF is ∼0.5 mm/a since ∼45 ka, consistent with the low slip rates observed on other faults northwest of the ATF. Paleoseismological trenches reveal three surface‐rupturing events on the NJSF in the last 2,500 years that may coincide temporally with the last two major earthquakes documented on the principal ATF, suggesting quasi‐simultaneous rupture behavior. Coulomb stress change modeling indicates that a future ATF earthquake is unlikely to trigger failure along the NJSF. Conversely, rupture of the NJSF could induce stress loading on the ATF, potentially bringing it to failure. A synchronous rupture on the ATF and its major branch faults could be facilitated by mechanically weakened fault rocks and supra‐hydrostatic fluid pressures within the deep southward‐dipping branch faults of the North Tibetan foreland. We conclude that improved prediction of future slip behavior along major strike‐slip fault systems requires detailed geochronological analysis of paleo‐earthquake events along subordinate branching faults.
Modeling the Nonlinear–To–Linear Relationship Between Bulk and Pore Water Electrical Conductivity in Saturated Porous Media Using a Padé Approximant
Authors: Fu Yongwei , Binley Andrew , Horton Robert , Heitman Joshua
Published: December 2024

A petrophysical model that accurately relates bulk electrical conductivity (σ) to pore fluid conductivity (σw) is critical to the interpretation of geophysical measurements. Classical models are either only applicable over a limited salinity regime or incorrectly explain the nonlinear‐to‐linear behavior of the σ(σw) relationship. In this study, asymptotic limits at zero and infinite salinity are first established in which, σ is expressed as a linear function of σw with four parameters: cementation exponent (m), the equivalent value of volumetric surface electrical conductivity (σs), the volume fraction of overlapped diffuse layer (ϕod) and parameter χ representing the ratio of the volume fraction of the water phase to that of the solid phases in the surface conduction pathway. Subsequently, we bridge the gap between the two extremes by employing the Padé approximant (PA). Given that parameter χ exhibits a marginal influence on the σ(σw) curve, based on measurements for 15 samples, we identify its optimal value to be 0.4. After setting the optimal value of χ, we proceed to evaluate the performance of the PA model by comparing its estimates and estimates made by two existing models to measured values from 27 rock samples and eight sediment samples. The comparison confirms that the PA model estimates are more accurate than estimates made by existing models, particularly at low salinity and for samples with higher cation exchange capacity. The PA model is advantageous in scenarios involving the interpretation of electrical data in freshwater environments.
Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice
Authors: Roh Junyeop Daniel , Bae Mihyun , Kim Hyosang , Yang Yeji , Lee Yeunkeum , Cho Yisul , Lee Suho , Li Yan , Yang Esther , Jang Hyunjee , Kim Hyeonji , Kim Hyun , Kang Hyojin , Ellegood Jacob , Lerch Jason P. , Bae Yong Chul , Kim Jin Young , Kim Eunjoon
Published: December 2024

Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.
Synergistic, multi-level understanding of psychedelics: three systematic reviews and meta-analyses of their pharmacology, neuroimaging and phenomenology
Authors: Shinozuka Kenneth , Jerotic Katarina , Mediano Pedro , Zhao Alex T. , Preller Katrin H. , Carhart-Harris Robin , Kringelbach Morten L.
Published: December 2024

Serotonergic psychedelics induce altered states of consciousness and have shown potential for treating a variety of neuropsychiatric disorders, including depression and addiction. Yet their modes of action are not fully understood. Here, we provide a novel, synergistic understanding of psychedelics arising from systematic reviews and meta-analyses of three hierarchical levels of analysis: (1) subjective experience (phenomenology), (2) neuroimaging and (3) molecular pharmacology. Phenomenologically, medium and high doses of LSD yield significantly higher ratings of visionary restructuralisation than psilocybin on the 5-dimensional Altered States of Consciousness Scale. Our neuroimaging results reveal that, in general, psychedelics significantly strengthen between-network functional connectivity (FC) while significantly diminishing within-network FC. Pharmacologically, LSD induces significantly more inositol phosphate formation at the 5-HT2A receptor than DMT and psilocin, yet there are no significant between-drug differences in the selectivity of psychedelics for the 5-HT2A, 5-HT2C, or D2 receptors, relative to the 5-HT1A receptor. Our meta-analyses link DMT, LSD, and psilocybin to specific neural fingerprints at each level of analysis. The results show a highly non-linear relationship between these fingerprints. Overall, our analysis highlighted the high heterogeneity and risk of bias in the literature. This suggests an urgent need for standardising experimental procedures and analysis techniques, as well as for more research on the emergence between different levels of psychedelic effects.
Colorectal cancer patients-derived immunity-organoid platform unveils cancer-specific tissue markers associated with immunotherapy resistance
Authors: Esposito A. , Agostini A. , Quero G. , Piro G. , Priori L. , Caggiano A. , Scaglione G. , Battaglia A. , Calegari M. A. , Salvatore L. , Bensi M. , Maratta M. G. , Ceccarelli A. , Trovato G. , Genovese G. , Gurreri E. , Ascrizzi S. , Martini M. , Fiorillo C. , Fattorossi A. , De Sanctis F. , Ugel S. , Corbo V. , Alfieri S. , Tortora G. , Carbone C.
Published: December 2024

Colorectal cancer (CRC) is a devastating disease, ranking as the second leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors (ICIs) have emerged as promising treatments; however, their efficacy is largely restricted to a subgroup of microsatellite instable (MSI) CRCs. In contrast, microsatellite stable (MSS) CRCs, which account for the majority of cases, exhibit variable and generally weaker response to ICIs, with only a subset demonstrating exceptional responsiveness. Identifying novel cancer-specific tissue (CST) markers predictive of immunotherapy response is crucial for refining patient selection and overcoming treatment resistance. In this study, we developed clinically relevant CRC organoids and autologous immune system interaction platforms to model ICI response. We conducted a comprehensive molecular characterization of both responder and non-responder models, identifying CST markers that predict ICI response. Validation of these findings was performed using an independent cohort of patient specimens through multiplex immunofluorescence. Furthermore, we demonstrated that knocking out a key gene from the identified predictive signature in resistant organoids restored immune sensitivity and induced T-cell-mediated apoptosis. Overall, our results provide novel insights into the mechanisms underlying immunotherapy resistance and suggest new markers for enhancing patient selection. These findings may pave the way for new therapeutic options in MSS patients, potentially broadening the cohort of individuals eligible for immunotherapy.
The history of uveitis: from antiquity to the present day
Authors: Ghadiri Nima
Published: December 2024

This comprehensive review traces the historical understanding and treatment of uveitis from ancient civilisations to modern medicine, a history which reflects the evolution of medical understanding and practice in general. Early descriptions of ocular inflammation appear in Egyptian medical papyri from 1700 BCE, with subsequent contributions from Greek and Roman physicians, including Hippocrates and Galen, who provided foundational observations of ocular inflammatory conditions. Medieval scholars in the Middle East, particularly Avicenna, preserved and advanced classical knowledge while recognising the systemic nature of ocular inflammation. The Renaissance and Enlightenment periods brought anatomical precision and the emergence of ophthalmology as a distinct specialty, notably through innovations such as Helmholtz’s ophthalmoscope in 1851. The twentieth century marked a paradigm shift with the evolution of immunological understanding, leading to the recognition of autoimmune mechanisms and genetic predispositions in uveitis. The introduction of corticosteroids mid-century revolutionised treatment, followed by the development of steroid-sparing immunomodulatory agents and, more recently, targeted biological therapies. Contemporary advances in imaging technology and the establishment of international collaborative groups have standardised classification and treatment approaches. This historical perspective demonstrates the progression from empirical observations to precision medicine in uveitis, highlighting the importance of understanding this evolution for advancing future therapeutic strategies.
The need for Cre-loci controls in conditional mouse experiments: Mrp8-cre transgene predisposes mice to antibody-induced arthritis
Authors: Xu Zhongwei , Romero‐Castillo Laura , Moreno-Giró Àlex , Pandey Rajan Kumar , Holmdahl Rikard
Published: December 2024

The Cre/loxP system is extensively utilized to pinpoint gene functions in specific cell types or developmental stages, typically without major disturbance to the host’s genome. However, we found that the random insertion of the Mrp8-cre transgene significantly promotes the host’s innate immune response. This effect is characterized by elevated susceptibility to cartilage antibody-induced arthritis, likely due to interference with genes near the insertion site. These findings underscore the potential biological disturbances caused by random transgene integration, and the necessity for stringent control strategies to avoid biased interpretations when using Cre-conditional strains.
Impact of inter-twin growth discordance on preeclampsia: based on ultrasonic estimated fetal weight
Authors: Chen Lan , Cao Zhijuan , Qiao Ping , Liu Xiaohua , Ying Hao
Published: December 2024

A retrospective cohort study with 4396 twins who registered before 13 gestational weeks and delivered between January 2013 and December 2020 at Shanghai First Maternity and Infant Hospital, China, was conducted to clarify causal associations between inter-twin estimated fetal weight discordance and preeclampsia. Ultrasound measurements of fetal biometry were collected until the confirmation of preeclampsia diagnosis or the termination of pregnancy (when preeclampsia did not occur). Inter-twin discordance was divided into binary variables using cut-offs of 10%, 15%, and 20%. The associations between inter-twin discordance and preeclampsia were analyzed using generalized estimating equations and group-based trajectory modeling methods. The incidence of preeclampsia was 13.9%, among which 21.8% of cases were diagnosed at early onset and 55.3% at a severe stage. Inter-twin discordance based on estimated fetal weight during pregnancy was positively associated with preeclampsia. The associations were robust and constant by treating the discordance as continuous and binary. Two groups, the stable trajectory group, including 92% of participants, and the changing trajectory group, including 8% of participants, were divided according to the group-based trajectory models. Compared with the stable trajectory group, the risk of developing preeclampsia in the changing trajectory group increased by 50.3% (OR = 1.502, 95%CI: 1.073, 2.105). Subgroup analysis showed positive association primarily in early-onset preeclampsia (OR: 3.859, CI: 2.293, 6.494) and severe preeclampsia (OR: 1.896, CI: 1.264, 2.844) subgroups. These findings can provide a direction to reduce the incidence of preeclampsia in twin pregnancies, considering growth discordance as a high-risk factor in clinical practice.
Potent AMA1-specific human monoclonal antibody against Plasmodium vivax Pre-erythrocytic and Blood Stages
Authors: Winnicki Anna C. , Dietrich Melanie H. , Yeoh Lee M. , Carias Lenore L. , Roobsoong Wanlapa , Drago Chiara L. , Malachin Alyssa N. , Redinger Karli R. , Feufack-Donfack Lionel Brice , Baldor Lea , Jung Nicolai C. , McLaine Olivia S. , Skomorovska-Prokvolit Yelenna , Orban Agnes , Opi D. Herbert , Kirtley Payton , Nielson Kiersey , Aleshnick Maya , Zanghi Gigliola , Rezakhani Nastaran , Vaughan Ashley M. , Wilder Brandon K. , Sattabongkot Jetsumon , Tham Wai-Hong , Popovici Jean , Beeson James G. , Bosch Jürgen , King Christopher L.
Published: December 2024

New therapeutics are necessary for preventing Plasmodium vivax malaria due to easy transmissibility and dormancy in the liver that increases the clinical burden due to recurrent relapse. In this manuscript we characterize 12 Pv Apical Membrane Antigen 1 (PvAMA1) specific human monoclonal antibodies from Peripheral Blood Mononuclear Cells of a Pv-exposed individual. PvAMA1 is essential for sporozoite and merozoite invasion, making it a unique therapeutic target. We show that humAb 826827 blocks the invasion of human reticulocytes using Pv clinical isolates and inhibits sporozoite invasion of human hepatocytes in vitro (IC50 of 0.3 – 3.7 µg/mL). Inoculation of human liver transgenic (FRG-humHep) female mice with humAb 826827 significantly reduces liver infection in vivo. The crystal structure of rPvAMA1 bound to 826827 shows that 826827 partially occupies the highly conserved hydrophobic groove in PvAMA1 that binds its known receptor, RON2. We have isolated a potent humAb that is isolate-transcendent, blocks both pre-erythrocytic and blood stage infection, and could be a potential therapy for Pv.
Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex
Authors: Steinhilper Ralf , Boß Linda , Freibert Sven-A. , Schulz Vinzent , Krapoth Nils , Kaltwasser Susann , Lill Roland , Murphy Bonnie J.
Published: December 2024

Iron-sulfur (FeS) protein biogenesis in eukaryotes begins with the de novo assembly of [2Fe-2S] clusters by the mitochondrial core iron-sulfur cluster assembly (ISC) complex. This complex comprises the scaffold protein ISCU2, the cysteine desulfurase subcomplex NFS1-ISD11-ACP1, the allosteric activator frataxin (FXN) and the electron donor ferredoxin-2 (FDX2). The structural interaction of FDX2 with the complex remains unclear. Here, we present cryo-EM structures of the human FDX2-bound core ISC complex showing that FDX2 and FXN compete for overlapping binding sites. FDX2 binds in either a ‘distal’ conformation, where its helix F interacts electrostatically with an arginine patch of NFS1, or a ‘proximal’ conformation, where this interaction tightens and the FDX2-specific C terminus binds to NFS1, facilitating the movement of the [2Fe-2S] cluster of FDX2 closer to the ISCU2 FeS cluster assembly site for rapid electron transfer. Structure-based mutational studies verify the contact areas of FDX2 within the core ISC complex.
Models optimized for real-world tasks reveal the task-dependent necessity of precise temporal coding in hearing
Authors: Saddler Mark R. , McDermott Josh H.
Published: December 2024

Neurons encode information in the timing of their spikes in addition to their firing rates. Spike timing is particularly precise in the auditory nerve, where action potentials phase lock to sound with sub-millisecond precision, but its behavioral relevance remains uncertain. We optimized machine learning models to perform real-world hearing tasks with simulated cochlear input, assessing the precision of auditory nerve spike timing needed to reproduce human behavior. Models with high-fidelity phase locking exhibited more human-like sound localization and speech perception than models without, consistent with an essential role in human hearing. However, the temporal precision needed to reproduce human-like behavior varied across tasks, as did the precision that benefited real-world task performance. These effects suggest that perceptual domains incorporate phase locking to different extents depending on the demands of real-world hearing. The results illustrate how optimizing models for realistic tasks can clarify the role of candidate neural codes in perception.
Group 2 innate lymphoid cells are a non-redundant source of interleukin-5 required for development and function of murine B1 cells
Authors: Troch Karoline F. , Jakob Manuel O. , Forster Patrycja M. , Jarick Katja J. , Schreiber Jonathan , Preusser Alexandra , Guerra Gabriela M. , Durek Pawel , Tizian Caroline , Sterczyk Nele , Helfrich Sofia , Duerr Claudia U. , Voehringer David , Witkowski Mario , Artis David , Rollenske Tim , Kruglov Andrey A. , Mashreghi Mir-Farzin , Klose Christoph S. N.
Published: December 2024

Tissue-resident immune cells, such as innate lymphoid cells, mediate protective or detrimental immune responses at barrier surfaces. Upon activation by stromal or epithelial cell-derived alarmins, group 2 innate lymphoid cells (ILC2s) are a rapid source of type 2 cytokines, such as IL-5. However, due to the overlap in effector functions, it remains unresolved whether ILC2s are an essential component of the type 2 response or whether their function can be compensated by other cells, such as T cells. Here we show a non-redundant role of ILC2s in supporting the development and function of B1 cells. We demonstrate that B1 cells fail to develop properly in the absence of ILC2s and identify the IL-33 receptor on ILC2s as an essential cell-intrinsic regulator of IL-5 production. Further, conditional deletion of Il5 in ILC2s results in defective B1 cell development and immunoglobulin production. Consequently, B1 cells with phosphatidylcholine specific B cell receptor rearrangements are diminished in ILC2-deficient mice. Thus, our data establish an essential function of ILC2s in supporting B1 cells and antibody production at barrier surfaces.
SHIV remission in macaques with early treatment initiation and ultra long-lasting antiviral activity
Authors: Daly Michele B. , Dinh Chuong , Holder Angela , Rudolph Donna , Ruone Susan , Swaims-Kohlmeier Alison , Khalil George , Sharma Sunita , Mitchell James , Condrey Jillian , Kim Daniel , Pan Yi , Curtis Kelly , Williams Peter , Spreen William , Heneine Walid , García-Lerma J. Gerardo
Published: December 2024

Studies in SIV-infected macaques show that the virus reservoir is particularly refractory to conventional suppressive antiretroviral therapy (ART). We posit that optimized ART regimens designed to have robust penetration in tissue reservoirs and long-lasting antiviral activity may be advantageous for HIV or SIV remission. Here we treat macaques infected with RT-SHIV with oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine without (n = 4) or with (n = 4) the immune activator vesatolimod after the initial onset of viremia. We document full suppression in all animals during treatment (4-12 months) and no virus rebound after treatment discontinuation (1.5-2 years of follow up) despite CD8 + T cell depletion. We show efficient multidrug penetration in virus reservoirs and persisting rilpivirine in plasma for 2 years after the last dose. Our results document a type of virus remission that is achieved through early treatment initiation and provision of ultra long-lasting antiviral activity that persists after treatment cessation.
Dynamics of the blood plasma proteome during hyperacute HIV-1 infection
Authors: Nazziwa Jamirah , Freyhult Eva , Hong Mun-Gwan , Johansson Emil , Årman Filip , Hare Jonathan , Gounder Kamini , Rezeli Melinda , Mohanty Tirthankar , Kjellström Sven , Kamali Anatoli , Karita Etienne , Kilembe William , Price Matt A. , Kaleebu Pontiano , Allen Susan , Hunter Eric , Ndung’u Thumbi , Gilmour Jill , Rowland-Jones Sarah L. , Sanders Eduard , Hassan Amin S. , Esbjörnsson Joakim
Published: December 2024

The complex dynamics of protein expression in plasma during hyperacute HIV-1 infection and its relation to acute retroviral syndrome, viral control, and disease progression are largely unknown. Here, we quantify 1293 blood plasma proteins from 157 longitudinally linked plasma samples collected before, during, and after hyperacute HIV-1 infection of 54 participants from four sub-Saharan African countries. Six distinct longitudinal expression profiles are identified, of which four demonstrate a consistent decrease in protein levels following HIV-1 infection. Proteins involved in inflammatory responses, immune regulation, and cell motility are significantly altered during the transition from pre-infection to one month post-infection. Specifically, decreased ZYX and SCGB1A1 levels, and increased LILRA3 levels are associated with increased risk of acute retroviral syndrome; increased NAPA and RAN levels, and decreased ITIH4 levels with viral control; and increased HPN, PRKCB, and ITGB3 levels with increased risk of disease progression. Overall, this study provides insight into early host responses in hyperacute HIV-1 infection, and present potential biomarkers and mechanisms linked to HIV-1 disease progression and viral load.
Fully printed zero-static power MoS2 switch coded reconfigurable graphene metasurface for RF/microwave electromagnetic wave manipulation and control
Authors: Xiao Xiaoyu , Peng Zixing , Zhang Zirui , Zhou Xinyao , Liu Xuzhao , Liu Yang , Wang Jingjing , Li Haiyu , Novoselov Kostya S. , Casiraghi Cinzia , Hu Zhirun
Published: December 2024

Reduction of power consumption is the key target for modern electronic devices. To this end, a lot of attention is paid to zero-static power switches, being able to change their state between highly resistive and highly conductive and remain in this state even in the absence of external voltage. Still, the implementation of such switches is slow because of compatibility issues of new materials with CMOS technology. At the same time, printable technology enables low-cost processes at ambient temperature and integration of devices onto flexible substrates. Here we demonstrate that printed Ag/MoS2/Ag heterostructures can be used as zero-static power switches in radiofrequency/microwave spectrum and fully-integrated reconfigurable metasurfaces. Combined with graphene, our printed platform enables reconfigurable metasurface for electromagnetic wave manipulation and control for wireless communications, sensing, and holography. In addition, it is also demonstrated that the localised MoS2 phase change may have promoted Ag diffusion in forming conductive filaments.
Self-assembly of 1T/1H superlattices in transition metal dichalcogenides
Authors: Luo Chaojie , Cao Guohua , Wang Beilin , Jiang Lili , Zhao Hengyi , Li Tongrui , Tai Xiaolin , Lin Zhiyong , Lin Yue , Sun Zhe , Cui Ping , Zhang Hui , Zhang Zhenyu , Zeng Changgan
Published: December 2024

Heterostructures and superlattices composed of layered transition metal dichalcogenides (TMDs), celebrated for their superior emergent properties over individual components, offer significant promise for the development of multifunctional electronic devices. However, conventional fabrication techniques for these structures depend on layer-by-layer artificial construction and are hindered by their complexity and inefficiency. Herein, we introduce a universal strategy for the automated synthesis of TMD superlattice single crystals through self-assembly, exemplified by the NbSe2-xTex 1T/1H superlattice. The core principle of this strategy is to balance the formation energies of T (octahedral) and H (trigonal prismatic) phases. By adjusting the Te to Se stoichiometric ratio in NbSe2-xTex, we reduce the formation energy disparity between the T and H phases, enabling the self-assembly of 1T and 1H layers into a 1T/1H superlattice. The resulting 1T/1H superlattices retain electronic characteristics of both 1T and 1H layers. We further validate the universality of this strategy by achieving 1T/1H superlattices through substituting Nb atoms in NbSe2 with V or Ti atoms. This self-assembly for superlattice crystal synthesis approach could extend to other layered materials, opening new avenues for efficient fabrication and broad applications of superlattices.
Coxsackievirus and adenovirus receptor expression facilitates enteroviral infections to drive the development of pancreatic cancer
Authors: Bastea Ligia I. , Liu Xiang , Fleming Alicia K. , Pandey Veethika , Döppler Heike , Edenfield Brandy H. , Krishna Murli , Zhang Lizhi , Thompson E. Aubrey , Grandgenett Paul M. , Hollingsworth Michael A. , Fairweather DeLisa , Clemens Dahn , Storz Peter
Published: December 2024

The development of pancreatic cancer requires both, acquisition of an oncogenic mutation in KRAS as well as an inflammatory insult. However, the physiological causes for pancreatic inflammation are less defined. We show here that oncogenic KRas-expressing pre-neoplastic lesion cells upregulate coxsackievirus (CVB) and adenovirus receptor (CAR). This facilitates infections from enteroviruses such as CVB3, which can be detected in approximately 50% of pancreatic cancer patients. Moreover, using an animal model we show that a one-time pancreatic infection with CVB3 in control mice is transient, but in the presence of oncogenic KRas drives chronic inflammation and rapid development of pancreatic cancer. We further demonstrate that a knockout of CAR in pancreatic lesion cells blocks these CVB3-induced effects. Our data demonstrate that KRas-caused lesions promote the development of pancreatic cancer by enabling certain viral infections.
Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes
Authors: Yin Jiang-An , Frick Lukas , Scheidmann Manuel C. , Liu Tingting , Trevisan Chiara , Dhingra Ashutosh , Spinelli Anna , Wu Yancheng , Yao Longping , Vena Dalila Laura , Knapp Britta , Guo Jingjing , De Cecco Elena , Ging Kathi , Armani Andrea , Oakeley Edward J. , Nigsch Florian , Jenzer Joel , Haegele Jasmin , Pikusa Michal , Täger Joachim , Rodriguez-Nieto Salvador , Bouris Vangelis , Ribeiro Rafaela , Baroni Federico , Bedi Manmeet Sakshi , Berry Scott , Losa Marco , Hornemann Simone , Kampmann Martin , Pelkmans Lucas , Hoepfner Dominic , Heutink Peter , Aguzzi Adriano
Published: December 2024

Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms. The quadruple-sgRNA libraries yielded high perturbation efficacies in deletion (75–99%) and silencing (76–92%) experiments and substantial fold changes in activation experiments. Moreover, an arrayed activation screen of 1,634 human transcription factors uncovered 11 novel regulators of the cellular prion protein PrPC, screening with a pooled version of the ablation library led to the identification of 5 novel modifiers of autophagy that otherwise went undetected, and ‘post-pooling’ individually produced lentiviruses eliminated template-switching artefacts and enhanced the performance of pooled screens for epigenetic silencing. Quadruple-sgRNA arrayed libraries are a powerful and versatile resource for targeted genome-wide perturbations.
Communicative health literacy and associated variables in nine European countries: results from the HLS19 survey
Authors: Metanmo Salvatore , Finbråten Hanne Søberg , Bøggild Henrik , Nowak Peter , Griebler Robert , Guttersrud Øystein , Bíró Éva , Unim Brigid , Charafeddine Rana , Griese Lennert , Kucera Zdenek , Le Christopher , Schaeffer Doris , Vrdelja Mitja , Mancini Julien ,   The HLS19 Consortium, Pelikan Jürgen , Straßmayr Christa , Griebler Robert , Dietscher Christina , van den Broucke Stephan , Charafeddine Rana , Yanakieva Antoniya , Dzhafer Nigyar , Kucera Zdeněk , Steflova Alena , Bøggild Henrik , Sørensen Andreas Jull , Mancini Julien , Allaire Cécile , Schaeffer Doris , Schmidt-Gernig Alexander , Bíró Éva , Bruton Lucy , Gibney Sarah , Levin-Zamir Diane , Palmieri Luigi , Galeone Daniela , Pettersen Kjell Sverre , Le Christopher , da Costa Andreia Jorge Silva , de Arriaga Miguel Telo , Lopatina Maria , Drapkina Oxana , Klocháňová Zuzana , Vrdelja Mitja , Kolnik Tamara Štemberger , De Gani Saskia Maria , Gasser Karin
Published: December 2024

Our study aimed to report on variables associated with communicative health literacy (COM-HL) in European adults. The HLS19 survey was conducted in 2019–2021 including nine countries which measured COM-HL by using a validated questionnaire (HLS19-COM-P-Q6 with a score ranging from 0 to 100). Linear regression models were used to study variables associated with COM-HL globally (multilevel model with random intercepts and slopes and at country level) and in each country. Additional models studied each of the HLS19-COM-P-Q6 items separately. The mean COM-HL score ranged between 62.5 and 76.6 across countries. Among the 18,137 pooled participants, COM-HL was positively associated with age, a higher self-perceived social status, previous training in healthcare, an increasing number of general practitioner visits; and negatively associated with female sex, reported financial difficulties, having a chronic condition and an increasing number of specialist visits. These effects were heterogeneous from one country to another, and from one item to another when analysing the different COM-HL items separately. However, there was a consistent statistically significant association between COM-HL (score and each item) and financial difficulties as well as self-perceived social status in all countries. Interventions to improve communication between patients and physicians should be a high priority to limit communication disparities.
Dual gene set enrichment analysis (dualGSEA); an R function that enables more robust biological discovery and pre-clinical model alignment from transcriptomics data
Authors: Bull Courtney , Byrne Ryan M. , Fisher Natalie C. , Corry Shania M. , Amirkhah Raheleh , Edwards Jessica , Hillson Lily V. S. , Lawler Mark , Ryan Aideen E. , Lamrock Felicity , Dunne Philip D. , Malla Sudhir B.
Published: December 2024

Gene set enrichment analysis (GSEA) tools can identify biological insights within gene expression-based studies. Although their statistical performance has been compared, the downstream biological implications that arise when choosing between the range of pairwise or single sample forms of GSEA methods remain understudied. We compare the statistical and biological results obtained from various pre-ranking methods/options for pairwise GSEA, followed by a stand-alone comparison of GSEA, single sample GSEA (ssGSEA) and gene set variation analysis (GSVA). Pairwise GSEA and fGSEA provide similar results when deployed using a range of gene pre-ranking methods. However, pairwise GSEA can overgeneralise biological enrichment, as when the most statistically significant signatures were assessed using single sample approaches, there was a complete absence of biological distinction between these groups. To avoid these issues, we developed a new dualGSEA tool, which provides users with multiple statistics and visuals to aid interpretation of results. This new tool removes the possibility of users inadvertently interpreting statistical findings as equating to biological distinction between samples within groups-of-interest. dualGSEA provides a more robust basis for discovery research, one which allows user to compare both statistical significance alongside biological distinctions in their data.
Mediterranean seagrasses provide essential coastal protection under climate change
Authors: Agulles M. , Marbà N. , Duarte C. M. , Jordà G.
Published: December 2024

Seagrasses are vital in coastal areas, offering crucial ecosystem services and playing a relevant role in coastal protection. The decrease in the density of Mediterranean seagrasses over recent decades, due to warming and anthropogenic stressors, may imply a serious environmental threat. Here we quantify the role of coastal impact reduction induced by seagrass presence under present and future climate. We focus in the Balearic Islands, a representative and well monitored region in the Mediterranean. Our results quantify how important the presence of seagrasses is for coastal protection. The complete loss of seagrasses would lead to an extreme water level (eTWL) increase comparable to the projected sea level rise (SLR) at the end of the century under the high end scenario of greenhouse gases emissions. Under that scenario, the eTWL could increase up to ~ 1.4 m, with 54% of that increase attributed to seagrass loss. These findings underscore the importance of seagrass conservation for coastal protection.