bluuebunny/crossref_metadata_2025 huggingface dataset:
Very Low Calorie Ketogenic Diet: What Effects on Lipid Metabolism?
Authors: Suarez Rosario , Chapela Sebastián , Llobera Natalia Daniela , Montalván Martha , Vásquez Celina Andrade , Martinuzzi Andres Luciano Nicolas , Katsanos Christos S. , Verde Ludovica , Frias-Toral Evelyn , Barrea Luigi , Muscogiuri Giovanna
Published: July 2024

Purpose of Review

This review aims to critically examine how VLCKD affects plasma lipoprotein, lipid and cholesterol metabolism. Cardiovascular disease is a worldwide health problem affecting millions of people and leading to high rates of mortality and morbidity. There is a well-established association between cardiovascular disease and circulating cholesterol. Various dietary recommendations are currently available for the management of dyslipidemia.

Recent Findings

The very low-calorie ketogenic diet (VLCKD) is becoming increasingly popular as a treatment option for several pathological conditions, including dyslipidemia. In addition to being low in calories, the VLCKD's main feature is its unique calorie distribution, emphasizing a reduction in carbohydrate consumption in favor of fat as the primary calorie source. Lowering calorie intake through a VLCKD can reduce the endogenous production of cholesterol. However, if the foods consumed are from animal sources, dietary cholesterol intake may increase due to the higher fat content of animal products. When combined, these dietary practices may have opposing effects on plasma cholesterol levels.

Studies investigating the impact of VLCKD on plasma cholesterol and low-density lipoprotein cholesterol levels report contradictory findings. While some studies found an increase in low-density lipoprotein cholesterol levels, others showed a decrease in total cholesterol and low-density lipoprotein cholesterol, along with an increase in high-density lipoprotein cholesterol.
Transferable preference learning in multi-objective decision analysis and its application to hydrocracking
Authors: Yu Guo , Wang Xinzhe , Jiang Chao , Liu Yang , Ma Lianbo , Bo Cuimei , Zhang Quanling
Published: July 2024

Hydrocracking represents a complex and time-consuming chemical process that converts heavy oil fractions into various valuable products with low boiling points. It plays a pivotal role in enhancing the quality of products within the oil refining process. Consequently, the development of efficient surrogate models for simulating the hydrocracking process and identifying appropriate solutions for multi-objective oil refining is now an important area of research. In this study, a novel transferable preference learning-driven evolutionary algorithm is proposed to facilitate multi-objective decision analysis in the oil refining process. Specifically, our approach involves considering user preferences to divide the objective space into a region of interest (ROI) and other subspaces. We then utilize Kriging models to approximate the sub-problems within the ROI. In order to enhance the robustness and generalization capability of the Kriging models during the evolutionary process, we transfer the mutual information between the sub-problems in the ROI. To validate the effectiveness as well as efficiency of our proposed method, we undertake a series of experiments on both benchmarks and the oil refining process. The experimental results conclusively demonstrate the superiority of our approach.
Stress or failure? An experimental protocol to distinguish the environmental determinants of decision-making
Authors: Vecchi Martina , Vitt Nicolai
Published: July 2024

Are economic decisions affected by short-term stress, failure, or both? Such effects have not been clearly distinguished in previous experimental research, and have the potential to worsen economic outcomes, especially in disadvantaged socioeconomic groups. We validate a novel experimental protocol to examine the individual and combined influences of stress, failure, and success. The protocol employs a 2 × 3 experimental design in two sessions and can be used online or in laboratory studies to analyse the impact of these factors on decision-making and behaviour. The stress protocol was perceived as significantly more stressful than a control task, and it induced a sizeable and significant rise in state anxiety. The provision of negative feedback (“failure”) significantly lowered participants’ assessment of their performance, induced feelings of failure, and raised state anxiety.
The ethics of personalised digital duplicates: a minimally viable permissibility principle
Authors: Danaher John , Nyholm Sven
Published: July 2024

With recent technological advances, it is possible to create personalised digital duplicates. These are partial, at least semi-autonomous, recreations of real people in digital form. Should such duplicates be created? When can they be used? This article develops a general framework for thinking about the ethics of digital duplicates. It starts by clarifying the object of inquiry– digital duplicates themselves– defining them, giving examples, and justifying the focus on them rather than other kinds of artificial being. It then identifies a set of generic harms and benefits associated with digital duplicates and uses this as the basis for formulating a minimally viable permissible principle (MVPP) that stipulates widely agreeable conditions that should be met in order for the creation and use of digital duplicates to be ethically permissible. It concludes by assessing whether it is possible for those conditions to be met in practice, and whether it is possible for the use of digital duplicates to be more or less permissible.
Operator means, barycenters, and fixed point equations
Authors: Virosztek Dániel
Published: July 2024

The seminal work of Kubo and Ando (Math Ann 246:205–224, 1979/80) provided us with an axiomatic approach to means of positive operators. As most of their axioms are algebraic in nature, this approach has a clear algebraic flavour. On the other hand, it is highly natural to take the geomeric viewpoint and consider a distance (understood in a broad sense) on the cone of positive operators, and define the mean of positive operators by an appropriate notion of the center of mass. This strategy often leads to a fixed point equation that characterizes the mean. The aim of this survey is to highlight those cases where the algebraic and the geometric approaches meet each other.
Differences in the Cellular Immune Response during and after Treatment of Sudanese Patients with Post-kala-azar Dermal Leishmaniasis, and Possible Implications for Outcome
Authors: Torres Ana , Younis Brima Musa , Alamin Mohammed , Tesema Samuel , Bernardo Lorena , Solana Jose Carlos , Moreno Javier , Mustafa Alaa-aldeen , Alves Fabiana , Musa Ahmed Mudawi , Carrillo Eugenia
Published: July 2024

Background

The host cellular immune response associated with two treatments for post-kala-azar dermal leishmaniasis (PKDL) - paromomycin plus miltefosine (Arm 1), and liposomal amphotericin B plus miltefosine (Arm 2) - was examined in Sudanese patients before treatment (D0), at the end of treatment (D42), and during the post-treatment period (D180).

Methods

Whole blood samples were stimulated with soluble Leishmania antigen for 24 h (whole blood assay [WBA]) and the concentrations of Th1/Th2/Th17-associated cytokines, IP-10, PDL-1 and granzyme B were determined.

Results

The Arm 1 treatment (98.2% cure rate) induced a Th1/Th2/Th17 response, while the Arm 2 treatment (80% cure rate) induced a Th1/Th2 response. Five Arm 2 patients relapsed and showed lower IFN-γ, TNF and IL-1β concentrations at D0 than non-relapsers in this Arm. In patients with low-IFN-γ-production at D0, Arm 1 treatment led to a better host immune response and clinical outcome than Arm 2 treatment.

Conclusions

A Th1/Th2/Th17 response was associated with a higher cure rate. Patients with low IFN-γ, TNF and IL-1β before treatment are more likely to relapse if they undergo Arm 2-type treatment. Determining IFN-γ, TNF and IL-10 levels prior to treatment could help predict patients at higher risk of relapse/recovery from PKDL.

Trial Registration

ClinicalTrials.gov NCT03399955, Registered 17 January 2018, https://clinicaltrials.gov/study/ NCT03399955.

Graphical Abstract
Optimization of operating parameters of a drum-type feed metering unit developed for a human-powered floating fish feeder
Authors: Prem Ritu , Tewari V. K. , Das Souvik , Maiti J. , Jayraj P. , Pareek C. M.
Published: July 2024

Feed wastage is one of the major concerns in aquaculture practice. A simple and unique floating fish feeder with drum-type metering mechanism was developed, which addresses this concern. A drum-type metering mechanism is an easy, effective, low cost metering method with low energy requirement. Optimizing the feed rate for any metering systems is a necessary pre-requisite to ensure proper feeding. In this study, the operating parameters of the drum-type feed metering unit have been optimized to achieve the desired feed rate. The influence of three independent parameters (number of metering holes, shaft speed and drum fill level) on the dependent parameter (feed rate) was studied and optimized using response surface methodology. A multilevel full factorial design approach has been adopted for the experimental design. The effect of variation in operating parameters was investigated experimentally and a response surface model was developed from experimental data. The fit of the model was expressed by an R2 value of 0.879. The optimal solutions obtained from the model with high desirability values were further used for validation experiments in aquaculture pond and found to be acceptable. It was observed that low shaft speeds and drum fill levels led to better feeding. The best settings recommended for the feeder operation were 24 metering holes, 31 % drum fill level and 30 rpm shaft speed. The feeder was found to improve feed application and reduce feed wastage. This kind of low-cost feeding systems is expected to encourage adoption of mechanized feeding among small and marginal farmers.
On the evolved psychological mechanisms that make peace and reconciliation between groups possible
Authors: McCullough Michael E. , Pietraszewski David
Published: July 2024

If group norms and decisions foster peace, then understanding how norms and decisions arise becomes important. Here, we suggest that neither norms nor other forms of group-based decision making (such as offering restitution) can be adequately understood without simultaneously considering (i) what individual psychologies are doing and (ii) the dynamics these psychologies produce when interacting with each other.
Group-structured cultural selection can explain both war and peace
Authors: Mathew Sarah , Zefferman Matthew
Published: July 2024

Glowacki recognizes the importance of norms in enabling war and peace, but does not focus on the cultural evolutionary mechanisms by which these norms are maintained. We highlight how group-structured cultural selection shapes the scale and nature of peaceful intergroup interactions. The mechanistic perspective reveals that there are many more cases of peaceful intergroup relations than the current account implies.
Investigating the Relationship Between Mood and Driver Behaviors
Authors: Öztürk İbrahim , Varankaya Merve , Öz Bahar
Published: July 2024

Abstract: Introduction: Mood and emotion variously affect our behaviors. The present study examined the relationship between positive and negative affect and driver behaviors as well as the mediating role of perceived stress and driving anger. Method: A total of 369 drivers (age: M = 35.52, SD = 10.61) participated in the study by completing the Positive and Negative Affect Schedule, the Perceived Stress Scale, the Driver Anger Scale, the Driver Behaviour Questionnaire, and the Positive Driver Behaviour Scale. Results: Six serial mediation analyses revealed multiple mediations explaining violations the most and positive behaviors the least. Both positive and negative affects were associated with greater anger, leading to more violations. Moreover, positive affect was negative and negative affect was positively related to perceived stress, which in turn was related to increased violations. For positive behaviors, positive affect was associated with less perceived stress, which was associated with more positive behaviors. Conclusion: Moods and emotions reveal a tendency to behave in ways that can be dangerous to drivers and other road users. The study was particularly important because it was the first in the literature to examine positive and negative affect on driver behaviors, perceived stress, and driving anger.
Optimal Transport Map With Prescribed Direction Indicator for Seismic Full‐Waveform Inversion
Authors: Dong Xingpeng , Yang Dinghui , Zhu Hejun
Published: July 2024

The quadratic Wasserstein (W2) metric has been proposed as a promising misfit function to mitigate cycle‐skipping phenomena in full‐waveform inversion. Mathematically, we demonstrate that the smoothness of the W2‐based adjoint source is two orders of magnitude higher than that based on L2‐norm, which guarantees a larger convergence radius of related inverse problems. However, the oscillatory characteristics of seismic signals and subsequent operations of transforming them into probability densities would decrease the accuracy of the optimal transport map T(t) and exacerbate the nonconvexity of the misfit function. To tackle these challenges, we propose the concept of prescribed direction indicator, which indicates the properly matching direction from predictions to observations, in order to correct inaccurate T(t). 1D synthetic examples suggest that reasonable bijection can be constructed through the proposed method. Numerical experiments demonstrate that it works well during optimization procedures, including enlarging the convergence radius of the inverse problem, improving the computational efficiency and enhancing the reliability of inversion results.
The Potential for Fracture Growth in Stepped Subglacial Topography as a Quarrying Mechanism
Authors: Theiss C. R. , Cuffey K. M. , Zhao Q.
Published: July 2024

Understanding the rates and mechanisms of erosion by subglacial quarrying is a major unsolved problem in geomorphology. Stress enhancement due to load concentration on bedrock ledges between cavities is hypothesized to drive the growth of fractures. Prior work assumed the formation of vertically oriented tensile fractures at the downstream margins of cavities as the controlling process, but did not account for the evolution of the stress field as fractures lengthen, and in particular the dominance of the shearing mode at fracture tips. We used 2D finite element analysis and J‐integral methods to analyze stress intensity factors and fracture growth potentials at the tips of preexisting fractures in loaded bedrock steps, taking into account normal and shear components and measured rock strengths. By examining different step heights, step riser angles, rock types, prior fracture locations and orientations, and extents of ice‐rock contact zones, we identified some situations favorable for fracture growth, especially in brittle rock types. Typically, however, the growth direction will not be vertically downward but angled up‐glacier away from the step riser, a situation unfavorable for quarrying. Moreover, in many situations, the normal stress across fracture planes will be compressive. Non‐vertical step risers buttress the bedrock and also suppress fracture growth. In contrast, reducing the sizes of ice‐rock contact zones not only increases the loading magnitude, as previously recognized, but also increases intensification of tensile stress at the tips of fractures located just up‐glacier. Thus, larger cavities, and hence, fast sliding and low effective pressures, favor quarrying more strongly than previously recognized.
How Interpretable Machine Learning Can Benefit Process Understanding in the Geosciences
Authors: Jiang Shijie , Sweet Lily‐belle , Blougouras Georgios , Brenning Alexander , Li Wantong , Reichstein Markus , Denzler Joachim , Shangguan Wei , Yu Guo , Huang Feini , Zscheischler Jakob
Published: July 2024

Interpretable Machine Learning (IML) has rapidly advanced in recent years, offering new opportunities to improve our understanding of the complex Earth system. IML goes beyond conventional machine learning by not only making predictions but also seeking to elucidate the reasoning behind those predictions. The combination of predictive power and enhanced transparency makes IML a promising approach for uncovering relationships in data that may be overlooked by traditional analysis. Despite its potential, the broader implications for the field have yet to be fully appreciated. Meanwhile, the rapid proliferation of IML, still in its early stages, has been accompanied by instances of careless application. In response to these challenges, this paper focuses on how IML can effectively and appropriately aid geoscientists in advancing process understanding—areas that are often underexplored in more technical discussions of IML. Specifically, we identify pragmatic application scenarios for IML in typical geoscientific studies, such as quantifying relationships in specific contexts, generating hypotheses about potential mechanisms, and evaluating process‐based models. Moreover, we present a general and practical workflow for using IML to address specific research questions. In particular, we identify several critical and common pitfalls in the use of IML that can lead to misleading conclusions, and propose corresponding good practices. Our goal is to facilitate a broader, yet more careful and thoughtful integration of IML into Earth science research, positioning it as a valuable data science tool capable of enhancing our current understanding of the Earth system.
Hybrid Kinetic Modeling of the Magnetosheath Impulsive Plasma Cloud Penetration Through the Magnetopause and Comparison With MMS and Other Spacecraft Observations
Authors: Lipatov A. S. , Avanov L. A. , Giles B. L. , Gershman D. J.
Published: July 2024

This research examines the plasma processes under penetration of the plasma clouds (plasmoids) across the magnetopause which is modeled as a tangential discontinuity (TD). Cases with the parallel magnetic field in both sides out of the TD are under investigation. Plasma parameters and magnetic field were chosen from the MMS mission and other spacecraft observations. The results are important for understanding the following basic space plasma physics problems: (a) plasma cloud deformation and strong phase mixing with magnetospheric plasma; (b) the transfer of mass, momentum and energy of magnetosheath and magnetic cloud plasma into magnetospheric plasmas; (c) necessary conditions for plasma cloud penetration via the magnetopause; (d) wave generation by plasma clouds inside the magnetopause.
Multiple Seismic Slip‐Rate Pulses and Mechanical and Textural Evolution of Calcite‐Bearing Fault Gouges
Authors: Cornelio C. , Aretusini S. , Spagnuolo E. , Di Toro G. , Cocco M.
Published: July 2024

Natural fault zones are complex, spatially heterogeneous systems. Rock deformation experimental studies simplify the complexity of natural fault zones either as a surface discontinuity between intact rocks (bare‐rock surfaces) or as a few mm‐thick gouge layer. However, depending on the simplified fault type and its slip history, the response to applied deformation can vary. In this work, we conduct laboratory experiments for investigating the evolution of mechanical parameters of simulated faults made of calcite gouge subjected to multiple (four) identical seismic slip‐rate pulses. We observed that, as the number of applied slip‐rate pulses increased, (a) initial friction and steady‐state friction remained approximatively constant, (b) peak friction and normalized strength excess increased and, (c) the slip distances to achieve peak and steady‐state friction, Da and Dc, decreased. The greatest changes occurred between the first and the second slip‐rate pulse. From this pulse onward, the dissipated energy of the calcite gouge fault was similar to those obtained in bare‐rock surfaces experiments. Microstructural analysis showed that, strain is localized in up to two (recrystallized) principal slip zones (PSZ) with sub‐micrometric grain size, surrounded by low porosity sintered and non‐sintered comminuted gouge domains. We conclude that previous seismic slip episodes impact on both the structure and the strain localization processes within a fault, contributing to its shear fabric evolution. We highlight that the strain localization process identifies the PSZ, dissipating the least amount of energy within the entire experimental fault zone.
Light People: Professor Manijeh Razeghi
Authors: Wang Hui , Yu Cun
Published: July 2024

Editorial

The sense of light is the first sensation the human body develops. The importance of light is self-evident. However, we all know that the light we can see and perceive covers only a small section of the spectrum. Today, for Light People, we feature a researcher who is committed to exploring different spectral bands of light ranging from deep ultraviolet to terahertz waves and working on quantum semiconductor technology, Prof. Manijeh Razeghi of the Northwestern University in the United States. Known for her quick thinking and witty remarks, Prof. Razeghi is passionate about life and always kind to others. As a scientist, she does not limit her research to a single focus, instead, she works on the entire process from material selection, device design, processing, and manufacturing, all the way to product application. She has a strong passion for education, a commitment unwavered by fame or fortune. For her students, she is both a reliable source of knowledge and a motherly figure with a caring heart. She firmly believes that all things in nature can give her energy and inspiration. In science, she is a true “pioneer” in research and a “miner” of scientific discoveries. She advises young scientists to enjoy and love what they do, and turn their research into their hobby. As a female scientist, she calls on all women to realize their true value and potential. Next, let’s hear from Professor Manijeh Razeghi, a true star who radiates energy and light.
Entangled photons enabled ultrafast stimulated Raman spectroscopy for molecular dynamics
Authors: Fan Jiahao Joel , Ou Zhe-Yu , Zhang Zhedong
Published: July 2024

Quantum entanglement has emerged as a great resource for studying the interactions between molecules and radiation. We propose a new scheme of stimulated Raman scattering with entangled photons. A quantum ultrafast Raman spectroscopy is developed for condensed-phase molecules, to monitor the exciton populations and coherences. Analytic results are obtained, showing an entanglement-enabled time-frequency scale not attainable by classical light. The Raman signal presents an unprecedented selectivity of molecular correlation functions, as a result of the Hong-Ou-Mandel interference. Our work suggests a new paradigm of using an unconventional interferometer as part of spectroscopy, with the potential to unveil advanced information about complex materials.
Inter-individual variability in neural response to low doses of LSD
Authors: Hutten Nadia R. P. W. , Quaedflieg Conny W. E. M. , Mason Natasha L. , Theunissen Eef L. , Liechti Matthias E. , Duthaler Urs , Kuypers Kim P. C. , Bonnelle Valerie , Feilding Amanda , Ramaekers Johannes G.
Published: July 2024

The repeated use of small doses of psychedelics (also referred to as “microdosing”) to facilitate benefits in mental health, cognition, and mood is a trending practice. Placebo-controlled studies however have largely failed to demonstrate strong benefits, possibly because of large inter-individual response variability. The current study tested the hypothesis that effects of low doses of LSD on arousal, attention and memory depend on an individual’s cognitive state at baseline. Healthy participants (N = 53) were randomly assigned to receive repeated doses of LSD (15 mcg) or placebo on 4 occasions divided over 2 weeks. Each treatment condition also consisted of a baseline and a 1-week follow-up visit. Neurophysiological measures of arousal (resting state EEG), pre-attentive processing (auditory oddball task), and perceptual learning and memory (visual long-term potentiation (LTP) paradigm) were assessed at baseline, dosing session 1 and 4, and follow-up. LSD produced stimulatory effects as reflected by a reduction in resting state EEG delta, theta, and alpha power, and enhanced pre-attentive processing during the acute dosing sessions. LSD also blunted the induction of LTP on dosing session 4. Stimulatory effects of LSD were strongest in individuals with low arousal and attention at baseline, while inhibitory effects were strongest in high memory performers at baseline. Decrements in delta EEG power and enhanced pre-attentive processing in the LSD treatment condition were still present during the 1-week follow-up. The current study demonstrates across three cognitive domains, that acute responses to low doses of LSD depend on the baseline state and provides some support for LSD induced neuroadaptations that sustain beyond treatment.
Genomic and single-cell analyses reveal genetic signatures of swimming pattern and diapause strategy in jellyfish
Authors: Dong Zhijun , Wang Fanghan , Liu Yali , Li Yongxue , Yu Haiyan , Peng Saijun , Sun Tingting , Qu Meng , Sun Ke , Wang Lei , Ma Yuanqing , Chen Kai , Zhao Jianmin , Lin Qiang
Published: July 2024

Jellyfish exhibit innovative swimming patterns that contribute to exploring the origins of animal locomotion. However, the genetic and cellular basis of these patterns remains unclear. Herein, we generated chromosome-level genome assemblies of two jellyfish species, Turritopsis rubra and Aurelia coerulea, which exhibit straight and free-swimming patterns, respectively. We observe positive selection of numerous genes involved in statolith formation, hair cell ciliogenesis, ciliary motility, and motor neuron function. The lineage-specific absence of otolith morphogenesis- and ciliary movement-related genes in T. rubra may be associated with homeostatic structural statocyst loss and straight swimming pattern. Notably, single-cell transcriptomic analyses covering key developmental stages reveal the enrichment of diapause-related genes in the cyst during reverse development, suggesting that the sustained diapause state favours the development of new polyps under favourable conditions. This study highlights the complex relationship between genetics, locomotion patterns and survival strategies in jellyfish, thereby providing valuable insights into the evolutionary lineages of movement and adaptation in the animal kingdom.
Actinium chelation and crystallization in a macromolecular scaffold
Authors: Wacker Jennifer N. , Woods Joshua J. , Rupert Peter B. , Peterson Appie , Allaire Marc , Lukens Wayne W. , Gaiser Alyssa N. , Minasian Stefan G. , Strong Roland K. , Abergel Rebecca J.
Published: July 2024

Targeted alpha therapy (TAT) pairs the specificity of antigen targeting with the lethality of alpha particles to eradicate cancerous cells. Actinium-225 [225Ac; t1/2 = 9.920(3) days] is an alpha-emitting radioisotope driving the next generation of TAT radiopharmaceuticals. Despite promising clinical results, a fundamental understanding of Ac coordination chemistry lags behind the rest of the Periodic Table due to its limited availability, lack of stable isotopes, and inadequate systems poised to probe the chemical behavior of this radionuclide. In this work, we demonstrate a platform that combines an 8-coordinate synthetic ligand and a mammalian protein to characterize the solution and solid-state behavior of the longest-lived Ac isotope, 227Ac [t1/2 = 21.772(3) years]. We expect these results to direct renewed efforts for 225Ac-TAT development, aid in understanding Ac coordination behavior relative to other +3 lanthanides and actinides, and more broadly inform this element’s position on the Periodic Table.
Large-scale 2D heterostructures from hydrogen-bonded organic frameworks and graphene with distinct Dirac and flat bands
Authors: Zhang Xin , Li Xiaoyin , Cheng Zhengwang , Chen Aixi , Wang Pengdong , Wang Xingyue , Lei Xiaoxu , Bian Qi , Li Shaojian , Yuan Bingkai , Gao Jianzhi , Li Fang-Sen , Pan Minghu , Liu Feng
Published: July 2024

The current strategies for building 2D organic-inorganic heterojunctions involve mostly wet-chemistry processes or exfoliation and transfer, leading to interface contaminations, poor crystallizing, or limited size. Here we show a bottom-up procedure to fabricate 2D large-scale heterostructure with clean interface and highly-crystalline sheets. As a prototypical example, a well-ordered hydrogen-bonded organic framework is self-assembled on the highly-oriented-pyrolytic-graphite substrate. The organic framework adopts a honeycomb lattice with faulted/unfaulted halves in a unit cell, resemble to molecular “graphene”. Interestingly, the topmost layer of substrate is self-lifted by organic framework via strong interlayer coupling, to form effectively a floating organic framework/graphene heterostructure. The individual layer of heterostructure inherits its intrinsic property, exhibiting distinct Dirac bands of graphene and narrow bands of organic framework. Our results demonstrate a promising approach to fabricate 2D organic-inorganic heterostructure with large-scale uniformity and highly-crystalline via the self-lifting effect, which is generally applicable to most of van der Waals materials.
Efficient and reproducible generation of human iPSC-derived cardiomyocytes and cardiac organoids in stirred suspension systems
Authors: Prondzynski Maksymilian , Berkson Paul , Trembley Michael A. , Tharani Yashasvi , Shani Kevin , Bortolin Raul H. , Sweat Mason E. , Mayourian Joshua , Yucel Dogacan , Cordoves Albert M. , Gabbin Beatrice , Hou Cuilan , Anyanwu Nnaemeka J. , Nawar Farina , Cotton Justin , Milosh Joseph , Walker David , Zhang Yan , Lu Fujian , Liu Xujie , Parker Kevin Kit , Bezzerides Vassilios J. , Pu William T.
Published: July 2024

Human iPSC-derived cardiomyocytes (hiPSC-CMs) have proven invaluable for cardiac disease modeling and regeneration. Challenges with quality, inter-batch consistency, cryopreservation and scale remain, reducing experimental reproducibility and clinical translation. Here, we report a robust stirred suspension cardiac differentiation protocol, and we perform extensive morphological and functional characterization of the resulting bioreactor-differentiated iPSC-CMs (bCMs). Across multiple different iPSC lines, the protocol produces 1.2E6/mL bCMs with ~94% purity. bCMs have high viability after cryo-recovery (>90%) and predominantly ventricular identity. Compared to standard monolayer-differentiated CMs, bCMs are more reproducible across batches and have more mature functional properties. The protocol also works with magnetically stirred spinner flasks, which are more economical and scalable than bioreactors. Minor protocol modifications generate cardiac organoids fully in suspension culture. These reproducible, scalable, and resource-efficient approaches to generate iPSC-CMs and organoids will expand their applications, and our benchmark data will enable comparison to cells produced by other cardiac differentiation protocols.
Investigating grey matter volumetric trajectories through the lifespan at the individual level
Authors: Shi Runye , Xiang Shitong , Jia Tianye , Robbins Trevor W. , Kang Jujiao , Banaschewski Tobias , Barker Gareth J. , Bokde Arun L. W. , Desrivières Sylvane , Flor Herta , Grigis Antoine , Garavan Hugh , Gowland Penny , Heinz Andreas , Brühl Rüdiger , Martinot Jean-Luc , Martinot Marie-Laure Paillère , Artiges Eric , Nees Frauke , Orfanos Dimitri Papadopoulos , Paus Tomáš , Poustka Luise , Hohmann Sarah , Millenet Sabina , Fröhner Juliane H. , Smolka Michael N. , Vaidya Nilakshi , Walter Henrik , Whelan Robert , Schumann Gunter , Lin Xiaolei , Sahakian Barbara J. , Feng Jianfeng ,   IMAGEN Consortium, Jia Tianye , Banaschewski Tobias , Barker Gareth J. , Bokde Arun L. W. , Desrivières Sylvane , Flor Herta , Grigis Antoine , Garavan Hugh , Gowland Penny , Heinz Andreas , Brühl Rüdiger , Martinot Jean-Luc , Martinot Marie-Laure Paillère , Artiges Eric , Nees Frauke , Orfanos Dimitri Papadopoulos , Paus Tomáš , Poustka Luise , Hohmann Sarah , Millenet Sabina , Fröhner Juliane H. , Smolka Michael N. , Vaidya Nilakshi , Walter Henrik , Whelan Robert , Schumann Gunter
Published: July 2024

Adolescents exhibit remarkable heterogeneity in the structural architecture of brain development. However, due to limited large-scale longitudinal neuroimaging studies, existing research has largely focused on population averages, and the neurobiological basis underlying individual heterogeneity remains poorly understood. Here we identify, using the IMAGEN adolescent cohort followed up over 9 years (14–23 y), three groups of adolescents characterized by distinct developmental patterns of whole-brain gray matter volume (GMV). Group 1 show continuously decreasing GMV associated with higher neurocognitive performances than the other two groups during adolescence. Group 2 exhibit a slower rate of GMV decrease and lower neurocognitive performances compared with Group 1, which was associated with epigenetic differences and greater environmental burden. Group 3 show increasing GMV and lower baseline neurocognitive performances due to a genetic variation. Using the UK Biobank, we show these differences may be attenuated in mid-to-late adulthood. Our study reveals clusters of adolescent neurodevelopment based on GMV and the potential long-term impact.
LARP3, LARP7, and MePCE are involved in the early stage of human telomerase RNA biogenesis
Authors: Kao Tsai-Ling , Huang Yu-Cheng , Chen Yi-Hsuan , Baumann Peter , Tseng Chi-Kang
Published: July 2024

Human telomerase assembly is a highly dynamic process. Using biochemical approaches, we find that LARP3 and LARP7/MePCE are involved in the early stage of human telomerase RNA (hTR) and that their binding to RNA is destabilized when the mature form is produced. LARP3 plays a negative role in preventing the processing of the 3′-extended long (exL) form and the binding of LARP7 and MePCE. Interestingly, the tertiary structure of the exL form prevents LARP3 binding and facilitates hTR biogenesis. Furthermore, low levels of LARP3 promote hTR maturation, increase telomerase activity, and elongate telomeres. LARP7 and MePCE depletion inhibits the conversion of the 3′-extended short (exS) form into mature hTR and the cytoplasmic accumulation of hTR, resulting in telomere shortening. Taken together our data suggest that LARP3 and LARP7/MePCE mediate the processing of hTR precursors and regulate the production of functional telomerase.
Charge-parity switching effects and optimisation of transmon-qubit design parameters
Authors: Papič Miha , Tuorila Jani , Auer Adrian , de Vega Inés , Hosseinkhani Amin
Published: July 2024

Enhancing the performance of noisy quantum processors requires improving our understanding of error mechanisms and the ways to overcome them. A judicious selection of qubit design parameters plays a pivotal role in improving the performance of quantum processors. In this study, we identify optimal ranges for qubit design parameters, grounded in comprehensive noise modeling. To this end, we also analyze the effect of a charge-parity switch caused by quasiparticles on a two-qubit gate. Due to the utilization of the second excited state of a transmon, where the charge dispersion is significantly larger, a charge-parity switch will affect the conditional phase of the two-qubit gate. We derive an analytical expression for the infidelity of a diabatic controlled-Z gate and see effects of similar magnitude in adiabatic controlled-phase gates in the tunable coupler architecture. Moreover, we show that the effect of a charge-parity switch can be the dominant quasiparticle-related error source of a two-qubit gate. We also demonstrate that charge-parity switches induce a residual longitudinal interaction between qubits in a tunable-coupler circuit. Furthermore, we introduce a performance metric for quantum circuit execution, encompassing the fidelity and number of single- and two-qubit gates in an algorithm, as well as the state preparation fidelity. This comprehensive metric, coupled with a detailed noise model, enables us to determine an optimal range for the qubit design parameters, as confirmed by numerical simulation. Our systematic analysis offers insights and serves as a guiding framework for the development of the next generation of transmon-based quantum processors.
Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition
Authors: Schwab Annemarie , Rao Zhigang , Zhang Jie , Gollowitzer André , Siebenkäs Katharina , Bindel Nino , D’Avanzo Elisabetta , van Roey Ruthger , Hajjaj Yussuf , Özel Ece , Armstark Isabell , Bereuter Leonhard , Su Fengting , Grander Julia , Bonyadi Rad Ehsan , Groenewoud Arwin , Engel Felix B. , Bell George W. , Henry Whitney S. , Angeli José Pedro Friedmann , Stemmler Marc P. , Brabletz Simone , Koeberle Andreas , Brabletz Thomas
Published: July 2024

Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial–mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1.
Consumer wearable devices for evaluation of heart rate control using digoxin versus beta-blockers: the RATE-AF randomized trial
Authors: Gill Simrat K. , Barsky Andrey , Guan Xin , Bunting Karina V. , Karwath Andreas , Tica Otilia , Stanbury Mary , Haynes Sandra , Folarin Amos , Dobson Richard , Kurps Julia , Asselbergs Folkert W. , Grobbee Diederick E. , Camm A. John , Eijkemans Marinus J. C. , Gkoutos Georgios V. , Kotecha Dipak ,   BigData@Heart Consortium,   the cardAIc group,   the RATE-AF trial team
Published: July 2024

Consumer-grade wearable technology has the potential to support clinical research and patient management. Here, we report results from the RATE-AF trial wearables study, which was designed to compare heart rate in older, multimorbid patients with permanent atrial fibrillation and heart failure who were randomized to treatment with either digoxin or beta-blockers. Heart rate (n = 143,379,796) and physical activity (n = 23,704,307) intervals were obtained from 53 participants (mean age 75.6 years (s.d. 8.4), 40% women) using a wrist-worn wearable linked to a smartphone for 20 weeks. Heart rates in participants treated with digoxin versus beta-blockers were not significantly different (regression coefficient 1.22 (95% confidence interval (CI) −2.82 to 5.27; P = 0.55); adjusted 0.66 (95% CI −3.45 to 4.77; P = 0.75)). No difference in heart rate was observed between the two groups of patients after accounting for physical activity (P = 0.74) or patients with high activity levels (≥30,000 steps per week; P = 0.97). Using a convolutional neural network designed to account for missing data, we found that wearable device data could predict New York Heart Association functional class 5 months after baseline assessment similarly to standard clinical measures of electrocardiographic heart rate and 6-minute walk test (F1 score 0.56 (95% CI 0.41 to 0.70) versus 0.55 (95% CI 0.41 to 0.68); P = 0.88 for comparison). The results of this study indicate that digoxin and beta-blockers have equivalent effects on heart rate in atrial fibrillation at rest and on exertion, and suggest that dynamic monitoring of individuals with arrhythmia using wearable technology could be an alternative to in-person assessment. ClinicalTrials.gov identifier: NCT02391337.
Unlocking opioid neuropeptide dynamics with genetically encoded biosensors
Authors: Dong Chunyang , Gowrishankar Raajaram , Jin Yihan , He Xinyi Jenny , Gupta Achla , Wang Huikun , Sayar-Atasoy Nilüfer , Flores Rodolfo J. , Mahe Karan , Tjahjono Nikki , Liang Ruqiang , Marley Aaron , Or Mizuno Grace , Lo Darren K. , Sun Qingtao , Whistler Jennifer L. , Li Bo , Gomes Ivone , Von Zastrow Mark , Tejeda Hugo A. , Atasoy Deniz , Devi Lakshmi A. , Bruchas Michael R. , Banghart Matthew R. , Tian Lin
Published: July 2024

Neuropeptides are ubiquitous in the nervous system. Research into neuropeptides has been limited by a lack of experimental tools that allow for the precise dissection of their complex and diverse dynamics in a circuit-specific manner. Opioid peptides modulate pain, reward and aversion and as such have high clinical relevance. To illuminate the spatiotemporal dynamics of endogenous opioid signaling in the brain, we developed a class of genetically encoded fluorescence sensors based on kappa, delta and mu opioid receptors: κLight, δLight and µLight, respectively. We characterized the pharmacological profiles of these sensors in mammalian cells and in dissociated neurons. We used κLight to identify electrical stimulation parameters that trigger endogenous opioid release and the spatiotemporal scale of dynorphin volume transmission in brain slices. Using in vivo fiber photometry in mice, we demonstrated the utility of these sensors in detecting optogenetically driven opioid release and observed differential opioid release dynamics in response to fearful and rewarding conditions.
An efficient learning based approach for automatic record deduplication with benchmark datasets
Authors: Ravikanth M , Korra Sampath , Mamidisetti Gowtham , Goutham Maganti , Bhaskar T.
Published: July 2024

With technological innovations, enterprises in the real world are managing every iota of data as it can be mined to derive business intelligence (BI). However, when data comes from multiple sources, it may result in duplicate records. As data is given paramount importance, it is also significant to eliminate duplicate entities towards data integration, performance and resource optimization. To realize reliable systems for record deduplication, late, deep learning could offer exciting provisions with a learning-based approach. Deep ER is one of the deep learning-based methods used recently for dealing with the elimination of duplicates in structured data. Using it as a reference model, in this paper, we propose a framework known as Enhanced Deep Learning-based Record Deduplication (EDL-RD) for improving performance further. Towards this end, we exploited a variant of Long Short Term Memory (LSTM) along with various attribute compositions, similarity metrics, and numerical and null value resolution. We proposed an algorithm known as Efficient Learning based Record Deduplication (ELbRD). The algorithm extends the reference model with the aforementioned enhancements. An empirical study has revealed that the proposed framework with extensions outperforms existing methods.
LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome
Authors: Pozojevic Jelena , Sivaprasad Radhika , Laß Joshua , Haarich Franziska , Trinh Joanne , Kakar Naseebullah , Schulz Kristin , Händler Kristian , Verrijn Stuart Annemarie A. , Giltay Jacques C. , van Gassen Koen L. , Caliebe Almuth , Holterhus Paul-Martin , Spielmann Malte , Hornig Nadine C.
Published: July 2024

Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation. Here, we present a patient with a 46,XY karyotype, born with undervirilized genitalia, age-appropriate testosterone levels and no uterus, characteristic for AIS. Diagnostic whole exome sequencing (WES) showed a maternally inherited LINE1 (L1) retrotransposon insertion in the 5′ untranslated region (5′UTR) of the AR gene. Long-read nanopore sequencing confirmed this as an insertion of a truncated L1 element of ≈ 2.7 kb and showed an increased DNA methylation at the L1 insertion site in patient-derived genital skin fibroblasts (GSFs) compared to healthy controls. The insertion coincided with reduced AR transcript and protein levels in patient-derived GSFs confirming the clinical diagnosis AIS. Our results underline the relevance of retrotransposons in human disease, and expand the growing list of human diseases associated with them.
Intratumoral microbiome of adenoid cystic carcinomas and comparison with other head and neck cancers
Authors: Karpinets Tatiana V. , Mitani Yoshitsugu , Chang Chia-Chi , Wu Xiaogang , Song Xingzhi , Flores Ivonne I. , McDaniel Lauren K. , Hoballah Yasmine M. , Veguilla Fabiana J. , Ferrarotto Renata , Colbert Lauren E. , Ajami Nadim J. , Jenq Robert R. , Zhang Jianhua , Futreal Andrew P. , El-Naggar Adel K.
Published: July 2024

Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the ACC exhibited diverse levels of species richness. We identified two main microbial subtypes within the ACC: oral-like and gut-like. Oral-like microbiomes, characterized by increased diversity and abundance of Neisseria, Leptotrichia, Actinomyces, Streptococcus, Rothia, and Veillonella (commonly found in healthy oral cavities), were associated with a less aggressive ACC-II molecular subtype and improved patient outcomes. Notably, we identified the same oral genera in oral cancer and head and neck squamous cell carcinomas. In both cancers, they were part of shared oral communities associated with a more diverse microbiome, less aggressive tumor phenotype, and better survival that reveal the genera as potential pancancer biomarkers for favorable microbiomes in ACC and other head and neck cancers. Conversely, gut-like intratumoral microbiomes, which feature low diversity and colonization by gut mucus layer-degrading species, such as Bacteroides, Akkermansia, Blautia, Bifidobacterium, and Enterococcus, were associated with poorer outcomes. Elevated levels of Bacteroides thetaiotaomicron were independently associated with significantly worse survival and positively correlated with tumor cell biosynthesis of glycan-based cell membrane components.