bluuebunny/crossref_metadata_2025 huggingface dataset:
Order–disorder transitions within deformable particle suspensions in planar Poiseuille flow
Authors: Millett Paul C.
Published: January 2024

Three-dimensional simulations of the ordering of elastic capsule suspensions within planar Poiseuille flow channels are reported. The simulations utilize the immersed boundary method coupled with the lattice Boltzmann method to capture the complex flow-induced capsule deformations and hydrodynamic interactions within the suspensions. A parametric study is presented whereby the confinement ratio and the particle deformability are varied independently within a two-dimensional range relevant to this ordering phenomenon. The initial distribution of capsules is random, and the simulations evolve the system from a disordered state to an ordered one, while an order parameter that quantifies the fraction of capsules belonging to one-dimensional train assemblies is computed throughout time. A monotonic increase in ordering is observed with increasing deformability. However, an optimal confinement ratio is identified corresponding to a peak in the order parameter. This peak is attributed to the competition between increasing long-range capsule attractions and decreasing in-plane capsule density (with fixed volume fraction) as the confinement ratio increases. Simulations are also performed to understand how dispersity in capsule size and deformability impact the degree of ordering. It is shown that ordering is quite sensitive to dispersity in capsule size, and much less sensitive to dispersity in deformability. Overall, the results provide important insights for the design of microfluidic devices.
Afterlives of Anders als die Andern and of Weimar
Authors: Friedman Sara
Published: January 2024

This article uses reconstructions of the 1919 German LGBTQ+ rights film Anders als die Andern (Different from the Others) to consider the meaning of the Weimar Republic. It surveys Weimar's historiography, memorialization efforts, public commemorations, museums, and film reconstruction, drawing connections between these fields. The film as an incomplete document becomes a metaphor for incomplete histories. As such, it offers suggestions for engaging with fragmentary pasts.
FULVIA AND THE CHEEKY RHETOR (SUET. RHET. 5)
Authors: Beness J. Lea , Hillard Tom
Published: January 2024

This paper concerns the translation and interpretation of a succinct quip of Sextus Clodius, a rhetorician in Antony's entourage, on the subject of Fulvia's swollen cheek. The jest is often interpreted as having suggested that she tempted Clodius’ pen, and various double meanings have been proposed. Contextualization may supply a key. The remark could mean that Fulvia seemed to be testing the point of her stylus, and the dark allusion might then be to reports of the manner in which Fulvia had allegedly mistreated the severed head of Cicero.
Game-theoretic policy computing and simulation for blockchained buffering system via diffusion approximation
Authors: Dai Wanyang
Published: January 2024

We study 2-stage game-theoretic problem oriented 3-stage service policy computing, convolutional neural network (CNN) based algorithm design, and simulation for a blockchained buffering system with federated learning. More precisely, based on the game-theoretic problem consisting of both “win-lose” and “win-win” 2-stage competitions, we derive a 3-stage dynamical service policy via a saddle point to a zero-sum game problem and a Nash equilibrium point to a non-zero-sum game problem. This policy is concerning users-selection, dynamic pricing, and online rate resource allocation via stable digital currency for the system. The main focus is on the design and analysis of the joint 3-stage service policy for given queue/environment state dependent pricing and utility functions. The asymptotic optimality and fairness of this dynamic service policy is justified by diffusion modeling with approximation theory. A general CNN based policy computing algorithm flow chart along the line of the so-called big model framework is presented. Simulation case studies are conducted for the system with three users, where only two of the three users can be selected into the service by a zero-sum dual cost game competition policy at a time point. Then, the selected two users get into service and share the system rate service resource through a non-zero-sum dual cost game competition policy. Applications of our policy in the future blockchain based Internet (e.g., metaverse and web3.0) and supply chain finance are also briefly illustrated.
On Research Ethics and Ethical Responsibilities: Facing Up to Sexual Harassment and Assault During Field Research
Authors: Mershon Carol
Published: January 2024

What are the ethical responsibilities that social science researchers have, not only to the people we study but also to ourselves as scholars and other scholars? This article argues that as political and social scientists, we need to expand our notion of research ethics, to adopt a notion that embraces treatment of our subject–participants and ourselves as researchers. This study is anchored in the still-growing literature on research ethics in fieldwork and draws on political science work on the ethical implications of the risks and realities of sexual violence for scholars who conduct fieldwork. The article looks beyond political science to feminist-informed research in the social sciences as it develops the argument about the ethical responsibilities of social scientists. In investigating the overarching question, the article addresses resources for survivors of sexual harassment and assault during field research.
Field Closeting: Navigating Fieldwork as a Queer Scholar
Authors: Stevens Campbell M.
Published: January 2024

Fieldwork is fraught with methodological and ethical concerns, particularly for those junior scholars seeking to establish themselves. There is a pressure to conduct research that pushes the boundaries of emerging techniques and brings our theories to bear on case studies that are underrepresented in the literature. Although this pressure is felt by nearly everyone, the barriers to accessing fieldwork and the premium of privilege lead to significant inequalities (Fujii 2016), which are becoming increasingly apparent as the academy diversifies. Being a white cis-male, I have benefited from overarching systems of privilege across my education, my career, and my international fieldwork. Yet as a gay man, international fieldwork poses potential challenges, illuminating additional realities with which researchers must contend.1
Introduction: Sexual Harassment and Gender-Based Violence in Political Science Fieldwork
Authors: Hunt Stacey Leigh
Published: January 2024

Political scientists recently have taken great strides in addressing sexual harassment and assault in the discipline. Little has been said, however, about sexual violence that political scientists may confront during field research. Field research involves any data-collection activity that occurs away from a researcher’s home institution, including visiting a prominent archive, interviewing political elites, and conducting direct observation of political phenomenon, and fieldwork is widely considered essential to data collection and career development across political science subfields. Field researchers may experience numerous power disparities that put them at acute risk for sexual or gender-based violence in the field, and evidence suggests that such experiences are pervasive and professionally devastating. In an effort to reduce gender-based violence and discrimination across academic worksites, several disciplines and institutions have developed specific guidelines and protocols to prevent and address sexual harassment and assault during fieldwork (Berkeley PATH to Care Center 2020; University of California, Riverside 2018; University of Toronto, Department of Anthropology 2019; Woodgate et al. 2018). Political scientists, however, have largely failed to conceptualize field placements as work settings or to address gender-based violence during fieldwork in our curriculum, training, and policies. Instead, they rely on deeply held methodological fallacies that insist on a field researcher’s absolute privilege, trivialize experiences of sexual violence, and weaponize rape myths to portray survivors as professionally incompetent (Hunt 2022).
From “Lab Rats” to “Mad Scientists”: Cultivating Agentic Learning Through Student-Led Simulation Redesign
Authors: Forester Summer , Jett Janel , Holtey Bjorn
Published: January 2024

Simulations are increasingly prominent in classrooms, and research shows that such activities provide an array of benefits. In general, simulations tend to situate students as “lab rats” (Asal 2005) who get to discuss the experiment. We call for bringing students into a simulation not as lab rats but instead as “mad scientists.” We specifically propose using a simulation’s debriefing step as an opportunity for students to imagine how they might revise the simulation that they experienced and to defend their revisions using concepts from class. We argue that such student-led revisions cultivate agentic engagement, a form of engagement in which students recognize themselves as co-constructors of knowledge with and for their peers. To test this notion, we modified the “Isle of Ted” with an expanded post-simulation debriefing. We found that our approach cultivated student engagement and buy-in, required students to think of concepts dynamically, and was relatively simple to implement. Our study contributes to the literature on simulations as effective and engaging classroom tools, and it also emphasizes the potential for simulations to spark agentic learning.
Untimely destruction: pestilence, war, and accumulation in the long run
Authors: Bell Clive , Gersbach Hans , Komarov Evgenij
Published: January 2024

This paper analyses the effects of disease and war on the accumulation of human and physical capital. We employ an overlapping generation framework in which young adults, motivated by old-age provision and possibly altruism, make decisions about investments in schooling and capital. A poverty trap exists for a wide range of constant war losses and premature adult mortality. If parents are altruistic and the sub-utility function for own consumption is more concave than that for their evaluation of their children’s full income in adulthood, the only possible steady-state growth path involves full education. Otherwise, steady-state paths with incompletely educated children may exist. When mortality and destruction rates are stochastic, the initial boundary conditions and agents’ beliefs have a strong influence on the paths generated by a sequence of shocks. Calibrating the model to Kenya, simulations for stochastic settings yield the finding that a trap exists and is always avoided, but the chances of a slow recovery are substantial.
Coupling GEDI LiDAR and Optical Satellite for Revealing Large‐Scale Maize Lodging in Northeast China
Authors: Zhang Qiang , Zhang Geli , Zhang Yao , Xiao Xiangming , You Nanshan , Li Zhichao , Tang Hao , Yang Tong , Di Yuanyuan , Dong Jinwei
Published: January 2024

Wind‐induced crop lodging can reduce agricultural production and impact food security. However, a systematic evaluation of large‐scale crop lodging and its drivers is lacking, mostly due to the limited observations available. Such knowledge gaps hinder the application of effective management practices to mitigate yield losses. Here, we quantify maize‐lodging induced by three consecutive typhoons in Northeast China in 2020 using direct crop canopy height observations from the Global Ecosystem Dynamics Investigations (GEDI) instrument and optical satellite imagery. We show that the canopy water‐related vegetation index provides a robust wall‐to‐wall mapping of crop lodging, supported by changes in GEDI canopy height. Our spatially contiguous lodging maps show that lodging intensity is mainly due to typhoon intensity (64.34%), with maize plantation fraction (11.94%) and phenology (7.94%) as secondary factors. The shelterbelt forest may partly alleviate the lodging risk, but its effect requires further investigation. Considering the recent expansion of maize cultivation and the poleward shift of landfalling typhoons alongside climate change, the lodging risk may increase for maize and further threaten China's food security.
Uncovering the Dynamics of Multi‐Sector Impacts of Hydrological Extremes: A Methods Overview
Authors: de Brito Mariana Madruga , Sodoge Jan , Fekete Alexander , Hagenlocher Michael , Koks Elco , Kuhlicke Christian , Messori Gabriele , de Ruiter Marleen , Schweizer Pia‐Johanna , Ward Philip J.
Published: January 2024

Hydrological extremes, such as droughts and floods, can trigger a complex web of compound and cascading impacts (CCI) due to interdependencies between coupled natural and social systems. However, current decision‐making processes typically only consider one impact and disaster event at a time, ignoring causal chains, feedback loops, and conditional dependencies between impacts. Analyses capturing these complex patterns across space and time are thus needed to inform effective adaptation planning. This perspective paper aims to bridge this critical gap by presenting methods for assessing the dynamics of the multi‐sector CCI of hydrological extremes. We discuss existing challenges, good practices, and potential ways forward. Rather than pursuing a single methodological approach, we advocate for methodological pluralism. We see complementary or even convergent roles for analyses based on quantitative (e.g., data‐mining, systems modeling) and qualitative methods (e.g., mental models, qualitative storylines). The data‐driven and knowledge‐driven methods provided here can serve as a useful starting point for understanding the dynamics of both high‐frequency CCI and low‐likelihood but high‐impact CCI. With this perspective, we hope to foster research on CCI to improve the development of adaptation strategies for reducing the risk of hydrological extremes.
The Altitudinal Dependences of the Inter‐Hemispheric Asymmetry in the Mid‐Latitude Ionospheric Post‐Midnight Enhancement During Equinox
Authors: Zhang H. , Cai H. T. , Wan X. , Hu K. , Xiong C. , Gao S. Z. , Yang L. B.
Published: January 2024

Using observations from multi‐satellites at different altitudes, including the CHAllenging Minisatellite Payload (CHAMP), the Gravity Recovery and Climate Experiment, Swarm B, and Defense Meteorological Satellites Program F17, the ionospheric post‐midnight enhancement at mid‐latitudes and the associated inter‐hemispheric asymmetry during equinox are investigated in this study. During equinox months, the ionospheric electron density enhancement during post‐nighttime at mid‐latitudes is visible in both hemispheres, however, it is asymmetric between the Northern and Southern Hemispheres. At most longitudes, inter‐hemispheric asymmetry of Mid‐latitude Ionospheric Post‐midnight Enhancement (MIPE) reverses with altitudes, from a stronger electron density in the Northern Hemisphere at CHAMP altitude to a stronger electron density in the Southern Hemisphere at top ionosphere during equinox. The reversal altitude and reversal time have significant longitudinal differences. The effective ionospheric uplifting induced by the combination of neutral winds and geomagnetic field configuration is the main contribution to the asymmetry reversal of MIPE at lower altitudes, as shown in the simulations from the SAMI2 and HWM14 models. In comparison with that in the Southern Hemisphere, the stronger neutral winds in the Northern Hemisphere move the plasma along the geomagnetic field lines to a higher altitude with lower chemical recombination, resulting in the enhancement of electron density.
The Importance of Local Thermal Circulations in PM2.5 Formation in a River Valley: A Case Study From the Lower Yangtze River, China
Authors: Shao Min , Liu Xuanming , Lv Shun , Dai Qili , Mu Qing
Published: January 2024

Poor air quality is often experienced in densely populated areas located alongside large rivers. The presence of a river valley can modify local meteorology, potentially interfering with the formation of air pollutants such as PM2.5. However, the mechanisms behind PM2.5 formation in river valleys and its impacts on surrounding regions remain poorly understood. This study investigates the formation mechanisms of PM2.5 in the Nanjing reach of the Yangtze River, considering its complex terrain and anthropogenic emissions, through numerical simulation. Simulated results revealed higher PM2.5 concentrations along the Yangtze River compared to the average concentrations in Nanjing, primarily driven by elevated nitrate level. Factors such as higher humidity, wind speed, ageostrophic wind field, and shallow boundary layer were identified as key contributors to the increased PM2.5 concentrations along the river. Our study demonstrates significant impact of local thermal circulations on PM2.5 formation, resulting from the interaction between the large water body of the Yangtze River and the urban area. This phenomenon was confirmed through sensitivity experiments, which showed attenuated local thermal circulations in the absence of the Yangtze River. Source apportionment and process analysis results confirm the dominant roles of local thermal circulation related horizontal and vertical advections, with diurnal fluctuations, in shaping PM2.5 variations along the river. Inorganic chemistry processes also played a non‐negligible role, particularly during polluted conditions. Local thermal circulations in river valleys are crucial for PM2.5 formation, highlighting the need for comprehensive strategies to tackle air pollution in similar regions.
Iron imbalance in neurodegeneration
Authors: Levi Sonia , Ripamonti Maddalena , Moro Andrea Stefano , Cozzi Anna
Published: January 2024

Iron is an essential element for the development and functionality of the brain, and anomalies in its distribution and concentration in brain tissue have been found to be associated with the most frequent neurodegenerative diseases. When magnetic resonance techniques allowed iron quantification in vivo, it was confirmed that the alteration of brain iron homeostasis is a common feature of many neurodegenerative diseases. However, whether iron is the main actor in the neurodegenerative process, or its alteration is a consequence of the degenerative process is still an open question. Because the different iron-related pathogenic mechanisms are specific for distinctive diseases, identifying the molecular mechanisms common to the various pathologies could represent a way to clarify this complex topic. Indeed, both iron overload and iron deficiency have profound consequences on cellular functioning, and both contribute to neuronal death processes in different manners, such as promoting oxidative damage, a loss of membrane integrity, a loss of proteostasis, and mitochondrial dysfunction. In this review, with the attempt to elucidate the consequences of iron dyshomeostasis for brain health, we summarize the main pathological molecular mechanisms that couple iron and neuronal death.
TKT-PARP1 axis induces radioresistance by promoting DNA double-strand break repair in hepatocellular carcinoma
Authors: Geng Longpo , Zhu Mingming , Luo Dongjun , Chen Huihui , Li Binghua , Lao Yuanxiang , An Hongda , Wu Yue , Li Yunzheng , Xia Anliang , Shi Yi , Tong Zhuting , Lu Shanshan , Xu Dengqiu , Wang Xu , Zhang Wenjun , Sun Beicheng , Xu Zhu
Published: January 2024

Hepatocellular carcinoma (HCC) stands as the fifth most prevalent malignant tumor on a global scale and presents as the second leading cause of cancer-related mortality. DNA damage-based radiotherapy (RT) plays a pivotal role in the treatment of HCC. Nevertheless, radioresistance remains a primary factor contributing to the failure of radiation therapy in HCC patients. In this study, we investigated the functional role of transketolase (TKT) in the repair of DNA double-strand breaks (DSBs) in HCC. Our research unveiled that TKT is involved in DSB repair, and its depletion significantly reduces both non-homologous end joining (NHEJ) and homologous recombination (HR)-mediated DSB repair. Mechanistically, TKT interacts with PARP1 in a DNA damage-dependent manner. Furthermore, TKT undergoes PARylation by PARP1, resulting in the inhibition of its enzymatic activity, and TKT can enhance the auto-PARylation of PARP1 in response to DSBs in HCC. The depletion of TKT effectively mitigates the radioresistance of HCC, both in vitro and in mouse xenograft models. Moreover, high TKT expression confers resistance of RT in clinical HCC patients, establishing TKT as a marker for assessing the response of HCC patients who received cancer RT. In summary, our findings reveal a novel mechanism by which TKT contributes to the radioresistance of HCC. Overall, we identify the TKT-PARP1 axis as a promising potential therapeutic target for improving RT outcomes in HCC.
Integrating rare genetic variants into DPYD pharmacogenetic testing may help preventing fluoropyrimidine-induced toxicity
Authors: Larrue Romain , Fellah Sandy , Hennart Benjamin , Sabaouni Naoual , Boukrout Nihad , Van der Hauwaert Cynthia , Delage Clément , Cheok Meyling , Perrais Michaël , Cauffiez Christelle , Allorge Delphine , Pottier Nicolas
Published: January 2024

Variability in genes involved in drug pharmacokinetics or drug response can be responsible for suboptimal treatment efficacy or predispose to adverse drug reactions. In addition to common genetic variations, large-scale sequencing studies have uncovered multiple rare genetic variants predicted to cause functional alterations in genes encoding proteins implicated in drug metabolism, transport and response. To understand the functional importance of rare genetic variants in DPYD, a pharmacogene whose alterations can cause severe toxicity in patients exposed to fluoropyrimidine-based regimens, massively parallel sequencing of the exonic regions and flanking splice junctions of the DPYD gene was performed in a series of nearly 3000 patients categorized according to pre-emptive DPD enzyme activity using the dihydrouracil/uracil ([UH2]/[U]) plasma ratio as a surrogate marker of DPD activity. Our results underscore the importance of integrating next-generation sequencing-based pharmacogenomic interpretation into clinical decision making to minimize fluoropyrimidine-based chemotherapy toxicity without altering treatment efficacy.
Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer
Authors: Mah Chui Yan , Nguyen An Dieu Trang , Niijima Takuto , Helm Madison , Dehairs Jonas , Ryan Feargal J. , Ryan Natalie , Quek Lake-Ee , Hoy Andrew J. , Don Anthony S. , Mills Ian G. , Swinnen Johannes V. , Lynn David J. , Nassar Zeyad D. , Butler Lisa M.
Published: January 2024

Background

Peroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis. As prostate cancer (PCa) is particularly reliant on fatty acid metabolism, we explored the contribution of peroxisomal β-oxidation (perFAO) to PCa viability and therapy response.

Methods

Bioinformatic analysis was performed on clinical transcriptomic datasets to identify the perFAO enzyme, 2,4-dienoyl CoA reductase 2 (DECR2) as a target gene of interest. Impact of DECR2 and perFAO inhibition via thioridazine was examined in vitro, in vivo, and in clinical prostate tumours cultured ex vivo. Transcriptomic and lipidomic profiling was used to determine the functional consequences of DECR2 inhibition in PCa.

Results

DECR2 is upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa (CRPC). Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and therapy-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. DECR2 influences cell cycle progression and lipid metabolism to support tumour cell proliferation. Further, co-targeting of perFAO and standard-of-care androgen receptor inhibition enhanced suppression of PCa cell proliferation.

Conclusion

Our findings support a focus on perFAO, specifically DECR2, as a promising therapeutic target for CRPC and as a novel strategy to overcome lethal treatment resistance.
The E3 ubiquitin ligase Itch regulates death receptor and cholesterol trafficking to affect TRAIL-mediated apoptosis
Authors: Holloway James , Seeley Aidan , Cobbe Neville , Turkington Richard C. , Longley Daniel B. , Evergren Emma
Published: January 2024

The activation of apoptosis signalling by TRAIL (TNF-related apoptosis-inducing ligand) through receptor binding is a fundamental mechanism of cell death induction and is often perturbed in cancer cells to enhance their cell survival and treatment resistance. Ubiquitination plays an important role in the regulation of TRAIL-mediated apoptosis, and here we investigate the role of the E3 ubiquitin ligase Itch in TRAIL-mediated apoptosis in oesophageal cancer cells. Knockdown of Itch expression results in resistance to TRAIL-induced apoptosis, caspase-8 activation, Bid cleavage and also promotes cisplatin resistance. Whilst the assembly of the death-inducing signalling complex (DISC) at the plasma membrane is not perturbed relative to the control, TRAIL-R2 is mis-localised in the Itch-knockdown cells. Further, we observe significant changes to mitochondrial morphology alongside an increased cholesterol content. Mitochondrial cholesterol is recognised as an important anti-apoptotic agent in cancer. Cells treated with a drug that increases mitochondrial cholesterol levels, U18666A, shows a protection from TRAIL-induced apoptosis, reduced caspase-8 activation, Bid cleavage and cisplatin resistance. We demonstrate that Itch knockdown cells are less sensitive to a Bcl-2 inhibitor, show impaired activation of Bax, cytochrome c release and an enhanced stability of the cholesterol transfer protein STARD1. We identify a novel protein complex composed of Itch, the mitochondrial protein VDAC2 and STARD1. We propose a mechanism where Itch regulates the stability of STARD1. An increase in STARD1 expression enhances cholesterol import to mitochondria, which inhibits Bax activation and cytochrome c release. Many cancer types display high mitochondrial cholesterol levels, and oesophageal adenocarcinoma tumours show a correlation between chemotherapy resistance and STARD1 expression which is supported by our findings. This establishes an important role for Itch in regulation of extrinsic and intrinsic apoptosis, mitochondrial cholesterol levels and provides insight to mechanisms that contribute to TRAIL, Bcl-2 inhibitor and cisplatin resistance in cancer cells.
The central role of tilted anisotropy for field-free spin–orbit torque switching of perpendicular magnetization
Authors: Hu Chen-Yu , Chen Wei-De , Liu Yan-Ting , Huang Chao-Chung , Pai Chi-Feng
Published: January 2024

The discovery of efficient magnetization switching upon device activation by spin Hall effect (SHE)-induced spin–orbit torque (SOT) changed the course of magnetic random-access memory (MRAM) research and development. However, for electronic systems with perpendicular magnetic anisotropy (PMA), the use of SOT is still hampered by the necessity of a longitudinal magnetic field to break magnetic symmetry and achieve deterministic switching. In this work, we demonstrate that robust and tunable field-free current-driven SOT switching of perpendicular magnetization can be controlled by the growth protocol in Pt-based magnetic heterostructures. We further elucidate that such growth-dependent symmetry breaking originates from the laterally tilted magnetic anisotropy of the ferromagnetic layer with PMA, a phenomenon that has been largely neglected in previous studies. We show experimentally and in simulation that in a PMA system with tilted anisotropy, the deterministic field-free switching exhibits a conventional SHE-induced damping-like torque feature, and the resulting current-induced effective field shows a nonlinear dependence on the applied current density. This relationship could be potentially misattributed to an unconventional SOT origin.
Epigenetic reprogramming shapes the cellular landscape of schwannoma
Authors: Liu S. John , Casey-Clyde Tim , Cho Nam Woo , Swinderman Jason , Pekmezci Melike , Dougherty Mark C. , Foster Kyla , Chen William C. , Villanueva-Meyer Javier E. , Swaney Danielle L. , Vasudevan Harish N. , Choudhury Abrar , Pak Joanna , Breshears Jonathan D. , Lang Ursula E. , Eaton Charlotte D. , Hiam-Galvez Kamir J. , Stevenson Erica , Chen Kuei-Ho , Lien Brian V. , Wu David , Braunstein Steve E. , Sneed Penny K. , Magill Stephen T. , Lim Daniel , McDermott Michael W. , Berger Mitchel S. , Perry Arie , Krogan Nevan J. , Hansen Marlan R. , Spitzer Matthew H. , Gilbert Luke , Theodosopoulos Philip V. , Raleigh David R.
Published: January 2024

Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy.
Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Authors: Chandramohan Arun , Josien Hubert , Yuen Tsz Ying , Duggal Ruchia , Spiegelberg Diana , Yan Lin , Juang Yu-Chi Angela , Ge Lan , Aronica Pietro G. , Kaan Hung Yi Kristal , Lim Yee Hwee , Peier Andrea , Sherborne Brad , Hochman Jerome , Lin Songnian , Biswas Kaustav , Nestor Marika , Verma Chandra S. , Lane David P. , Sawyer Tomi K. , Garbaccio Robert , Henry Brian , Kannan Srinivasaraghavan , Brown Christopher J. , Johannes Charles W. , Partridge Anthony W.
Published: January 2024

Although stapled α-helical peptides can address challenging targets, their advancement is impeded by poor understandings for making them cell permeable while avoiding off-target toxicities. By synthesizing >350 molecules, we present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects. Key insights include a clear correlation between lipophilicity and permeability, removal of positive charge to avoid off-target toxicities, judicious anionic residue placement to enhance solubility/behavior, optimization of C-terminal length/helicity to enhance potency, and optimization of staple type/number to avoid polypharmacology. Workflow application gives peptides with >292x improved cell proliferation potencies and no off-target cell proliferation effects ( > 3800x on-target index). Application of these ‘design rules’ to a distinct Mdm2(X) peptide series improves ( > 150x) cellular potencies and removes off-target toxicities. The outlined workflow should facilitate therapeutic impacts, especially for those targets such as Mdm2(X) that have hydrophobic interfaces and are targetable with a helical motif.
Towards provably efficient quantum algorithms for large-scale machine-learning models
Authors: Liu Junyu , Liu Minzhao , Liu Jin-Peng , Ye Ziyu , Wang Yunfei , Alexeev Yuri , Eisert Jens , Jiang Liang
Published: January 2024

Large machine learning models are revolutionary technologies of artificial intelligence whose bottlenecks include huge computational expenses, power, and time used both in the pre-training and fine-tuning process. In this work, we show that fault-tolerant quantum computing could possibly provide provably efficient resolutions for generic (stochastic) gradient descent algorithms, scaling as $${{{{{{{\mathcal{O}}}}}}}}({T}^{2}\times {{{{{{{\rm{polylog}}}}}}}}(n))$$
O

(

T

2

×
polylog

(

n

)

)

, where n is the size of the models and T is the number of iterations in the training, as long as the models are both sufficiently dissipative and sparse, with small learning rates. Based on earlier efficient quantum algorithms for dissipative differential equations, we find and prove that similar algorithms work for (stochastic) gradient descent, the primary algorithm for machine learning. In practice, we benchmark instances of large machine learning models from 7 million to 103 million parameters. We find that, in the context of sparse training, a quantum enhancement is possible at the early stage of learning after model pruning, motivating a sparse parameter download and re-upload scheme. Our work shows solidly that fault-tolerant quantum algorithms could potentially contribute to most state-of-the-art, large-scale machine-learning problems.
Improving rechargeable magnesium batteries through dual cation co-intercalation strategy
Authors: Roy Ananyo , Sotoudeh Mohsen , Dinda Sirshendu , Tang Yushu , Kübel Christian , Groß Axel , Zhao-Karger Zhirong , Fichtner Maximilian , Li Zhenyou
Published: January 2024

The development of competitive rechargeable Mg batteries is hindered by the poor mobility of divalent Mg ions in cathode host materials. In this work, we explore the dual cation co-intercalation strategy to mitigate the sluggishness of Mg2+ in model TiS2 material. The strategy involves pairing Mg2+ with Li+ or Na+ in dual-salt electrolytes in order to exploit the faster mobility of the latter with the aim to reach better electrochemical performance. A combination of experiments and theoretical calculations details the charge storage and redox mechanism of co-intercalating cationic charge carriers. Comparative evaluation reveals that the redox activity of Mg2+ can be improved significantly with the help of the dual cation co-intercalation strategy, although the ionic radius of the accompanying monovalent ion plays a critical role on the viability of the strategy. More specifically, a significantly higher Mg2+ quantity intercalates with Li+ than with Na+ in TiS2. The reason being the absence of phase transition in the former case, which enables improved Mg2+ storage. Our results highlight dual cation co-intercalation strategy as an alternative approach to improve the electrochemical performance of rechargeable Mg batteries by opening the pathway to a rich playground of advanced cathode materials for multivalent battery applications.
Nb3Cl8: a prototypical layered Mott-Hubbard insulator
Authors: Grytsiuk Sergii , Katsnelson Mikhail I. , Loon Erik G.C.P. van , Rösner Malte
Published: January 2024

Despite its simplicity and relevance for the description of electronic correlations in solids, the Hubbard model is seldom inarguably realized in real materials. Here, we show that monolayer Nb3Cl8 is an ideal candidate to be described within a single-orbital Hubbard model, constructed within a “molecular” rather than atomic basis set using ab initio constrained random phase approximation calculations. We provide the necessary ingredients to connect experimental reality with ab initio material descriptions and correlated electron theory, which clarifies that monolayer Nb3Cl8 is a Mott insulator with a gap of about 1.4 to 2.0 eV depending on its dielectric environment. Comparisons to an atomistic three-orbital model show that the single-molecular-orbital description is adequate and reliable. We further comment on the electronic and magnetic structure of the compound and show that the Mott insulating state survives in the low-temperature bulk phases of the material featuring distinct experimentally verifiable characteristics.
Dopamine-independent effect of rewards on choices through hidden-state inference
Authors: Blanco-Pozo Marta , Akam Thomas , Walton Mark E.
Published: January 2024

Dopamine is implicated in adaptive behavior through reward prediction error (RPE) signals that update value estimates. There is also accumulating evidence that animals in structured environments can use inference processes to facilitate behavioral flexibility. However, it is unclear how these two accounts of reward-guided decision-making should be integrated. Using a two-step task for mice, we show that dopamine reports RPEs using value information inferred from task structure knowledge, alongside information about reward rate and movement. Nonetheless, although rewards strongly influenced choices and dopamine activity, neither activating nor inhibiting dopamine neurons at trial outcome affected future choice. These data were recapitulated by a neural network model where cortex learned to track hidden task states by predicting observations, while basal ganglia learned values and actions via RPEs. This shows that the influence of rewards on choices can stem from dopamine-independent information they convey about the world’s state, not the dopaminergic RPEs they produce.
Production and characterization of human hair keratin bioplastic films with novel plasticizers
Authors: Shubha Anand , Sharmita Gupta , Anita Lakhani
Published: January 2024

Since their invention, conventional plastics have contributed in the betterment of the society in numerous ways, nevertheless their deleterious impacts on the natural ecosystems and living creatures is irrefutable. The management of plastic waste generated is a concern worldwide and therefore quest for the plastic alternates or bioplastics is imminent. Here, we explore the suitability of keratin from human hair waste as the candidate for the production of bioplastic films. Keratin extracted from hair was used to form the films or ‘kertics’ by solution casting and curing. Ethanediol, di-ethylene glycol and tri-ethylene glycol were used as novel plasticizers along with glycerol in the keratin film formation. The film prepared were of the thickness 190–220 µm with the area of about 4.54 ± 0.2 cm2. Water uptake by G100, ED100, DEG100 and TEG100 films was recorded to be 4.8, 6.2, 4.9 and 6.3% respectively. FESEM analysis revealed that the films with 100 µl of 1% glycerol (G100) had continuous surface morphology except few pits of 0.1 µm, also DEG100 and TEG100 films have the most uniform surface morphology with no evident pits, holes or bulges. X-ray diffractogram showed characteristic peak of keratin at 19.5° and the d-spacing value observed was 0.45 nm. The FTIR studies suggested that the films retained keratin in non degraded form, and possessed the characteristic Amide peaks. The films were also found to be biodegradable in studies involving keratinophilic fungal strain of A. oryzae. These films could found potential applications in packaging industry, disposable items manufacturing and biomaterial generation.
RadioLab project: knowledge of radon gas in Italy
Authors: Ambrosino F. , La Verde G. , Colucci M. , Fanti V. , Barrale D. , Caciolli A. , Hemmer S. , De Giorgi M. L. , Ventura A. , Immè J. , Pagano A. , Budinich M. , Vascotto M. , Montalbano V. , Capua M. , Tucci R. , Chiosso M. , Visca L. , Groppi F. , Pugliese M.
Published: January 2024

RadioLab is an Italian project, addressed to school-age people, and designed for the dissemination of scientific culture on the theme of environmental radioactivity, with particular regards to the importance of knowledge of radon gas exposure. The project is a nationwide initiative promoted by the National Institute of Nuclear Physics- INFN. First tool used by the project, and of immediate impact to assess the public awareness on radon, is the administration of the survey “do you know the radon gas?”. In the survey, together with the knowledge of radon and of its sources, information on personal, cultural and territorial details regarding the interviewees are also taken. Reasonably, the survey invests not only young people, but also their relatives, school workers and, gradually, the public. The survey is administrated during exhibitions or outreach events devoted to schools, but also open to the public. The survey is in dual form: printed and online. The online mode clearly leads RadioLab project even outside the school environment. Based on the results of the survey, several statistical analyses have been performed and many conclusions are drawn about the knowledge of the population on the radon risk. The RadioLab benefit and the requirement to carry on the project goals, spreading awareness of environmental radioactivity from radon, emerge. The dataset involves all twenty Italian regions and consists of 28,612 entries covering the 5-year period 2018–2022.
Assessment of safety profile of secukinumab in real-world scenario using United States food and drug administration adverse event reporting system database
Authors: Eshwar Vishnu , Kamath Ashwin
Published: January 2024

Secukinumab is an anti-IL-17 monoclonal antibody approved for treating psoriasis and various arthritides. A comprehensive evaluation of its safety, especially in a real-world setting, is necessary. This study aimed to describe the adverse events (AE) associated with secukinumab use using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. FAERS data files containing AE reports from 2015 to 2021 were downloaded for data mining. Primary or secondary suspect medications indicated for psoriasis were identified and analyzed. Medical dictionary for regulatory activities (MedDRA version 24.1) was used to analyze the AE terms. To detect potential safety signals of AE from secukinumab use, disproportionality analysis was used. A total of 365,590 adverse event reports were identified; of these, 44,761 reports involved the use of secukinumab. Safety signals were identified for ocular infections and gastrointestinal adverse events at the standardised MedDRA query level. Safety signals for oral candidiasis, oral herpes, conjunctivitis, eye infections, and ulcerative colitis were identified at the preferred term level. The findings of our study are consistent with those of earlier studies, such as the increased risk of infections and inflammatory bowel disease. However, our study also identified additional safety signals that need to be further evaluated.
The post-diapause vibrational behavior, motility, and survival of the brown marmorated stink bug Halyomorpha halys (Stål) adults at different temperatures
Authors: Fouani Jalal M. , Scala Marica , Zaffaroni-Caorsi Valentina , Verrastro Vincenzo , Anfora Gianfranco , Mazzoni Valerio
Published: January 2024

Substrate-borne vibrational communication is common in pentatomids. Although several works exist on the vibrational communication of Halyomorpha halys, its vibrational behavior post diapause has not been investigated. In this study, we recorded H. halys overwintered adults using laser doppler vibrometers at three temperatures: 10 °C (inactivity), 18 °C (breaking of diapause), and 25 °C (peak of mating activity). The aim was to assess the effect of temperature on the signaling, motility, and survival of H. halys. The insects were sexed into different cages and recorded separately or joined with a cage of the opposite sex. We calculated the total time spent on signaling and walking per replica. The males predominantly emitted male signal 1 (MS1) throughout the four months of recordings. The females exclusively emitted female signal 2 (FS2) when joined with the opposite sex cage the first two months of recordings. Interestingly, they also started FS2 signaling when recorded separately, after two months. No signaling was recorded at 10 °C. At 25 °C, the signaling latency time before vibrational signaling was 24 h compared to 23 days at 18 °C. The short latency time at 25 °C correlated with a higher death rate in early stages of recording. Male walking activity was significantly higher in joined cages at 18 °C and 25 °C, suggesting the increased searching behavior near the opposite sex. Overwintered H. halys could adapt to different conditions whereas low temperatures maintain the diapause which is characterized by no signaling activity. Our results provide a foundation for bioclimatic modeling of climate change effects on H. halys and insights into the use of vibrational playbacks for mass trapping and monitoring as control techniques.
Phenotypic characterisation and production system of the Nordestino horse from a multivariate perspective
Authors: Ribeiro Neila Lidiany , de Medeiros Geovergue Rodrigues , da Silva Núbia Michelle Vieira , Soares Kilmer Oliveira , Arandas Janaína Kelli Gomes , do Nascimento George Vieira , Ribeiro Maria Norma
Published: January 2024

Zootechnical data is a big challenge in the extensive rearing system of Brazilian locally adapted breeds once smallholdings with limited resources and funds rear them. So, information on Brazil's breeding system of locally adapted breeds is still scarce; this situation is more challenging for equine breeds. The present study aimed to describe the local rearing systems and the phenotypic profile of the Nordestino horse breed in Paraíba state and contribute to breed conservation. Data from males (entire and castrated) and females from 50 municipalities in Paraíba state were used. Two hundred sixty-nine animals (111 females, 121 castrated males, and 37 entire males) from 129 breeders were analyzed. A questionnaire consisting of direct and objective questions was applied to understand the breeding system adopted. There was a predominance of the extensive breeding system (85%), which reflects the adaptation of the Nordestino Horse to the region's natural conditions. The lower frequency of use of cultivated pastures may be related to issues of economic viability since the maintenance of cultivated pastures may require additional investments compared to the use of natural pastures. Entire males had a minimum withers height (WH) of 135 cm. Of the 11 morphometric measurements, only five were considered discriminating by the stepwise analysis. The remaining Nordestino horses have morphological characteristics within the breed standard.
Identification of an inflammation-related risk signature for prognosis and immunotherapeutic response prediction in bladder cancer
Authors: Wang Yanjun , Tang Yi , Liu Zhicheng , Tan Xingliang , Zou Yuantao , Luo Sihao , Yao Kai
Published: January 2024

Tumor inflammation is one of the hallmarks of tumors and is closely related to tumor occurrence and development, providing individualized prognostic prediction. However, few studies have evaluated the relationship between inflammation and the prognosis of bladder urothelial carcinoma (BLCA) patients. Therefore, we constructed a novel inflammation-related prognostic model that included six inflammation-related genes (IRGs) that can precisely predict the survival outcomes of BLCA patients. RNA-seq expression and corresponding clinical data from BLCA patients were downloaded from The Cancer Genome Atlas database. Enrichment analysis was subsequently performed to determine the enrichment of GO terms and KEGG pathways. K‒M analysis was used to compare overall survival (OS). Cox regression and LASSO regression were used to identify prognostic factors and construct the model. Finally, this prognostic model was used to evaluate cell infiltration in the BLCA tumor microenvironment and analyze the effect of immunotherapy in high- and low-risk patients. We established an IRG signature-based prognostic model with 6 IRGs (TNFRSF12A, NR1H3, ITIH4, IL1R1, ELN and CYP26B1), among which TNFRSF12A, IL1R1, ELN and CYP26B1 were unfavorable prognostic factors and NR1H3 and ITIH4 were protective indicators. High-risk score patients in the prognostic model had significantly poorer OS. Additionally, high-risk score patients were associated with an inhibitory immune tumor microenvironment and poor immunotherapy response. We also found a correlation between IRS-related genes and bladder cancer chemotherapy drugs in the drug sensitivity data. The IRG signature-based prognostic model we constructed can predict the prognosis of BLCA patients, providing additional information for individualized prognostic judgment and treatment selection.