bluuebunny/crossref_metadata_2025 huggingface dataset:
Stochastic Optimization for Long-Term Planning of a Mining Complex with In-Pit Crushing and Conveying Systems
Authors: Findlay Liam , Dimitrakopoulos Roussos
Published: June 2024

Semi-mobile in-pit crushing and conveying (IPCC) systems can help reduce truck haulage in open-pit mines by bringing the crusher closer to the excavation areas. Optimizing a production schedule with semi-mobile IPCC requires integrating extraction sequence, destination policy, crusher relocation, conveyor layout, and truck fleet investment decisions. A mining complex with multiple mines and IPCC systems should be optimized simultaneously to find an optimal schedule for the entire value chain. An integrated stochastic optimization framework is proposed to produce long-term production schedules for mining complexes using multiple semi-mobile IPCC systems. The optimization model has flexibility to select the crusher locations and conveyor routes from anywhere inside the pits. The framework uses simulated orebody realizations to consider multi-element grade uncertainty and manage associated risk. A hybrid metaheuristic solution approach based on simulated annealing and evolutionary algorithms is implemented. The method is demonstrated using an iron ore mining complex.
Metaverse ethics: exploring the social implications of the metaverse
Authors: Yasuda Arisa
Published: June 2024

The emergence of the metaverse transforms the way humans interact with computers; the metaverse brings about a new form of human-computer interaction that is more immersive, intuitive, and seamless. In the present paper we thus aim to elucidate the role of human-computer interactions in the age of the metaverse. New forms of human-computer interaction via the metaverse are beneficial for humans in many ways; at the same time, however, there are new types of social issues that are emerging as the metaverse develops and that need to be taken seriously. Specifically, we focus upon issues such as privacy, surveillance capitalism, cyber-syndromes, amplifications of other social problems, environmental problems, and discuss what regulations would be appropriate in order to balance the adequate development of the metaverse with the safety and security of it that is required for social good, in particular for sustainable development goals. We finally propose ethical design principles for the sustainable metaverse in order to address the aforementioned and other social issues.
Associations between diabetes mellitus and subsequent non-communicable diseases in Indonesia
Authors: Pratiwi Jasmine A. Dwi , Huang Chun-Ta , Juber Nirmin F. , Liu Jason J.
Published: June 2024

Objective

To understand how diabetes mellitus (DM) diagnosed at different ages of adulthood are associated with various incident subsequent non-communicable diseases (NCDs).

Methods

We performed a nationwide population-based analysis comparing 212 participants first diagnosed with DM at 20–39, 40–49, 50–59, or 60–69 years of age, with 17,541 participants without DM history, using data from the Indonesian Family Life Survey. Subsequent NCDs that were examined included hypertension, lung diseases, heart diseases, arthritis, liver diseases, kidney diseases, and digestive diseases. We estimated weighted risk ratios and 95% confidence intervals using Poisson regression, adjusting for age, sex, urbanicity, and tobacco use history.

Results

Those diagnosed with DM in all age groups had significantly higher risk of hypertension, compared with those without DM history. Compared with those without DM history, younger individuals with DM diagnosed at 20–39 years of age had significantly higher risks of lung diseases and arthritis, and those with DM diagnosed at 20–49 years of age had significantly higher risk of digestive diseases. Older individuals with DM diagnosed at 40–69 years of age had significantly higher risk of liver diseases, and those with DM diagnosed at 40–59 years of age had significantly higher risk of heart diseases, compared with those without DM history. Participants with DM were diagnosed with subsequent NCDs at younger ages compared with those without DM history.

Conclusion

Our findings contribute to health surveillance and may promote beneficial lifestyle changes in those with early-onset and later-onset DM, which can help prevent subsequent NCDs and improve public health.
Fuzzy Decision Support Systems to Improve the Effectiveness of Training Programs in the Field of Sports Fitness
Authors: An Peng
Published: June 2024

To maximize training programs and improve individual performance, the sports fitness profession is always looking for new and innovative solutions. Fuzzy decision support systems provide a strong basis for improving training regimen efficacy through flexible and adaptive decision-making. In sports fitness, doing things differently might affect the way one can train and even lead to injury. Particularly if exercises call for expert training regimens, determining if fitness requirements are sufficiently satisfied is a difficult task. Athletes participate in training programs focusing on strengthening their bodies and minds to perform better. Each sport has unique needs, and athletes should prepare to meet those demands while still meeting their sport’s general fitness activity requirements. A novel strategy for assisting athletes with fitness-related decision-making is presented in this study as the Fitness Mamdani Decision System. At the outset, the system provides an adaptive decision framework to improve the effectiveness of training programs by applying the principles of intuitionistic fuzzy numbers and fuzzy logic. The study wants to know how to train effectively, and it takes important factors like your mood, degree of preparation, sleep quality, and stress levels into account. Using language-specific terminology and triangle membership functions, the Mamdani fuzzy inference system generates rules based on analyzing these crucial elements. Regarding measures like adaptability index, training load capacity, long-term program efficiency, and participation ratio among sports fitness individuals, the system is guided by fuzzy rules that infer decisions.
Core knowledge as a neuro-ethologist views it
Authors: Vallortigara Giorgio
Published: June 2024

Innateness of core knowledge mechanisms (in the form of “cognitive priors”) can be revealed by proper comparisons of altricial and precocial species. Cognitive priors and sensitive periods in their expression may also provide clues for the development of plausible artificial intelligence systems.
The role of language in transcending core knowledge
Authors: Carey Susan
Published: June 2024

What Babies Know (WBK) argues that core knowledge has a unique place in cognitive architecture, between fully perceptual and fully conceptual systems of representation. Here I argue that WBK's core knowledge is on the perception side of the perception/cognition divide. I discuss some implications of this conclusion for the roles language learning might play in transcending core knowledge.
Core knowledge and its role in explaining uniquely human cognition: Some questions
Authors: Schulz Armin W.
Published: June 2024

Questions can be raised about the central status that evolutionarily ancient core knowledge systems are given in Spelke's otherwise very compelling theory. So, the existence of domain-general learning capacities has to be admitted, too, and no clear reason is provided to doubt the existence of uniquely human cognitive adaptations. All of these factors should be acknowledged when explaining human thought.
Response to commentaries on What Babies Know
Authors: Spelke Elizabeth S.
Published: June 2024

Twenty-five commentaries raise questions concerning the origins of knowledge, the interplay of iconic and propositional representations in mental life, the architecture of numerical and social cognition, the sources of uniquely human cognitive capacities, and the borders among core knowledge, perception, and thought. They also propose new methods, drawn from the vibrant, interdisciplinary cognitive sciences, for addressing these questions and deepening understanding of infant minds.
Developmental cascades from early childhood attachment security to adolescent level of personality functioning among high-risk youth
Authors: O’Gorman Emily T. , Meyer Gregory J.
Published: June 2024

This study examines associations between early childhood attachment security and adolescent personality functioning in a high-risk sample within a developmental psychopathology framework. Data from 2,268 children (1165 male; 1103 female) and caregivers participating in Future of Families and Child Well-Being Study (FFCWS) were used to examine (1) effects of genetic polymorphisms of the serotonin transporter (5-HTTLPR) and dopamine D4 receptor (DRD4) genes and adverse childhood experiences (ACEs) on attachment security and emotional and behavioral dysregulation in early childhood and (2) longitudinal associations and transactional relationships among attachment security, dysregulation, negative parenting attitudes and behaviors, social competence, and adolescent personality functioning. Results revealed that ACEs predicted attachment security over and above sex or the genetic risk, and gene × environment interactions did not increment prediction. Results of cascade models showed that greater early childhood attachment security predicted higher adolescent level of personality functioning via pathways through intermediary variables. Limitations and future research directions are discussed.
Intravascular lithotripsy in peripheral lesions with severe	calcification and its use in TAVI procedure – a	meta-analysis
Authors: Sagris Marios , Ktenopoulos Nikolaos , Soulaidopoulos Stergios , Dimitriadis Kyriakos , Papanikolaou Angelos , Tzoumas Andreas , Terentes-Printzios Dimitrios , Lichtenberg Michael , Korosoglou Grigorios , Toutouzas Konstantinos , Honton Benjamin , Tousoulis Dimitris , Tsioufis Konstantinos
Published: June 2024

Summary: Background: Heavily calcified peripheral artery lesions increase the risk of vascular complications, constituting a severe challenge for the operator during catheter-based cardiovascular interventions. Intravascular Lithotripsy (IVL) technology disrupts subendothelial calcification by using localized pulsative sonic pressure waves and represents a promising technique for plaque modification in patients with severe calcification in peripheral arteries. Purpose: Our aim was to systematically review and summarize available data regarding the safety and efficacy of IVL in preparing severely calcified peripheral arteries and its use in Transcatheter Aortic Valve Implantation (TAVI). Patients and methods: This study was conducted according to the PRISMA guidelines. We systematically searched PubMed, SCOPUS, and Cochrane databases from their inception to February 23, 2023, for studies assessing the characteristics and outcomes of patients undergoing IVL in the peripheral vasculature. The diameter of the vessel lumen before and after IVL was estimated. The occurrence of peri-procedural complications was assessed using a random-effects model. Results: 20 studies with a total of 1,223 patients with heavily calcified peripheral lesions were analysed. The mean age of the cohort was 70.6 ± 17.4 years. Successful IVL delivery achieved in 100% (95% CI: 100%-100%, I2 = 0%), with an increase in the luminal diameter (SMD: 4.66, 95% CI: 3.41-5.92, I2 = 90.8%) and reduction in diameter stenosis (SMD: –4.15, 95% CI: –4.75 to –3.55, I2 = 92.8%), and a concomitant low rate of complications. The procedure was free from dissection in 97% (95% CI: 91%-100%, I2 = 81.4%) while dissections of any type (A, B, C, or D) were observed in 6% (95% CI: 2%-10%, I2 = 85.3%) of the patients. Several rare cases of abrupt closure, no-reflow phenomenon, perforation, thrombus formation, and distal embolization were recorded. Finally, the subgroup analysis of patients who underwent a TAVI with IVL assistance presented successful implantation in 100% (95% CI: 100%–100%, I2 = 0%) of the cases, with only 4% (95% CI: 0%-12%, I2 = 68.96%) presenting dissections of any sort. Conclusions: IVL seems to be an effective and safe technique for modifying severely calcified lesions in peripheral arteries and it is a promising modality in TAVI settings. Future prospective studies are needed to validate our results.
Model‐Based Investigation of Electron Precipitation‐Driven Density Structures and Their Effects on Auroral Scintillation
Authors: Vaggu Pralay Raj , Zettergren Matt , Deshpande Kshitija , Nishimura Yukitoshi , Semeter Joshua , Hirsch Michael , Hampton Don , Lamarche Leslie , Datta‐Barua Seebany
Published: June 2024

Electron density irregularities in the ionosphere can give rise to scintillations, affecting radio wave phase and amplitude. While scintillations in the cusp and polar cap regions are commonly associated with mesoscale density inhomogeneities and/or shearing, the auroral regions exhibit a strong correlation between scintillation and density structures generated by electron precipitation (arcs). We aim to examine the impact of electron precipitation on the formation of scintillation‐producing density structures using a high‐resolution physics‐based plasma model, the “Geospace Environment Model of Ion‐Neutral Interactions,” coupled with a radio propagation model, the “Satellite‐beacon Ionospheric‐scintillation Global Model of the upper Atmosphere.” Specifically, we explore the effects of varying spatial and temporal characteristics of the precipitation, including electron total energy flux and their characteristic energies, obtained from the all‐sky‐imagers and Poker Flat Incoherent Scatter Radar observations, on auroral scintillation. To capture small‐scale structures, we incorporate a power‐law turbulence spectrum that induces short wavelength features sensitive to scintillation. Finally, we compare our simulated scintillation results with satellite‐observed scintillations, along with spectral comparisons.
Why do adolescents attempt suicide? Insights from leading ideation-to-action suicide theories: a systematic review
Authors: Kirshenbaum Jaclyn S. , Pagliaccio David , Bitran Alma , Xu Elisa , Auerbach Randy P.
Published: June 2024

Suicide is a leading cause of death among adolescents, and recent suicide theories have sought to clarify the factors that facilitate the transition from suicide ideation to action. Specifically, the Interpersonal Theory of Suicide (IPTS), Integrated Motivational-Volitional Model (IMV), and Three Step Theory (3ST) have highlighted risk factors central to the formation of suicidal ideation and suicidal behaviors, which is necessary for suicide death. However, these models were initially developed and tested among adults, and given core socioemotional and neurodevelopmental differences in adolescents, the applicability of these models remains unclear. Directly addressing this gap in knowledge, this systematic review aimed to (1) describe the evidence of leading ideation-to-action theories (i.e., IPTS, IMV, 3ST) as they relate to suicide risk among adolescents, (2) integrate ideation-to-action theories within prevailing biological frameworks of adolescent suicide, and (3) provide recommendations for future adolescent suicide research. Overall, few studies provided a complete test of models in adolescent samples, and empirical research testing components of these theories provided mixed support. Future research would benefit from integrating neurodevelopmental and developmentally sensitive psychosocial frameworks to increase the applicability of ideation-to-action theories to adolescents. Further, utilizing real-time monitoring approaches may serve to further clarify the temporal association among risk factors and suicide.
Distinct functions of wild-type and R273H mutant Δ133p53α differentially regulate glioblastoma aggressiveness and therapy-induced senescence
Authors: Joruiz Sebastien M. , Von Muhlinen Natalia , Horikawa Izumi , Gilbert Mark R. , Harris Curtis C.
Published: June 2024

Despite being mutated in 92% of TP53 mutant cancers, how mutations on p53 isoforms affect their activities remain largely unknown. Therefore, exploring the effect of mutations on p53 isoforms activities is a critical, albeit unexplored area in the p53 field. In this article, we report for the first time a mutant Δ133p53α-specific pathway which increases IL4I1 and IDO1 expression and activates AHR, a tumor-promoting mechanism. Accordingly, while WT Δ133p53α reduces apoptosis to promote DNA repair, mutant R273H also reduces apoptosis but fails to maintain genomic stability, increasing the risks of accumulation of mutations and tumor’s deriving towards a more aggressive phenotype. Furthermore, using 2D and 3D spheroids culture, we show that WT Δ133p53α reduces cell proliferation, EMT, and invasion, while the mutant Δ133p53α R273H enhances all three processes, confirming its oncogenic potential and strongly suggesting a similar in vivo activity. Importantly, the effects on cell growth and invasion are independent of mutant full-length p53α, indicating that these activities are actively carried by mutant Δ133p53α R273H. Furthermore, both WT and mutant Δ133p53α reduce cellular senescence in a senescence inducer-dependent manner (temozolomide or radiation) because they regulate different senescence-associated target genes. Hence, WT Δ133p53α rescues temozolomide-induced but not radiation-induced senescence, while mutant Δ133p53α R273H rescues radiation-induced but not temozolomide-induced senescence. Lastly, we determined that IL4I1, IDO1, and AHR are significantly higher in GBMs compared to low-grade gliomas. Importantly, high expression of all three genes in LGG and IL4I1 in GBM is significantly associated with poorer patients’ survival, confirming the clinical relevance of this pathway in glioblastomas. These data show that, compared to WT Δ133p53α, R273H mutation reorientates its activities toward carcinogenesis and activates the oncogenic IL4I1/IDO1/AHR pathway, a potential prognostic marker and therapeutic target in GBM by combining drugs specifically modulating Δ133p53α expression and IDO1/Il4I1/AHR inhibitors.
MicroRNA miR-20a-5p targets CYCS to inhibit apoptosis in hepatocellular carcinoma
Authors: Olarewaju Olaniyi , Hu Yuhai , Tsay Hsin-Chieh , Yuan Qinggong , Eimterbäumer Simon , Xie Yu , Qin Renyi , Ott Michael , Sharma Amar Deep , Balakrishnan Asha
Published: June 2024

Hepatocellular carcinoma is a primary liver cancer, characterised by diverse etiology, late diagnoses, and poor prognosis. Hepatocellular carcinoma is mostly resistant to current treatment options, therefore, identification of more effective druggable therapeutic targets is needed. We found microRNA miR-20a-5p is upregulated during mouse liver tumor progression and in human hepatocellular carcinoma patients. In this study, we elucidated the therapeutic potential of targeting oncogenic miR-20a-5p, in vivo, in a xenograft model and in two transgenic hepatocellular carcinoma mouse models via adeno-associated virus-mediated miR-20a-Tough-Decoy treatment. In vivo knockdown of miR-20a-5p attenuates tumor burden and prolongs survival in the two independent hepatocellular carcinoma mouse models. We identified and validated cytochrome c as a novel target of miR-20a-5p. Cytochrome c plays a key role in initiation of the apoptotic cascade and in the electron transport chain. We show for the first time, that miR-20a modulation affects both these key functions of cytochrome c during HCC development. Our study thus demonstrates the promising ‘two birds with one stone’ approach of therapeutic in vivo targeting of an oncogenic miRNA, whereby more than one key deregulated cellular process is affected, and unequivocally leads to more effective attenuation of HCC progression and significantly longer overall survival.
The adhesion-GPCR ADGRF5 fuels breast cancer progression by suppressing the MMP8-mediated antitumorigenic effects
Authors: Wu Yalan , Liu Huixia , Sun Zhe , Liu Jieling , Li Kai , Fan Ronghui , Dai Fujun , Tang Hui , Hou Qi , Li JinSong , Tang Xiaolong
Published: June 2024

ADGRF5 (GPR116) has been identified as a facilitator of breast cancer cell migration and metastasis, yet the underlying mechanisms remain largely elusive. Our current study reveals that the absence of ADGRF5 in breast cancer cells impairs extracellular matrix (ECM)-associated cell motility and impedes in vivo tumor growth. This correlates with heightened expression of matrix metalloproteinase 8 (MMP8), a well-characterized antitumorigenic MMP, and a shift in the polarization of tumor-associated neutrophils (TANs) towards the antitumor N1 phenotype in the tumor microenvironment (TME). Mechanistically, ADGRF5 inhibits ERK1/2 activity by enhancing RhoA activation, leading to decreased phosphorylation of C/EBPβ at Thr235, hindering its nuclear translocation and subsequent activation. Crucially, two C/EBPβ binding motifs essential for MMP8 transcription are identified within its promoter region. Consequently, ADGRF5 silencing fosters MMP8 expression and CXCL8 secretion, attracting increased infiltration of TANs; simultaneously, MMP8 plays a role in decorin cleavage, which leads to trapped-inactivation of TGF-β in the TME, thereby polarizing TANs towards the antitumor N1 neutrophil phenotype and mitigating TGF-β-enhanced cell motility in breast cancer. Our findings reveal a novel connection between ADGRF5, an adhesion G protein-coupled receptor, and the orchestration of the TME, which dictates malignancy progression. Overall, the data underscore ADGRF5 as a promising therapeutic target for breast cancer intervention.
Efficient removal of nanoplastics from industrial wastewater through synergetic electrophoretic deposition and particle-stabilized foam formation
Authors: Abdeljaoued Amna , Ruiz Beatriz López , Tecle Yikalo-Eyob , Langner Marie , Bonakdar Natalie , Bleyer Gudrun , Stenner Patrik , Vogel Nicolas
Published: June 2024

Microplastic particles have been discovered in virtually all ecosystems worldwide, yet they may only represent the surface of a much larger issue. Nanoplastics, with dimensions well below 1 µm, pose an even greater environmental concern. Due to their size, they can infiltrate and disrupt individual cells within organisms, potentially exacerbating ecological impacts. Moreover, their minute dimensions present several hurdles for removal, setting them apart from microplastics. Here, we describe a process to remove colloidally stable nanoplastics from wastewater, which synergistically combines electrophoretic deposition and the formation of particle-stabilized foam. This approach capitalizes on localized changes in particle hydrophilicity induced by pH fluctuations resulting from water electrolysis at the electrode surface. By leveraging these pH shifts to enhance particle attachment to nascent bubbles proximal to the electrode, separation of colloidal particles from aqueous dispersions is achieved. Using poly(methyl methacrylate) (PMMA) colloidal particles as a model, we gain insights into the separation mechanisms, which are subsequently applied to alternative model systems with varying surface properties and materials, as well as to real-world industrial wastewaters from dispersion paints and PMMA fabrication processes. Our investigations demonstrate removal efficiencies surpassing 90%.
Distributable, metabolic PET reporting of tuberculosis
Authors: Khan R. M. Naseer , Ahn Yong-Mo , Marriner Gwendolyn A. , Via Laura E. , D’Hooge Francois , Seo Lee Seung , Yang Nan , Basuli Falguni , White Alexander G. , Tomko Jaime A. , Frye L. James , Scanga Charles A. , Weiner Danielle M. , Sutphen Michelle L. , Schimel Daniel M. , Dayao Emmanuel , Piazza Michaela K. , Gomez Felipe , Dieckmann William , Herscovitch Peter , Mason N. Scott , Swenson Rolf , Kiesewetter Dale O. , Backus Keriann M. , Geng Yiqun , Raj Ritu , Anthony Daniel C. , Flynn JoAnne L. , Barry Clifton E. , Davis Benjamin G.
Published: June 2024

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose – 2-[18F]fluoro-2-deoxytrehalose ([18F]FDT) – is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [18F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [18F]FDT from the most globally-abundant organic 18F-containing molecule, [18F]FDG. The full, pre-clinical validation of both production method and [18F]FDT now creates a new, bacterium-selective candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.
Hydrogen bond symmetrisation in D2O ice observed by neutron diffraction
Authors: Komatsu Kazuki , Hattori Takanori , Klotz Stefan , Machida Shinichi , Yamashita Keishiro , Ito Hayate , Kobayashi Hiroki , Irifune Tetsuo , Shinmei Toru , Sano-Furukawa Asami , Kagi Hiroyuki
Published: June 2024

Hydrogen bond symmetrisation is the phenomenon where a hydrogen atom is located at the centre of a hydrogen bond. Theoretical studies predict that hydrogen bonds in ice VII eventually undergo symmetrisation upon increasing pressure, involving nuclear quantum effect with significant isotope effect and drastic changes in the elastic properties through several intermediate states with varying hydrogen distribution. Despite numerous experimental studies conducted, the location of hydrogen and hence the transition pressures reported up to date remain inconsistent. Here we report the atomic distribution of deuterium in D2O ice using neutron diffraction above 100 GPa and observe the transition from a bimodal to a unimodal distribution of deuterium at around 80 GPa. At the transition pressure, a significant narrowing of the peak widths of 110 is also observed, attributed to the structural relaxation by the change of elastic properties.
Expression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response
Authors: Webb Mason J. , Sangsuwannukul Thanich , van Vloten Jacob , Evgin Laura , Kendall Benjamin , Tonne Jason , Thompson Jill , Metko Muriel , Moore Madelyn , Chiriboga Yerovi Maria P. , Olin Michael , Borgatti Antonella , McNiven Mark , Monga Satdarshan P. S. , Borad Mitesh J. , Melcher Alan , Roberts Lewis R. , Vile Richard
Published: June 2024

Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.
Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies
Authors: Figarol Sarah , Delahaye Célia , Gence Rémi , Doussine Aurélia , Cerapio Juan Pablo , Brachais Mathylda , Tardy Claudine , Béry Nicolas , Asslan Raghda , Colinge Jacques , Villemin Jean-Philippe , Maraver Antonio , Ferrer Irene , Paz-Ares Luis , Kessler Linda , Burrows Francis , Lajoie-Mazenc Isabelle , Dongay Vincent , Morin Clara , Florent Amélie , Pagano Sandra , Taranchon-Clermont Estelle , Casanova Anne , Pradines Anne , Mazieres Julien , Favre Gilles , Calvayrac Olivier
Published: June 2024

Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we combine real-time monitoring of the cell-cycle dynamics and single-cell RNA sequencing in a broad panel of oncogenic addiction such as EGFR-, ALK-, BRAF- and KRAS-mutant NSCLC, treated with their corresponding TT. We identify a common path of drug adaptation, which invariably involves alveolar type 1 (AT1) differentiation and Rho-associated protein kinase (ROCK)-mediated cytoskeletal remodeling. We also isolate and characterize a rare population of early escapers, which represent the earliest resistance-initiating cells that emerge in the first hours of treatment from the AT1-like population. A phenotypic drug screen identify farnesyltransferase inhibitors (FTI) such as tipifarnib as the most effective drugs in preventing relapse to TT in vitro and in vivo in several models of oncogenic addiction, which is confirmed by genetic depletion of the farnesyltransferase. These findings pave the way for the development of treatments combining TT and FTI to effectively prevent tumor relapse in oncogene-addicted NSCLC patients.
Late Cretaceous ammonoids show that drivers of diversification are regionally heterogeneous
Authors: Flannery-Sutherland Joseph T. , Crossan Cameron D. , Myers Corinne E. , Hendy Austin J. W. , Landman Neil H. , Witts James D.
Published: June 2024

Palaeontologists have long sought to explain the diversification of individual clades to whole biotas at global scales. Advances in our understanding of the spatial distribution of the fossil record through geological time, however, has demonstrated that global trends in biodiversity were a mosaic of regionally heterogeneous diversification processes. Drivers of diversification must presumably have also displayed regional variation to produce the spatial disparities observed in past taxonomic richness. Here, we analyse the fossil record of ammonoids, pelagic shelled cephalopods, through the Late Cretaceous, characterised by some palaeontologists as an interval of biotic decline prior to their total extinction at the Cretaceous-Paleogene boundary. We regionally subdivide this record to eliminate the impacts of spatial sampling biases and infer regional origination and extinction rates corrected for temporal sampling biases using Bayesian methods. We then model these rates using biotic and abiotic drivers commonly inferred to influence diversification. Ammonoid diversification dynamics and responses to this common set of diversity drivers were regionally heterogeneous, do not support ecological decline, and demonstrate that their global diversification signal is influenced by spatial disparities in sampling effort. These results call into question the feasibility of seeking drivers of diversity at global scales in the fossil record.
Maternal transmission as a microbial symbiont sieve, and the absence of lactation in male mammals
Authors: Fagan Brennen T. , Constable George W. A. , Law Richard
Published: June 2024

Gut microbiomes of mammals carry a complex symbiotic assemblage of microorganisms. Feeding newborn infants milk from the mammary gland allows vertical transmission of the parental milk microbiome to the offspring’s gut microbiome. This has benefits, but also has hazards for the host population. Using mathematical models, we demonstrate that biparental vertical transmission enables deleterious microbial elements to invade host populations. In contrast, uniparental vertical transmission acts as a sieve, preventing these invasions. Moreover, we show that deleterious symbionts generate selection on host modifier genes that keep uniparental transmission in place. Since microbial transmission occurs during birth in placental mammals, subsequent transmission of the milk microbiome needs to be maternal to avoid the spread of deleterious elements. This paper therefore argues that viviparity and the hazards from biparental transmission of the milk microbiome, together generate selection against male lactation in placental mammals.
Superporous sponge prepared by secondary network compaction with enhanced permeability and mechanical properties for non-compressible hemostasis in pigs
Authors: Jiang Tianshen , Chen Sirong , Xu Jingwen , Zhang Yuxiao , Fu Hao , Ling Qiangjun , Xu Yan , Chu Xiangyu , Wang Ruinan , Hu Liangcong , Li Hao , Huang Weitong , Bian Liming , Zhao Pengchao , Wei Fuxin
Published: June 2024

Developing superporous hemostatic sponges with simultaneously enhanced permeability and mechanical properties remains challenging but highly desirable to achieve rapid hemostasis for non-compressible hemorrhage. Typical approaches to improve the permeability of hemostatic sponges by increasing porosity sacrifice mechanical properties and yield limited pore interconnectivity, thereby undermining the hemostatic efficacy and subsequent tissue regeneration. Herein, we propose a temperature-assisted secondary network compaction strategy following the phase separation-induced primary compaction to fabricate the superporous chitosan sponge with highly-interconnected porous structure, enhanced blood absorption rate and capacity, and fatigue resistance. The superporous chitosan sponge exhibits rapid shape recovery after absorbing blood and maintains sufficient pressure on wounds to build a robust physical barrier to greatly improve hemostatic efficiency. Furthermore, the superporous chitosan sponge outperforms commercial gauze, gelatin sponges, and chitosan powder by enhancing hemostatic efficiency, cell infiltration, vascular regeneration, and in-situ tissue regeneration in non-compressible organ injury models, respectively. We believe the proposed secondary network compaction strategy provides a simple yet effective method to fabricate superporous hemostatic sponges for diverse clinical applications.
Observation of discrete-light temporal refraction by moving potentials with broken Galilean invariance
Authors: Qin Chengzhi , Ye Han , Wang Shulin , Zhao Lange , Liu Menglin , Li Yinglan , Hu Xinyuan , Liu Chenyu , Wang Bing , Longhi Stefano , Lu Peixiang
Published: June 2024

Refraction is a basic beam bending effect at two media’s interface. While traditional studies focus on stationary boundaries, moving boundaries or potentials could enable new laws of refractions. Meanwhile, media’s discretization plays a pivotal role in refraction owing to Galilean invariance breaking principle in discrete-wave mechanics, making refraction highly moving-speed dependent. Here, by harnessing a synthetic temporal lattice in a fiber-loop circuit, we observe discrete time refraction by a moving gauge-potential barrier. We unveil the selection rules for the potential moving speed, which can only take an integer v = 1 or fractional v = 1/q (odd q) value to guarantee a well-defined refraction. We observe reflectionless/reflective refractions for v = 1 and v = 1/3 speeds, transparent potentials with vanishing refraction/reflection, refraction of dynamic moving potential and refraction for relativistic Zitterbewegung effect. Our findings may feature applications in versatile time control and measurement for optical communications and signal processing.
Data-driven prediction of continuous renal replacement therapy survival
Authors: Zamanzadeh Davina , Feng Jeffrey , Petousis Panayiotis , Vepa Arvind , Sarrafzadeh Majid , Karumanchi S. Ananth , Bui Alex A. T. , Kurtz Ira
Published: June 2024

Continuous renal replacement therapy (CRRT) is a form of dialysis prescribed to severely ill patients who cannot tolerate regular hemodialysis. However, as the patients are typically very ill to begin with, there is always uncertainty whether they will survive during or after CRRT treatment. Because of outcome uncertainty, a large percentage of patients treated with CRRT do not survive, utilizing scarce resources and raising false hope in patients and their families. To address these issues, we present a machine learning-based algorithm to predict short-term survival in patients being initiated on CRRT. We use information extracted from electronic health records from patients who were placed on CRRT at multiple institutions to train a model that predicts CRRT survival outcome; on a held-out test set, the model achieves an area under the receiver operating curve of 0.848 (CI = 0.822–0.870). Feature importance, error, and subgroup analyses provide insight into bias and relevant features for model prediction. Overall, we demonstrate the potential for predictive machine learning models to assist clinicians in alleviating the uncertainty of CRRT patient survival outcomes, with opportunities for future improvement through further data collection and advanced modeling.
NPY-mediated synaptic plasticity in the extended amygdala prioritizes feeding during starvation
Authors: Dodt Stephan , Widdershooven Noah V. , Dreisow Marie-Luise , Weiher Lisa , Steuernagel Lukas , Wunderlich F. Thomas , Brüning Jens C. , Fenselau Henning
Published: June 2024

Efficient control of feeding behavior requires the coordinated adjustment of complex motivational and affective neurocircuits. Neuropeptides from energy-sensing hypothalamic neurons are potent feeding modulators, but how these endogenous signals shape relevant circuits remains unclear. Here, we examine how the orexigenic neuropeptide Y (NPY) adapts GABAergic inputs to the bed nucleus of the stria terminalis (BNST). We find that fasting increases synaptic connectivity between agouti-related peptide (AgRP)-expressing ‘hunger’ and BNST neurons, a circuit that promotes feeding. In contrast, GABAergic input from the central amygdala (CeA), an extended amygdala circuit that decreases feeding, is reduced. Activating NPY-expressing AgRP neurons evokes these synaptic adaptations, which are absent in NPY-deficient mice. Moreover, fasting diminishes the ability of CeA projections in the BNST to suppress food intake, and NPY-deficient mice fail to decrease anxiety in order to promote feeding. Thus, AgRP neurons drive input-specific synaptic plasticity, enabling a selective shift in hunger and anxiety signaling during starvation through NPY.
Spatiotemporal optical vortices with controllable radial and azimuthal quantum numbers
Authors: Liu Xin , Cao Qian , Zhang Nianjia , Chong Andy , Cai Yangjian , Zhan Qiwen
Published: June 2024

Optical spatiotemporal vortices with transverse photon orbital angular momentum (OAM) have recently become a focal point of research. In this work we theoretically and experimentally investigate optical spatiotemporal vortices with radial and azimuthal quantum numbers, known as spatiotemporal Laguerre-Gaussian (STLG) wavepackets. These 3D wavepackets exhibit phase singularities and cylinder-shaped edge dislocations, resulting in a multi-ring topology in its spatiotemporal profile. Unlike conventional ST optical vortices, STLG wavepackets with non-zero $${{{{{\boldsymbol{p}}}}}}$$
p
and $${{{{{\boldsymbol{l}}}}}}$$
l
values carry a composite transverse OAM consisting of two directionally opposite components. We further demonstrate mode conversion between an STLG wavepacket and an ST Hermite-Gaussian (STHG) wavepacket through the application of strong spatiotemporal astigmatism. The converted STHG wavepacket is de-coupled in intensity in space-time domain that can be utilized to implement the efficient and accurate recognition of ultrafast STLG wavepackets carried various $${{{{{\boldsymbol{p}}}}}}$$
p
and $${{{{{\boldsymbol{l}}}}}}.$$
l
.
This study may offer new insights into high-dimensional quantum information, photonic topology, and nonlinear optics, while promising potential applications in other wave phenomena such as acoustics and electron waves.
Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury
Authors: Zhao Ying , Fan Shijie , Zhu Hong , Zhao Qingqing , Fang Zimin , Xu Diyun , Lin Wante , Lin Liming , Hu Xiang , Wu Gaojun , Min Julian , Liang Guang
Published: June 2024

Recent studies have shown the crucial role of podocyte injury in the development of diabetic kidney disease (DKD). Deubiquitinating modification of proteins is widely involved in the occurrence and development of diseases. Here, we explore the role and regulating mechanism of a deubiquitinating enzyme, OTUD5, in podocyte injury and DKD. RNA-seq analysis indicates a significantly decreased expression of OTUD5 in HG/PA-stimulated podocytes. Podocyte-specific Otud5 knockout exacerbates podocyte injury and DKD in both type 1 and type 2 diabetic mice. Furthermore, AVV9-mediated OTUD5 overexpression in podocytes shows a therapeutic effect against DKD. Mass spectrometry and co-immunoprecipitation experiments reveal an inflammation-regulating protein, TAK1, as the substrate of OTUD5 in podocytes. Mechanistically, OTUD5 deubiquitinates K63-linked TAK1 at the K158 site through its active site C224, which subsequently prevents the phosphorylation of TAK1 and reduces downstream inflammatory responses in podocytes. Our findings show an OTUD5-TAK1 axis in podocyte inflammation and injury and highlight the potential of OTUD5 as a promising therapeutic target for DKD.
Facile fabrication of recyclable robust noncovalent porous crystals from low-symmetry helicene derivative
Authors: Zhang Guoli , Zhang Jian , Tao Yu , Gan Fuwei , Lin Geyu , Liang Juncong , Shen Chengshuo , Zhang Yuebiao , Qiu Huibin
Published: June 2024

Porous frameworks constructed via noncovalent interactions show wide potential in molecular separation and gas adsorption. However, it remains a major challenge to prepare these materials from low-symmetry molecular building blocks. Herein, we report a facile strategy to fabricate noncovalent porous crystals through modular self-assembly of a low-symmetry helicene racemate. The P and M enantiomers in the racemate first stack into right- and left-handed triangular prisms, respectively, and subsequently the two types of prisms alternatively stack together into a hexagonal network with one-dimensional channels with a diameter of 14.5 Å. Remarkably, the framework reveals high stability upon heating to 275 °C, majorly due to the abundant π-interactions between the complementarily engaged helicene building blocks. Such porous framework can be readily prepared by fast rotary evaporation, and is easy to recycle and repeatedly reform. The refined porous structure and enriched π-conjugation also favor the selective adsorption of a series of small molecules.
T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis
Authors: Kedia Shreeya , Ji Hao , Feng Ruoqing , Androvic Peter , Spieth Lena , Liu Lu , Franz Jonas , Zdiarstek Hanna , Anderson Katrin Perez , Kaboglu Cem , Liu Qian , Mattugini Nicola , Cherif Fatma , Prtvar Danilo , Cantuti-Castelvetri Ludovico , Liesz Arthur , Schifferer Martina , Stadelmann Christine , Tahirovic Sabina , Gokce Ozgun , Simons Mikael
Published: June 2024

Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer’s disease remains uncertain, despite age being a major risk factor. Using a mouse model of Alzheimer’s disease, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8+ T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, our data suggest that immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis.
A significant exploration on meta-heuristic based approaches for optimization in the waste management route problems
Authors: Thakur Gauri , Pal Ashok , Mittal Nitin , Yajid Mohd Shukri Ab , Gared Fikreselam
Published: June 2024

In metropolitan cities, it is very complicated to govern the optimum routes for garbage collection vehicles due to high waste production and very dense population. Furthermore, wrongly designed routes are the source of wasting time, fuel and other resources in the collection of municipal trash procedure. The Vehicle Routing Problem (VRP) published between 2011 and 2023 was systematically analysed. The majority of the surveyed research compute the waste collecting problems using metaheuristic approaches. This manuscript serves two purposes: first, categorising the VRP and its variants in the field of waste collection; second, examining the role played by most of the metaheuristics in the solution of the VRP problems for a waste collection. Three case study of Asia continent has been analysed and the results show that the metaheuristic algorithms have the capability in providing good results for large-scale data. Lastly, some promising paths ranging from highlighting research gap to future scope are drawn to encourage researchers to conduct their research work in the field of waste management route problems.
Molecular modeling analysis for functionalized graphene/sodium alginate composite
Authors: Elhaes Hanan , Ibrahim Asmaa , Osman Osama , Ibrahim Medhat A.
Published: June 2024

This study examined the functionalization of graphene with easily ionizable elements, such as lithium, and subsequently its interaction with the biopolymer sodium alginate (SA), to highlight its potential for biomedical applications. Utilizing Density Functional Theory (DFT), the research comprehensively investigated the structural, electronic, and spectroscopic properties of these graphene-based composites. The electronic properties of functionalized graphene were investigated using DFT at the B3LYP/6-31G(d,p) level. Among the various configurations studied, graphene exhibited weak interaction with two lithium atoms, displaying the highest reactivity in terms of total dipole moment (TDM) at 5.967 Debye and a HOMO/LUMO energy gap (ΔE) of 0.748 eV. Electrostatic potential mapping revealed that graphene when enhanced with lithium and three units of SA, exhibited an augmented potential density on its surface, a finding corroborated by other investigated physical properties. Notably, the configuration of graphene/3SA/Li, with weak interaction occurring at two side carbons, demonstrated the highest reactivity with a TDM of 15.509 Debye and ΔE of 0.280 eV. Additionally, a shift in the spectral characteristics of graphene towards lower wavenumbers was observed as lithium and SA interacted with the graphene substrate. The PDOS plot for Graphene/3SA/Li, showed the highest contribution in the HOMO orbitals was equally from lithium, sodium, hydrogen, and oxygen, while the lowest contribution was from carbon. This computational analysis provides comprehensive insights into the functionalized graphene systems, aiding in their further development and optimization for practical biomedical use.