bluuebunny/crossref_metadata_2025 huggingface dataset:
Interplanetary Magnetic Field By Effects on the Strength and Latitude of Field‐Aligned Currents in Different Magnetic Local Time Sectors
Authors: Wang Hui , Sun Yu , Lühr Hermann
Published: February 2024

In this work, IMF By effects on field‐aligned currents (FACs) are examined in different local time sectors, seasons, and hemispheres. At dusk and 09–14 MLT, when the eastward polar electrojet (PEJ) prevails, the northern FACp (poleward side FACs) are stronger when IMF By < 0 than when IMF By > 0. Conversely, at dawn, 21–02 MLT, and 09–14 MLT with westward PEJ, the northern FACp are stronger with IMF By > 0 compared to IMF By < 0. The southern FACp shows a reversed relationship with IMF By direction. The dependence of FACe (equatorward side FACs) on IMF By is weaker, except for the midday FACe, which shows opposite variations with respect to IMF By when compared to FACp. Stronger IMF By effect is observed in local summer in most of local times. The northern FACs are located at higher latitude for IMF By > 0 than for IMF By < 0 in local times with eastward PEJ, while the opposite trend is observed in other local times and in the Southern Hemisphere. The hemispheric difference in the peak latitude of FACs demonstrates an inverse relationship with its intensity, with stronger FACs located at lower latitudes. Overall, the local time and hemispheric differences in FACs strength and latitude are discussed in the context of interhemispheric field‐aligned currents linked to IMF By.
Enhanced Late Spring Ozone in Southern China by Early Onset of the South China Sea Summer Monsoon
Authors: Zhang Xiaorui , Lu Xiao , Wang Fan , Zhou Wen , Wang Peng , Gao Meng
Published: February 2024

The onset of the South China Sea summer monsoon (SCSSM) has profound impacts on meteorological conditions over East Asia. However, whether the interannual variability in monsoon onset date impacts ozone (O3) pollution remains unclear. Here, we investigate the relationship between early onset of SCSSM and late spring O3 in southern China. Our results show notable differences in surface O3 concentrations before and after SCSSM onset during early onset events in southern China. The enhanced O3 of 11.1 μg m−3 is supported by increased air temperature and solar radiation of 1.1 K and 30.9 W m−2 and reduced relative humidity of −5.7%. Both observation and model simulations confirm that O3‐favorable meteorological conditions modulated by early SCSSM onset can be found in May. It increases the boundary layer height and biogenic emissions of volatile organic compounds, enhancing O3 by 10 μg m−3 over southern China. Chemical processes dominate such increases in O3 with enhanced chemical production of 0.27 Tg month−1. Descending motion in southern China vertically transports O3 to surface by 0.10 Tg month−1, whereas horizontal advection reduces O3 concentration by 0.12 Tg month−1. The meteorological responses to colder sea surface temperature (SST) in the central equatorial Pacific are pronounced, leading to higher O3 concentrations over the Yangtze River Delta, while warmer SST in the Philippine Sea contributes O3 over the Pearl River Delta and eastern China. This study highlights the importance of SCSSM onset with respect to O3 in southern China, with promising applications in management of air pollution and agriculture.
Fludarabine-treosulfan versus fludarabine-melphalan or busulfan-cyclophosphamide conditioning in older AML or MDS patients – A clinical trial to registry data comparison
Authors: Beelen Dietrich Wilhelm , Iacobelli Simona , Koster Linda , Eikema Dirk-Jan , van Biezen Anja , Stölzel Friedrich , Ciceri Fabio , Bethge Wolfgang , Dreger Peter , Wagner-Drouet Eva-Maria , Reményi Péter , Stelljes Matthias , Markiewicz Miroslaw , McLornan Donal P. , Yakoub-Agha Ibrahim , Mohty Mohamad
Published: February 2024

A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.
CAnceR IN PreGnancy (CARING) – a retrospective study of cancer diagnosed during pregnancy in the United Kingdom
Authors: Baxter M. A. , Denholm M. , Kingdon S. J. , Kathirgamakarthigeyan S. , Parikh S. , Shakir R. , Johnson R. , Martin H. , Walton M. , Yao W. , Swan A. , Samuelson C. , Ren X. , Cooper A. , Gray H-L , Clifton S. , Ball J. , Gullick G. , Anderson M. , Dodd L. , Hayhurst H. , Salama M. , Shotton R. , Britton F. , Christodoulou T. , Abdul-Hamid A. , Eichholz A. , Evans R. M. , Wallroth P. , Gibson F. , Poole K. , Rowe M. , Harris J. ,   National Oncology Trainees Collaborative for Healthcare Research (NOTCH)
Published: February 2024

Background

The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population.

Methods

In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020).

Results

Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%.

Conclusions

This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.
CaSSiDI: novel single-cell “Cluster Similarity Scoring and Distinction Index” reveals critical functions for PirB and context-dependent Cebpb repression
Authors: Nechanitzky Robert , Ramachandran Parameswaran , Nechanitzky Duygu , Li Wanda Y. , Wakeham Andrew C. , Haight Jillian , Saunders Mary E. , Epelman Slava , Mak Tak W.
Published: February 2024

PirB is an inhibitory cell surface receptor particularly prominent on myeloid cells. PirB curtails the phenotypes of activated macrophages during inflammation or tumorigenesis, but its functions in macrophage homeostasis are obscure. To elucidate PirB-related functions in macrophages at steady-state, we generated and compared single-cell RNA-sequencing (scRNAseq) datasets obtained from myeloid cell subsets of wild type (WT) and PirB-deficient knockout (PirB KO) mice. To facilitate this analysis, we developed a novel approach to clustering parameter optimization called “Cluster Similarity Scoring and Distinction Index” (CaSSiDI). We demonstrate that CaSSiDI is an adaptable computational framework that facilitates tandem analysis of two scRNAseq datasets by optimizing clustering parameters. We further show that CaSSiDI offers more advantages than a standard Seurat analysis because it allows direct comparison of two or more independently clustered datasets, thereby alleviating the need for batch-correction while identifying the most similar and different clusters. Using CaSSiDI, we found that PirB is a novel regulator of Cebpb expression that controls the generation of Ly6Clo patrolling monocytes and the expansion properties of peritoneal macrophages. PirB’s effect on Cebpb is tissue-specific since it was not observed in splenic red pulp macrophages (RPMs). However, CaSSiDI revealed a segregation of the WT RPM population into a CD68loIrf8+ “neuronal-primed” subset and an CD68hiFtl1+ “iron-loaded” subset. Our results establish the utility of CaSSiDI for single-cell assay analyses and the determination of optimal clustering parameters. Our application of CaSSiDI in this study has revealed previously unknown roles for PirB in myeloid cell populations. In particular, we have discovered homeostatic functions for PirB that are related to Cebpb expression in distinct macrophage subsets.
DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response
Authors: Jiao Huipeng , James Sharmy J. , Png Chin Wen , Cui Chaoyu , Li Heng , Li Liang , Chia Wan Ni , Min Nyo , Li Weiyun , Claser Carla , Rénia Laurent , Wang Hongyan , Chen Mark I-Cheng , Chu Justin Jang Hann , Tan Kevin Shyong Wei , Deng Yinyue , Zhang Yongliang
Published: February 2024

Detection of cytosolic nucleic acids by pattern recognition receptors, including STING and RIG-I, leads to the activation of multiple signalling pathways that culminate in the production of type I interferons (IFNs) which are vital for host survival during virus infection. In addition to protective immune modulatory functions, type I IFNs are also associated with autoimmune diseases. Hence, it is important to elucidate the mechanisms that govern their expression. In this study, we identified a critical regulatory function of the DUSP4 phosphatase in innate immune signalling. We found that DUSP4 regulates the activation of TBK1 and ERK1/2 in a signalling complex containing DUSP4, TBK1, ERK1/2 and IRF3 to regulate the production of type I IFNs. Mice deficient in DUSP4 were more resistant to infections by both RNA and DNA viruses but more susceptible to malaria parasites. Therefore, our study establishes DUSP4 as a regulator of nucleic acid sensor signalling and sheds light on an important facet of the type I IFN regulatory system.
Transcription of endogenous retroviruses in senescent cells contributes to the accumulation of double-stranded RNAs that trigger an anti-viral response that reinforces senescence
Authors: Di Giorgio Eros , Ranzino Liliana , Tolotto Vanessa , Dalla Emiliano , Burelli Matteo , Gualandi Nicolò , Brancolini Claudio
Published: February 2024

An important epigenetic switch marks the onset and maintenance of senescence. This allows transcription of the genetic programs that arrest the cell cycle and alter the microenvironment. Transcription of endogenous retroviruses (ERVs) is also a consequence of this epigenetic switch. In this manuscript, we have identified a group of ERVs that are epigenetically silenced in proliferating cells but are upregulated during replicative senescence or during various forms of oncogene-induced senescence, by RAS and Akt, or after HDAC4 depletion. In a HDAC4 model of senescence, removal of the repressive histone mark H3K27me3 is the plausible mechanism that allows the transcription of intergenic ERVs during senescence. We have shown that ERVs contribute to the accumulation of dsRNAs in senescence, which can initiate the antiviral response via the IFIH1-MAVS signaling pathway and thus contribute to the maintenance of senescence. This pathway, and MAVS in particular, plays an active role in shaping the microenvironment and maintaining growth arrest, two essential features of the senescence program.
The reverse quantum limit and its implications for unconventional quantum oscillations in YbB12
Authors: Mizzi Christopher A. , Kushwaha Satya K. , Rosa Priscila F. S. , Phelan W. Adam , Arellano David C. , Pressley Lucas A. , McQueen Tyrel M. , Chan Mun K. , Harrison Neil
Published: February 2024

The quantum limit in a Fermi liquid, realized when a single Landau level is occupied in strong magnetic fields, gives rise to unconventional states, including the fractional quantum Hall effect and excitonic insulators. Stronger interactions in metals with nearly localizedf-electron degrees of freedom increase the likelihood of these unconventional states. However, access to the quantum limit is typically impeded by the tendency off-electrons to polarize in a strong magnetic field, consequently weakening the interactions. In this study, we propose that the quantum limit in such systems must be approached in reverse, starting from an insulating state at zero magnetic field. In this scenario, Landau levels fill in the reverse order compared to regular metals and are closely linked to a field-induced insulator-to-metal transition. We identify YbB12as a prime candidate for observing this effect and propose the presence of an excitonic insulator state near this transition.
Non-orthogonal optical multiplexing empowered by deep learning
Authors: Pan Tuqiang , Ye Jianwei , Liu Haotian , Zhang Fan , Xu Pengbai , Xu Ou , Xu Yi , Qin Yuwen
Published: February 2024

Orthogonality among channels is a canonical basis for optical multiplexing featured with division multiplexing, which substantially reduce the complexity of signal post-processing in demultiplexing. However, it inevitably imposes an upper limit of capacity for multiplexing. Herein, we report on non-orthogonal optical multiplexing over a multimode fiber (MMF) leveraged by a deep neural network, termed speckle light field retrieval network (SLRnet), where it can learn the complicated mapping relation between multiple non-orthogonal input light field encoded with information and their corresponding single intensity output. As a proof-of-principle experimental demonstration, it is shown that the SLRnet can effectively solve the ill-posed problem of non-orthogonal optical multiplexing over an MMF, where multiple non-orthogonal input signals mediated by the same polarization, wavelength and spatial position can be explicitly retrieved utilizing a single-shot speckle output with fidelity as high as ~ 98%. Our results resemble an important step for harnessing non-orthogonal channels for high capacity optical multiplexing.
Effects of total sleep deprivation on performance in a manual spacecraft docking task
Authors: Piechowski Sarah , Kalkoffen Lennard J. , Benderoth Sibylle , Wolf Oliver T. , Rittweger Jörn , Aeschbach Daniel , Mühl Christian
Published: February 2024

Sleep deprivation and circadian rhythm disruptions are highly prevalent in shift workers, and also among astronauts. Resulting sleepiness can reduce cognitive performance, lead to catastrophic occupational events, and jeopardize space missions. We investigated whether 24 hours of total sleep deprivation would affect performance not only in thePsychomotor Vigilance Task(PVT), but also in a complex operational task, i.e. simulated manual spacecraft docking. Sixty-two healthy participants completed the manual docking simulation6dfand the PVT once after a night of total sleep deprivation and once after eight hours of scheduled sleep in a counterbalanced order. We assessed the impact of sleep deprivation on docking as well as PVT performance and investigated if sustained attention is an essential component of operational performance after sleep loss. The results showed that docking accuracy decreased significantly after sleep deprivation in comparison to the control condition, but only at difficult task levels. PVT performance deteriorated under sleep deprivation. Participants with larger impairments in PVT response speed after sleep deprivation also showed larger impairments in docking accuracy. In conclusion, sleep deprivation led to impaired6dfperformance, which was partly explained by impairments in sustained attention. Elevated motivation levels due to the novelty and attractiveness of the task may have helped participants to compensate for the effects of sleepiness at easier task levels. Continued testing of manual docking skills could be a useful tool both to detect sleep loss-related impairments and assess astronauts’ readiness for duty during long-duration missions.
Laying the experimental foundation for corrosion inhibitor discovery through machine learning
Authors: Özkan Can , Sahlmann Lisa , Feiler Christian , Zheludkevich Mikhail , Lamaka Sviatlana , Sewlikar Parth , Kooijman Agnieszka , Taheri Peyman , Mol Arjan
Published: February 2024

Creating durable, eco-friendly coatings for long-term corrosion protection requires innovative strategies to streamline design and development processes, conserve resources, and decrease maintenance costs. In this pursuit, machine learning emerges as a promising catalyst, despite the challenges presented by the scarcity of high-quality datasets in the field of corrosion inhibition research. To address this obstacle, we have created an extensive electrochemical library of around 80 inhibitor candidates. The electrochemical behaviour of inhibitor-exposed AA2024-T3 substrates was captured using linear polarisation resistance, electrochemical impedance spectroscopy, and potentiodynamic polarisation techniques at different exposure times to obtain the most comprehensive electrochemical picture of the corrosion inhibition over a 24-h period. The experimental results yield target parameters and additional input features that can be combined with computational descriptors to develop quantitative structure–property relationship (QSPR) models augmented by mechanistic input features.
Asymmetric oligomerization state and sequence patterning can tune multiphase condensate miscibility
Authors: Rana Ushnish , Xu Ke , Narayanan Amal , Walls Mackenzie T. , Panagiotopoulos Athanassios Z. , Avalos José L. , Brangwynne Clifford P.
Published: February 2024

Endogenous biomolecular condensates, composed of a multitude of proteins and RNAs, can organize into multiphasic structures with compositionally distinct phases. This multiphasic organization is generally understood to be critical for facilitating their proper biological function. However, the biophysical principles driving multiphase formation are not completely understood. Here we use in vivo condensate reconstitution experiments and coarse-grained molecular simulations to investigate how oligomerization and sequence interactions modulate multiphase organization in biomolecular condensates. We demonstrate that increasing the oligomerization state of an intrinsically disordered protein results in enhanced immiscibility and multiphase formation. Interestingly, we find that oligomerization tunes the miscibility of intrinsically disordered proteins in an asymmetric manner, with the effect being more pronounced when the intrinsically disordered protein, exhibiting stronger homotypic interactions, is oligomerized. Our findings suggest that oligomerization is a flexible biophysical mechanism that cells can exploit to tune the internal organization of biomolecular condensates and their associated biological functions.
Making cities mental health friendly for adolescents and young adults
Authors: Collins Pamela Y. , Sinha Moitreyee , Concepcion Tessa , Patton George , Way Thaisa , McCay Layla , Mensa-Kwao Augustina , Herrman Helen , de Leeuw Evelyne , Anand Nalini , Atwoli Lukoye , Bardikoff Nicole , Booysen Chantelle , Bustamante Inés , Chen Yajun , Davis Kelly , Dua Tarun , Foote Nathaniel , Hughsam Matthew , Juma Damian , Khanal Shisir , Kumar Manasi , Lefkowitz Bina , McDermott Peter , Moitra Modhurima , Ochieng Yvonne , Omigbodun Olayinka , Queen Emily , Unützer Jürgen , Uribe-Restrepo José Miguel , Wolpert Miranda , Zeitz Lian
Published: February 2024

Urban life shapes the mental health of city dwellers, and although cities provide access to health, education and economic gain, urban environments are often detrimental to mental health1,2. Increasing urbanization over the next three decades will be accompanied by a growing population of children and adolescents living in cities3. Shaping the aspects of urban life that influence youth mental health could have an enormous impact on adolescent well-being and adult trajectories4. We invited a multidisciplinary, global group of researchers, practitioners, advocates and young people to complete sequential surveys to identify and prioritize the characteristics of a mental health-friendly city for young people. Here we show a set of ranked characteristic statements, grouped by personal, interpersonal, community, organizational, policy and environmental domains of intervention. Life skills for personal development, valuing and accepting young people’s ideas and choices, providing safe public space for social connection, employment and job security, centring youth input in urban planning and design, and addressing adverse social determinants were priorities by domain. We report the adversities that COVID-19 generated and link relevant actions to these data. Our findings highlight the need for intersectoral, multilevel intervention and for inclusive, equitable, participatory design of cities that support youth mental health.
Avoiding fusion plasma tearing instability with deep reinforcement learning
Authors: Seo Jaemin , Kim SangKyeun , Jalalvand Azarakhsh , Conlin Rory , Rothstein Andrew , Abbate Joseph , Erickson Keith , Wai Josiah , Shousha Ricardo , Kolemen Egemen
Published: February 2024

For stable and efficient fusion energy production using a tokamak reactor, it is essential to maintain a high-pressure hydrogenic plasma without plasma disruption. Therefore, it is necessary to actively control the tokamak based on the observed plasma state, to manoeuvre high-pressure plasma while avoiding tearing instability, the leading cause of disruptions. This presents an obstacle-avoidance problem for which artificial intelligence based on reinforcement learning has recently shown remarkable performance1–4. However, the obstacle here, the tearing instability, is difficult to forecast and is highly prone to terminating plasma operations, especially in the ITER baseline scenario. Previously, we developed a multimodal dynamic model that estimates the likelihood of future tearing instability based on signals from multiple diagnostics and actuators5. Here we harness this dynamic model as a training environment for reinforcement-learning artificial intelligence, facilitating automated instability prevention. We demonstrate artificial intelligence control to lower the possibility of disruptive tearing instabilities in DIII-D6, the largest magnetic fusion facility in the United States. The controller maintained the tearing likelihood under a given threshold, even under relatively unfavourable conditions of low safety factor and low torque. In particular, it allowed the plasma to actively track the stable path within the time-varying operational space while maintaining H-mode performance, which was challenging with traditional preprogrammed control. This controller paves the path to developing stable high-performance operational scenarios for future use in ITER.
The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons
Authors: Makhlouf Linda , Peter Joshua J. , Magnussen Helge M. , Thakur Rohan , Millrine David , Minshull Thomas C. , Harrison Grace , Varghese Joby , Lamoliatte Frederic , Foglizzo Martina , Macartney Thomas , Calabrese Antonio N. , Zeqiraj Elton , Kulathu Yogesh
Published: February 2024

Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26 (also known as uL24)1,2. This modification, which is known as UFMylation, is orchestrated by the UFM1 ribosome E3 ligase (UREL) complex, comprising UFL1, UFBP1 and CDK5RAP3 (ref. 3). However, the catalytic mechanism of UREL and the functional consequences of UFMylation are unclear. Here we present cryo-electron microscopy structures of UREL bound to 60S ribosomes, revealing the basis of its substrate specificity. UREL wraps around the 60S subunit to form a C-shaped clamp architecture that blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other. A UFL1 loop inserts into and remodels the peptidyl transferase centre. These features of UREL suggest a crucial function for UFMylation in the release and recycling of stalled or terminated ribosomes from the ER membrane. In the absence of functional UREL, 60S–SEC61 translocon complexes accumulate at the ER membrane, demonstrating that UFMylation is necessary for releasing SEC61 from 60S subunits. Notably, this release is facilitated by a functional switch of UREL from a ‘writer’ to a ‘reader’ module that recognizes its product—UFMylated 60S ribosomes. Collectively, we identify a fundamental role for UREL in dissociating 60S subunits from the SEC61 translocon and the basis for UFMylation in regulating protein homeostasis at the ER.
IL-10 constrains sphingolipid metabolism to limit inflammation
Authors: York Autumn G. , Skadow Mathias H. , Oh Joonseok , Qu Rihao , Zhou Quan D. , Hsieh Wei-Yuan , Mowel Walter K. , Brewer J. Richard , Kaffe Eleanna , Williams Kevin J. , Kluger Yuval , Smale Stephen T. , Crawford Jason M. , Bensinger Steven J. , Flavell Richard A.
Published: February 2024

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice—however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2–5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that ‘metabolic correction’ of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.
Mechanisms of action and resistance in histone methylation-targeted therapy
Authors: Yamagishi Makoto , Kuze Yuta , Kobayashi Seiichiro , Nakashima Makoto , Morishima Satoko , Kawamata Toyotaka , Makiyama Junya , Suzuki Kako , Seki Masahide , Abe Kazumi , Imamura Kiyomi , Watanabe Eri , Tsuchiya Kazumi , Yasumatsu Isao , Takayama Gensuke , Hizukuri Yoshiyuki , Ito Kazumi , Taira Yukihiro , Nannya Yasuhito , Tojo Arinobu , Watanabe Toshiki , Tsutsumi Shinji , Suzuki Yutaka , Uchimaru Kaoru
Published: February 2024

Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated1–7. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1–EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2–compound interface result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.
Quality assessment of gene repertoire annotations with OMArk
Authors: Nevers Yannis , Warwick Vesztrocy Alex , Rossier Victor , Train Clément-Marie , Altenhoff Adrian , Dessimoz Christophe , Glover Natasha M.
Published: February 2024

In the era of biodiversity genomics, it is crucial to ensure that annotations of protein-coding gene repertoires are accurate. State-of-the-art tools to assess genome annotations measure the completeness of a gene repertoire but are blind to other errors, such as gene overprediction or contamination. We introduce OMArk, a software package that relies on fast, alignment-free sequence comparisons between a query proteome and precomputed gene families across the tree of life. OMArk assesses not only the completeness but also the consistency of the gene repertoire as a whole relative to closely related species and reports likely contamination events. Analysis of 1,805 UniProt Eukaryotic Reference Proteomes with OMArk demonstrated strong evidence of contamination in 73 proteomes and identified error propagation in avian gene annotation resulting from the use of a fragmented zebra finch proteome as a reference. This study illustrates the importance of comparing and prioritizing proteomes based on their quality measures.
Direct evidence of plant consumption in Neolithic Eastern Sudan from dental calculus analysis
Authors: Capasso Giusy , Neves Dulce , Sperduti Alessandra , Cristiani Emanuela , Manzo Andrea
Published: February 2024

The Neolithic communities of Eastern Sudan combined intensive pastoralism with plant exploitation as their main subsistence strategies. However, to date, it remains unclear which plant species were part of the human diet during the Neolithic. This contribution presents direct data on plant consumption in Eastern Sudan from the Early to Late Neolithic, obtained through the analysis of microdebris inclusions in the dental calculus of 37 individuals, integrated by dentoalveolar pathology analysis of 78 individuals, from the sites UA53 (4th millennium BCE) and Mahal Teglinos (3rd–2nd millennium BCE), located in the Gash Delta/Kassala region. Dental calculus inclusions indicate a diverse intake of cereals, legumes, and tubers during the Middle Neolithic, thus supporting the hypothesis of high reliance on plant resources. Dentoalveolar pathologies, possibly related to the consumption of carbohydrate-rich foods, have also been recorded. For the Late Neolithic, consistent with the shift towards aridity that occurred in the Middle/Late Holocene, dental calculus exclusively indicates the exploitation of sorghum and tubers—species well adapted to arid conditions—showing how the Neolithic communities modified their subsistence in response to environmental changes. Evidence of plant processing techniques, such as cooking/heating, was also revealed from the dental calculus analysis.
Correction of high-rate motion for photoacoustic microscopy by orthogonal cross-correlation
Authors: Zou Zilong , Mao Qiuqin , Cheng Renxiang , Tao Chao , Liu Xiaojun
Published: February 2024

Photoacoustic imaging is a promising technology for in vivo imaging. However, its imaging performance can be hampered by motion artifacts, especially when dealing with high-rate motion. In this paper, we propose an orthogonal motion correction method that utilizes cross-correlation along orthogonal scan directions to extract accurate motion displacements from the photoacoustic data. The extracted displacements are then applied to remove artifacts and compensate for motion-induced distortions. Phantom experiments demonstrate that the proposed method can extract the motion information and the structural similarity index measurement after correction is increased by 26.5% and 11.2% compared to no correction and the previous correction method. Then the effectiveness of our method is evaluated in vivo imaging of a mouse brain. Our method shows a stable and effective performance under high-rate motion. The high accuracy of the motion correction method makes it valuable in improving the accuracy of photoacoustic imaging.
A novel extension of half-logistic distribution with statistical inference, estimation and applications
Authors: Bhat A. A. , Ahmad S. P. , Gemeay Ahmed M. , Muse Abdisalam Hassan , Bakr M. E. , Balogun Oluwafemi Samson
Published: February 2024

In the present study, we develop and investigate the odd Frechet Half-Logistic (OFHL) distribution that was developed by incorporating the half-logistic and odd Frechet-G family. The OFHL model has very adaptable probability functions: decreasing, increasing, bathtub and inverted U shapes are shown for the hazard rate functions, illustrating the model’s capacity for flexibility. A comprehensive account of the mathematical and statistical properties of the proposed model is presented. In estimation viewpoint, six distinct estimation methodologies are used to estimate the unknown parameters of the OFHL model. Furthermore, an extensive Monte Carlo simulation analysis is used to evaluate the effectiveness of these estimators. Finally, two applications to real data are used to demonstrate the versatility of the suggested method, and the comparison is made with the half-logistic and some of its well-known extensions. The actual implementation shows that the suggested model performs better than competing models.
Scalable and efficient grating couplers on low-index photonic platforms enabled by cryogenic deep silicon etching
Authors: Lomonte Emma , Stappers Maik , Krämer Linus , Pernice Wolfram H. P. , Lenzini Francesco
Published: February 2024

Efficient fiber-to-chip couplers for multi-port access to photonic integrated circuits are paramount for a broad class of applications, ranging, e.g., from telecommunication to photonic computing and quantum technologies. Grating-based approaches are often desirable for providing out-of-plane access to the photonic circuits. However, on photonic platforms characterized by a refractive index ≃ 2 at telecom wavelength, such as silicon nitride or thin-film lithium niobate, the limited scattering strength has thus far hindered the achievement of coupling efficiencies comparable to the ones attainable in silicon photonics. Here we present a flexible strategy for the realization of highly efficient grating couplers on such low-index photonic platforms. To simultaneously reach a high scattering efficiency and a near-unitary modal overlap with optical fibers, we make use of self-imaging gratings designed with a negative diffraction angle. To ensure high directionality of the diffracted light, we take advantage of a metal back-reflector patterned underneath the grating structure by cryogenic deep reactive ion etching of the silicon handle. Using silicon nitride as a testbed material, we experimentally demonstrate coupling efficiency up to − 0.55 dB in the telecom C-band with high chip-scale device yield.
A dynamic fuzzy rule-based inference system using fuzzy inference with semantic reasoning
Authors: Shoaip Nora , El-Sappagh Shaker , Abuhmed Tamer , Elmogy Mohammed
Published: February 2024

The challenge of making flexible, standard, and early medical diagnoses is significant. However, some limitations are not fully overcome. First, the diagnosis rules established by medical experts or learned from a trained dataset prove static and too general. It leads to decisions that lack adaptive flexibility when finding new circumstances. Secondly, medical terminological interoperability is highly critical. It increases realism and medical progress and avoids isolated systems and the difficulty of data exchange, analysis, and interpretation. Third, criteria for diagnosis are often heterogeneous and changeable. It includes symptoms, patient history, demographic, treatment, genetics, biochemistry, and imaging. Symptoms represent a high-impact indicator for early detection. It is important that we deal with these symptoms differently, which have a great relationship with semantics, vary widely, and have linguistic information. This negatively affects early diagnosis decision-making. Depending on the circumstances, the diagnosis is made solo on imaging and some medical tests. In this case, although the accuracy of the diagnosis is very high, can these decisions be considered an early diagnosis or prove the condition is deteriorating? Our contribution in this paper is to present a real medical diagnostic system based on semantics, fuzzy, and dynamic decision rules. We attempt to integrate ontology semantics reasoning and fuzzy inference. It promotes fuzzy reasoning and handles knowledge representation problems. In complications and symptoms, ontological semantic reasoning improves the process of evaluating rules in terms of interpretability, dynamism, and intelligence. A real-world case study, ADNI, is presented involving the field of Alzheimer’s disease (AD). The proposed system has indicated the possibility of the system to diagnose AD with an accuracy of 97.2%, 95.4%, 94.8%, 93.1%, and 96.3% for AD, LMCI, EMCI, SMC, and CN respectively.
A precise model for skin cancer diagnosis using hybrid U-Net and improved MobileNet-V3 with hyperparameters optimization
Authors: Kumar Lilhore Umesh , Simaiya Sarita , Sharma Yogesh Kumar , Kaswan Kuldeep Singh , Rao K. B. V. Brahma , Rao V. V. R. Maheswara , Baliyan Anupam , Bijalwan Anchit , Alroobaea Roobaea
Published: February 2024

Skin cancer is a frequently occurring and possibly deadly disease that necessitates prompt and precise diagnosis in order to ensure efficacious treatment. This paper introduces an innovative approach for accurately identifying skin cancer by utilizing Convolution Neural Network architecture and optimizing hyperparameters. The proposed approach aims to increase the precision and efficacy of skin cancer recognition and consequently enhance patients' experiences. This investigation aims to tackle various significant challenges in skin cancer recognition, encompassing feature extraction, model architecture design, and optimizing hyperparameters. The proposed model utilizes advanced deep-learning methodologies to extract complex features and patterns from skin cancer images. We enhance the learning procedure of deep learning by integrating Standard U-Net and Improved MobileNet-V3 with optimization techniques, allowing the model to differentiate malignant and benign skin cancers. Also substituted the crossed-entropy loss function of the Mobilenet-v3 mathematical framework with a bias loss function to enhance the accuracy. The model's squeeze and excitation component was replaced with the practical channel attention component to achieve parameter reduction. Integrating cross-layer connections among Mobile modules has been proposed to leverage synthetic features effectively. The dilated convolutions were incorporated into the model to enhance the receptive field. The optimization of hyperparameters is of utmost importance in improving the efficiency of deep learning models. To fine-tune the model's hyperparameter, we employ sophisticated optimization methods such as the Bayesian optimization method using pre-trained CNN architecture MobileNet-V3. The proposed model is compared with existing models, i.e., MobileNet, VGG-16, MobileNet-V2, Resnet-152v2 and VGG-19 on the “HAM-10000 Melanoma Skin Cancer dataset". The empirical findings illustrate that the proposed optimized hybrid MobileNet-V3 model outperforms existing skin cancer detection and segmentation techniques based on high precision of 97.84%, sensitivity of 96.35%, accuracy of 98.86% and specificity of 97.32%. The enhanced performance of this research resulted in timelier and more precise diagnoses, potentially contributing to life-saving outcomes and mitigating healthcare expenditures.
Elevated blood malondialdehyde level contributed to a high stroke risk in a Chinese elderly population from rural areas: a cross-sectional study
Authors: Wan Rong , Su Yuhao , Zhu Meilan , Huang Ying
Published: February 2024

Individuals living in rural areas have a higher incidence rate of stroke than their urban counterparts in China. However, few studies have investigated the association between blood malondialdehyde (MDA), an end product of lipid oxidation caused by reactive oxygen species (ROS), and stroke risk in rural populations. We aimed to investigate whether blood MDA levels contribute to a higher stroke risk in a Chinese elderly population from rural areas. Data from 2011 to 2012 from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a national cohort of older adults in China, were analyzed. Smooth curve and multivariable correction analyses were used to evaluate the association between blood MDA levels and stroke risk in elderly populations from rural and urban areas, respectively. The median age of all included participants (N = 1598) was 84.04 years. The results of the smooth curve model revealed a gradual upward trend in the association of blood MDA levels with stroke risk in rural participants but not in urban participants. Similarly, the conditional logistic regression analysis suggested a significant association between MDA levels and stroke risk in rural participants but not in urban participants after adjustments for related confounding factors (age, sex, current smoker, current drinker, regular exercise, BMI and cardiovascular diseases (hypertension, heart disease, atrial fibrillation and diabetes)) were made. In brief, among the elderly population in China, elevated blood MDA levels were associated with increased stroke risk in rural participants but not in urban participants.
Electrocardiographic activity depends on the relative position between intimate persons
Authors: Mukai Kae , Isomura Tomoko , Onagawa Ryoji , Watanabe Katsumi
Published: February 2024

Interpersonal space (IPS) refers to the area surrounding the body in which we engage in social interactions while maintaining our comfort. Numerous previous studies have reported the psychological and physiological changes associated with the proximity of two people engaged in face-to-face interaction. Currently, there is limited knowledge about how the relative position between two socially intimate individuals affects their psychological and physiological states. This research measured the subjective discomfort and electrocardiographic responses of participants when standing static at various relative positions. The highest discomfort, lowest heart rate, and highest heart rate variability (HRV; parasympathetic activity index) were observed when the friend stood in the face-to-face position. Interestingly, heart rate also decreased when the friend stood on the right side, although HRV did not change. We interpreted the results as suggesting that the presence of a familiar person elicits the electrocardiographic responses associated with an increase in parasympathetic activity.
A population level study on the determinants of COVID-19 vaccination rates at the U.S. county level
Authors: Dong Ensheng , Nixon Kristen , Gardner Lauren M.
Published: February 2024

Multiple COVID-19 vaccines were proven to be safe and effective in curbing severe illness, but despite vaccine availability, vaccination rates were relatively low in the United States (U.S.). To better understand factors associated with low COVID-19 vaccine uptake in the U.S., our study provides a comprehensive, data-driven population-level statistical analysis at the county level. We find that political affiliation, as determined by the proportion of votes received by the Republican candidate in the 2020 presidential election, has the strongest association with our response variable, the percent of the population that received no COVID-19 vaccine. The next strongest association was median household income, which has a negative association. The percentage of Black people and the average number of vehicles per household are positively associated with the percent unvaccinated. In contrast, COVID-19 infection rate, percentage of Latinx people, postsecondary education percentage, median age, and prior non-COVID-19 childhood vaccination coverage are negatively associated with percent unvaccinated. Unlike previous studies, we do not find significant relationships between cable TV news viewership or Twitter misinformation variables with COVID-19 vaccine uptake. These results shed light on some factors that may impact vaccination choice in the U.S. and can be used to target specific populations for educational outreach and vaccine campaign strategies in efforts to increase vaccination uptake.
Blood and urine multi-omics analysis of the impact of e-vaping, smoking, and cessation: from exposome to molecular responses
Authors: Poussin Carine , Titz Bjoern , Xiang Yang , Baglia Laurel , Berg Rachel , Bornand David , Choukrallah Mohammed-Amin , Curran Timothy , Dijon Sophie , Dossin Eric , Dulize Remi , Etter Doris , Fatarova Maria , Medlin Loyse Felber , Haiduc Adrian , Kishazi Edina , Kolli Aditya R. , Kondylis Athanasios , Kottelat Emmanuel , Laszlo Csaba , Lavrynenko Oksana , Eb-Levadoux Yvan , Nury Catherine , Peric Dariusz , Rizza Melissa , Schneider Thomas , Guedj Emmanuel , Calvino Florian , Sierro Nicolas , Guy Philippe , Ivanov Nikolai V. , Picavet Patrick , Spinelli Sherry , Hoeng Julia , Peitsch Manuel C.
Published: February 2024

Cigarette smoking is a major preventable cause of morbidity and mortality. While quitting smoking is the best option, switching from cigarettes to non-combustible alternatives (NCAs) such as e-vapor products is a viable harm reduction approach for smokers who would otherwise continue to smoke. A key challenge for the clinical assessment of NCAs is that self-reported product use can be unreliable, compromising the proper evaluation of their risk reduction potential. In this cross-sectional study of 205 healthy volunteers, we combined comprehensive exposure characterization with in-depth multi-omics profiling to compare effects across four study groups: cigarette smokers (CS), e-vapor users (EV), former smokers (FS), and never smokers (NS). Multi-omics analyses included metabolomics, transcriptomics, DNA methylomics, proteomics, and lipidomics. Comparison of the molecular effects between CS and NS recapitulated several previous observations, such as increased inflammatory markers in CS. Generally, FS and EV demonstrated intermediate molecular effects between the NS and CS groups. Stratification of the FS and EV by combustion exposure markers suggested that this position on the spectrum between CS and NS was partially driven by non-compliance/dual use. Overall, this study highlights the importance of in-depth exposure characterization before biological effect characterization for any NCA assessment study.