bluuebunny/crossref_metadata_2025 huggingface dataset:
Food group intakes and high-sensitivity C-reactive protein among community-dwelling Japanese adults: a cross-sectional study
Authors: Matsunaga Takashi , Wakai Kenji , Imaeda Nahomi , Goto Chiho , Tamada Yudai , Kato Yasufumi , Kubo Yoko , Okada Rieko , Nagayoshi Mako , Tamura Takashi , Hishida Asahi , Ikezaki Hiroaki , Otonari Jun , Takashima Naoyuki , Miyagawa Naoko , Matsuo Keitaro ,   Japan Multi-Institutional Collaborative Cohort (J-MICC) Study Group
Published: October 2024

Objective:

Healthy dietary patterns have been linked to lower levels of chronic inflammation. The present study aimed to investigate the associations between food group intakes and high-sensitivity C-reactive protein (hsCRP) among community-dwelling adults.

Design:

Cross-sectional.

Setting:

Three areas in Japan (Shiga, Fukuoka, or Kyushu and Okinawa).

Participants:

The present analysis included 13 648 participants (5126 males and 8522 females; age range, 35–69 years) who had been enrolled in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Food group intakes were estimated using a FFQ. Multiple linear regression was used to examine associations between the quartiles of each energy-adjusted food group intake and log-transformed hsCRP.

Results:

The following concentration ratios of hsCRP after comparing the highest and lowest quartiles of food group intake were significant: in males, 1·12 (95 % CI 1·02, 1·22) for processed meat, 1·13 (95 % CI 1·03, 1·24) for fish and 0·83 (95 % CI 0·76, 0·90) for nuts; in females, 0·89 (95 % CI 0·81, 0·97) for bread, 1·11 (95 % CI 1·03, 1·19) for processed meat, 0·86 (95 % CI 0·80, 0·92) for vegetables, 1·19 (95 % CI 1·11, 1·29) for fruit, 0·90 (95 % CI 0·84, 0·97) for nuts and 0·88 (95 % CI 0·82, 0·95) for green tea.

Conclusions:

Processed meat and nut intakes were associated with higher and lower hsCRP levels, respectively, in both sexes. However, for several food groups, including fish and fruit, previous findings from dietary pattern analyses were not supported by the present analyses at the food group level.
Young women’s perceptions of cervical screening in the UK: a qualitative study
Authors: Taratula-Lyons Monique , Hill Marie C.
Published: October 2024

Aim:

To understand young women’s views of cervical screening, what obstacles they face, and what encourages them when considering attending their cervical screening.

Background:

Cervical screening figures have been steadily decreasing in the United Kingdom (UK). There is limited research on this trend, especially around views and knowledge of young women, aged 20–24 years, have before they are eligible for cervical screening.

Methods:

This qualitative study conducted 15 semi-structured Zoom in-depth interviews to discuss young women’s knowledge and perceptions of cervical screening in 2022. Participants were based in the UK. Thematic analysis was used to systematically manage, analyse, and identify themes including cervical screening knowledge; perceptions of cervical screening; barriers to cervical screening; and facilitators of cervical screening.

Findings:

The findings demonstrate significant gaps in knowledge and negative perceptions of cervical screening. Barriers to attending cervical screening were perceived pain and embarrassment. Facilitators suggested to promote attendance were ensuring access to appointments, creating pop-up clinics, and utilising incentives. The level of knowledge demonstrated by the participants, their negatively framed perceptions; and the vast number of barriers identified present substantial factors that could affect future attendance to cervical screening. Overall, action needs to be taken to prevent decreasing cervical screening attendance rates and eradicate any barriers women may experience.
Boosting Barlow Twins Reduced Order Modeling for Machine Learning‐Based Surrogate Models in Multiphase Flow Problems
Authors: Kadeethum T. , Silva V. L. S. , Salinas P. , Pain C. C. , Yoon H.
Published: October 2024

We present an innovative approach called boosting Barlow Twins reduced order modeling (BBT‐ROM) to enhance the reliability of machine learning surrogate models for multiphase flow problems. BBT‐ROM builds upon Barlow Twins reduced order modeling that leverages self‐supervised learning to effectively handle linear and nonlinear manifolds by constructing well‐structured latent spaces of input parameters and output quantities. To address the challenge of high contrast data in multiphase flow problems due to injection wells and faults, we employ a boosting algorithm within BBT‐ROM. This algorithm sequentially trains a set of weak models (i.e., inaccurate models), improving prediction accuracy through ensemble learning. To evaluate the performance of BBT‐ROM, we conduct three three‐dimensional multiphase flow problems, including waterflooding and geologic carbon storage (GCS), with varying numbers of input parameter cases and model domain features. The results demonstrate that BBT‐ROM excels at predicting non‐wetting phase saturation (e.g., oil or saturation) and fluid pressure, with average relative errors ranging from 0.5% to 3%. Importantly, BBT‐ROM showcases robustness when faced with limited input parameter space during GCS testing.
Ion Diffusive Transport Across the Separatrix Between the Low‐Latitude Mantle and the Plasma Sheet by Kinetic Alfvén Waves: MMS Observation
Authors: Wang Chih‐Ping , Johnson Jay R. , Xing Xiaoyan , Avanov Levon A. , Wei H. Y. , Ahmadi Narges
Published: October 2024

To understand the entry of the cool low‐latitude mantle ions into the tail plasma sheet near the flanks under persistent interplanetary magnetic field By, we evaluate the role of the cross‐field diffusive transport by kinetic Alfvén waves (KAWs) by investigating two events observed by multiscale (MMS) spacecraft. Around the separatrix between the open and closed field‐line regions, a two‐component mixing of hot plasma sheet ions of a few keV with cool mantle ions of a few hundred eV was observed, indicating transport across the separatrix. The waves observed between 0.01 and 10 Hz around the separatrix had characteristics consistent with those of KAWs. The consistency allowed us to estimate the wave vectors as a function of frequency by fitting KAW dispersion to the observations. Using the observed wave powers, plasma moments, and the estimated wave vectors, we computed the cross‐field diffusion rates associated with KAWs. The diffusion rates were found to be comparable to or larger than the Bohm diffusion rates during the intervals when the two‐component mixing was observed, indicating that the KAW diffusive transport can play a role in the entry of low‐latitude mantle ions into the plasma sheet.
Epigenetic programming of obesity in early life through modulation of the kynurenine pathway
Authors: Gharipour Mojgan , Craig Jeffrey M. , Stephenson Garth
Published: October 2024

Childhood obesity is a global health concern that has its origins before birth. Although genetics plays a crucial role, increasing evidence suggests that epigenetic modifications during fetal life could also influence its incidence. In this model, during the fetal period, interactions between genetic makeup, intrauterine factors, and environmental conditions, increase the risk of childhood obesity. This is in accordance with the Developmental Origins of Health and Disease (DOHaD) hypothesis, in which specific intrauterine environments can have long-lasting effects on the immune system’s essential functions during crucial stages of fetal growth, resulting in permanent changes to the immune function of the offspring. Consequently, dysfunction can consequently make the offspring more prone to inflammatory and immune-related disorders later in life. In this review, we examine how maternal inflammation could influence the risk of childhood obesity. We propose that during pregnancy, modification of the expression of critical genes in metabolic and signaling pathways, such as the kynurenine (Kyn) pathway, occurs due to increased levels of maternal inflammation. We also propose that such expression differences are mediated by epigenetic changes. Furthermore, we also hypothesize that the Kyn pathway produces metabolites that have immunoregulatory effects and may play a crucial role in regulating inflammation during pregnancy. As a result, interventions aimed at improving maternal inflammation may be able to help alleviate the risk of childhood obesity.
4.8-μm CO-filled hollow-core silica fiber light source
Authors: Li Xuanxi , Yang Linyong , Zhou Zhiyue , Li Zhixian , Li Hao , Pei Wenxi , Huang Wei , Shi Jing , Lei Luohao , Wang Meng , Wang Zefeng
Published: October 2024

Mid-infrared (MIR) fiber lasers are important for a wide range of applications in sensing, spectroscopy, imaging, defense, and security. Some progress has been made in the research of MIR fiber lasers based on soft glass fibers, however, the emission range of rare-earth ions and the robustness of the host materials are still a major challenge for MIR fiber lasers. The large number of gases provide a variety of optical transitions in the MIR band. When combined with recent advances in low-loss hollow-core fiber (HCF), there is a great opportunity for gas-filled fiber lasers to further extend the radiation to the MIR region. Here, a 4.8-μm CO-filled silica-based HCF laser is reported for the first time. This is enabled by an in-house manufactured broadband low-loss HCF with a measured loss of 1.81 dB/m at 4.8 μm. A maximum MIR output power of 46 mW and a tuning range of 180 nm (from 4644 to 4824 nm) are obtained by using an advanced 2.33-μm narrow-linewidth fiber laser. This demonstration represents the longest-wavelength silica-based fiber laser to date, while the absorption loss of bulk silica at 4824 nm is up to 13, 000 dB/m. Further wavelength expansion could be achieved by changing the pump absorption line and optimizing the laser structure.
Nanomechanical thermometry for probing sub-nW thermal transport
Authors: Oh Sangmin , Shekhawat Nehpal Singh , Jameel Osama , Lal Amit , Lee Chung Hoon
Published: October 2024

Accurate local temperature measurement at micro and nanoscales requires thermometry with high resolution because of ultra-low thermal transport. Among the various methods for measuring temperature, optical techniques have shown the most precise temperature detection, with resolutions reaching (~10−9 K). In this work, we present a nanomechanical device with nano-Kelvin resolution (~10−9 K) at room temperature and 1 atm. The device uses a 20 nm thick silicon nitride (SiN) membrane, forming an air chamber as the sensing area. The presented device has a temperature sensing area >1 mm2 for micro/nanoscale objects with reduced target placement constraints as the target can be placed anywhere on the >1 mm2 sensing area. The temperature resolution of the SiN membrane device is determined by deflection at the center of the membrane. The temperature resolution is inversely proportional to the membrane’s stiffness, as detailed through analysis and measurements of stiffness and noise equivalent temperature (NET) in the pre-stressed SiN membrane. The achievable heat flow resolution of the membrane device is 100 pW, making it suitable for examining thermal transport on micro and nanoscales.
Visual body size estimation in adolescent anorexia nervosa: Behavioural and neurophysiological data suggest intact visual perception and biased emotional attention
Authors: Romero Frausto Hugo , Rahder Isabel , Dalhoff Anke W. , Roesmann Kati , Romer Georg , Junghöfer Markus , Wessing Ida
Published: October 2024

Body image disturbance is a key symptom of anorexia nervosa (AN). AN patients report body dissatisfaction and overestimate their own body size in several tasks. This study aimed to clarify whether this overestimation arises from deficits in visual perception. To this end, 36 adolescent restrictive-type AN patients and 42 matched healthy controls performed metric and depictive body size estimation (BSE) tasks. Magneto- and electroencephalography were measured during the size estimation of 66 computer-generated body pictures varying in size from underweight to overweight. AN patients versus controls showed overestimation across self-referential metric and depictive BSE tasks, but similar performance in a depictive BSE task without self-reference and similar early neurophysiological responses. Starting mid-latency (200 ms), AN patients showed relatively more neural activity in response to underweight body pictures and less neural activity in response to higher-weight body pictures in distributed brain regions. A secondary comparison of AN patients with slight vs. distinct overestimation during self-referential BSE uncovered relatively stronger neural responses to body pictures corresponding to the estimated body mass index. These results suggest that body image disturbances in adolescent restrictive-type AN patients depend on self-reference and do not represent a deficit of visual perception, but rather biased emotional attention.
Myeloid Mir34a suppresses colitis-associated colon cancer: characterization of mediators by single-cell RNA sequencing
Authors: König Janine , Rokavec Matjaz , Öner-Ziegler Meryem Gülfem , Fei Ye , Hermeking Heiko
Published: October 2024

We have previously shown that general deletion of the gene encoding the p53-inducible Mir34a microRNA enhances the number and invasion of colitis-associated colorectal cancers (CACs) in mice. Since the p53-pathway has been implicated in tumor-suppression mediated by cells in the tumor microenvironment (TME) we deleted Mir34a in myeloid cells and characterized CACs in these with scRNA-Seq (single cell RNA sequencing). This revealed an increase in specific macrophage subtypes, such as Cdk8
+ macrophages and Mrc1
+, M2-like macrophages. The latter displayed elevated expression of 21 known Mir34a target mRNAs, including Csf1r, Axl, Foxp1, Ccr1, Nampt, and Tgfbr2, and 32 predicted Mir34a target mRNAs. Furthermore, Mir34a-deficient BMDMs showed enhanced migration, elevated expression of Csf1r and a shift towards M2-like polarization when compared to Mir34a-proficient BMDMs. Concomitant deletion of Csf1r or treatment with a Csf1r inhibitor reduced the CAC burden and invasion in these mice. Notably, loss of myeloid Mir34a function resulted in a prominent, inflammatory CAC cell subtype, which displayed epithelial and macrophage markers. These cells displayed high levels of the EMT transcription factor Zeb2 and may therefore enhance the invasiveness of CACs. Taken together, our results provide in vivo evidence for a tumor suppressive role of myeloid Mir34a in CACs which is, at least in part, mediated by maintaining macrophages in an M1-like state via repression of Mir34a targets, such as Csf1r. Collectively, these findings may serve to identify new therapeutic targets and approaches for treatment of CAC.
Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity
Authors: de Lima Jean , Leite Jefferson Antônio , Basso Paulo José , Ghirotto Bruno , Martins da Silva Eloisa , Menezes-Silva Luisa , Hiyane Meire Ioshie , Goes Carolina Purcell , Coutinho Luiz Lehmann , de Andrade Oliveira Vinicius , Olsen Saraiva Câmara Niels
Published: October 2024

Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC3) that plays a crucial role in regulating the activation and differentiation of dendritic cells (DCs) as well as controlling the polarization and activation of T cells. Obesity, a chronic inflammatory condition, is characterized by the activation of immune cells in various tissues. We hypothesized that SIRT1 might influence the phenotype and functions of DCs through the Ido1 pathway, ultimately leading to the polarization towards pro-inflammatory T cells in obesity. In our study, we observed that SIRT1 activity was reduced in bone marrow-derived DCs (BMDCs) from obese animals. These BMDCs exhibited elevated oxidative phosphorylation (OXPHOS) and increased extracellular acidification rates (ECAR), along with enhanced expression of class II MHC, CD86, and CD40, and elevated secretion of IL-12p40, while the production of TGF-β was reduced. The kynurenine pathway activity was decreased in BMDCs from obese animals, particularly under SIRT1 inhibition. SIRT1 positively regulated the expression of Ido1 in DCs in a PPARγ-dependent manner. To support these findings, ATAC-seq analysis revealed that BMDCs from obese mice had differentially regulated open chromatin regions compared to those from lean mice, with reduced chromatin accessibility at the Sirt1 genomic locus in BMDCs from obese WT mice. Gene Ontology (GO) enrichment analysis indicated that BMDCs from obese animals had disrupted metabolic pathways, including those related to GTPase activity and insulin response. Differential expression analysis showed reduced levels of Pparg and Sirt1 in BMDCs from obese mice, which was challenged and confirmed using BMDCs from mice with conditional knockout of Sirt1 in dendritic cells (SIRT1∆). This study highlights that SIRT1 controls the metabolism and functions of DCs through modulation of the kynurenine pathway, with significant implications for obesity-related inflammation.
NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation
Authors: Chen Ssu-Yu , Wu Jianli , Chen Yubin , Wang Ya-En , Setayeshpour Yasaman , Federico Chiara , Mestre Alexander A. , Lin Chao-Chieh , Chi Jen-Tsan
Published: October 2024

Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture (PMR) during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis is less well elucidated. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced only by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that the ferroptosis protective effect caused by NINJ1 knockdown can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhancing cystine uptake and thereby providing protection against ferroptosis. Conversely, NINJ1 overexpression reduced xCT levels and sensitized ferroptosis. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths.
NLRP10 maintains epidermal homeostasis by promoting keratinocyte survival and P63-dependent differentiation and barrier function
Authors: Cho Yeonhee , Cao Zhongzheng , Luo Xin , Tian Jennifer J. , Hukkanen Renee R. , Hussien Rajaa , Cancilla Belinda , Chowdhury Priyanka , Li Fei , Ma Shining , LaGory Edward L. , Schroeder Mark , Dusenberry Amanda , Marshall Leslie , Hawkins Jenn , van Lookeren Campagne Menno , Zhou Yi
Published: October 2024

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder characterized by disrupted epidermal barrier function and aberrant immune responses. Despite recent developments in new therapeutics for AD, there is still a large unmet medical need for disease management due to the complex and multifactorial nature of AD. Recent genome-wide association studies (GWAS) have identified NLRP10 as a susceptible gene for AD but the physiological role of NLRP10 in skin homeostasis and AD remains unknown. Here we show that NLRP10 is downregulated in AD skin samples. Using an air-lift human skin equivalent culture, we demonstrate that NLRP10 promotes keratinocyte survival and is required for epidermal differentiation and barrier function. Mechanistically, NLRP10 limits cell death by preventing the recruitment of caspase-8 to the death inducing signaling complex (DISC) and by inhibiting its subsequent activation. NLRP10 also stabilizes p63, the master regulator of keratinocyte differentiation, to drive proper keratinocyte differentiation and to reinforce the barrier function. Our findings underscore NLRP10 as a key player in atopic dermatitis pathogenesis, highlighting NLRP10 as a potential target for therapeutic intervention to restore skin barrier function and homeostasis in AD.
Diverse weaning foods and diet patterns at multiple time points during infancy period and their association with neurodevelopmental outcomes in 6-year-old children
Authors: Kim Ju Hee , Ha Eun Kyo , Lee Gi Chun , Han Boeun , Shin Jeewon , Han Man Yong , Rhie Seonkyeong
Published: October 2024

Background/Objectives

Understanding the impact of early-life nutritional choices on neurodevelopment in children is a growing area of research. To investigate the association between dietary patterns at multiple timelines and neurodevelopmental outcomes in 6-year-old children.

Subjects/Methods

This administrative observational study utilized a merged data from the national health insurance database and the health screening program for children. Information on the diet patterns from infancy to 3 years of age was obtained from parent-administered questionnaires. Dietary pattern clusters of the participants were identified using Polytomous Latent Class Analysis. The outcome was neurodevelopment using the Korean Developmental Screening Test (K-DST) at the age of 6 years.

Results

The study identified four distinct clusters among with the 133,243 eligible children (49.6% male, birth weight 3.22 kg, head circumference 42.7 cm at 4 months). The control cluster (53.4%) exhibited a diet including breast milk feeding and a variety of dietary patterns at the age of 1 year. In contrast, cluster 1 (36.0%) showed a skewed dietary pattern at the same age. Cluster 2 (6.6%) displayed diverse dietary patterns at one year but primarily consumed formula at four months, while cluster 3 (4.0%) had reduced dietary diversity and formula feeding. Compared with the control cluster, the adjusted odds ratio for unfavorable development was 1.209 (95% CI, 1.156–1.266) in cluster 1, 1.418 (95% CI, 1.312–1.532) in cluster 2, and 1.741 (95% CI, 1.593–1.903) in cluster 3. These findings remained consistent across individual domains of the K-DST.

Conclusions

Dietary patterns during infancy and early childhood may be associated with neurodevelopment at the age of 6 years.
The integrated molecular and histological analysis defines subtypes of esophageal squamous cell carcinoma
Authors: Jiang Guozhong , Wang Zhizhong , Cheng Zhenguo , Wang Weiwei , Lu Shuangshuang , Zhang Zifang , Anene Chinedu A. , Khan Faraz , Chen Yue , Bailey Emma , Xu Huisha , Dong Yunshu , Chen Peinan , Zhang Zhongxian , Gao Dongling , Wang Zhimin , Miao Jinxin , Xue Xia , Wang Pengju , Zhang Lirong , Gangeswaran Rathi , Liu Peng , Chard Dunmall Louisa S. , Li Junkuo , Guo Yongjun , Dong Jianzeng , Lemoine Nicholas R. , Li Wencai , Wang Jun , Wang Yaohe
Published: October 2024

Esophageal squamous cell carcinoma (ESCC) is highly heterogeneous. Our understanding of full molecular and immune landscape of ESCC remains limited, hindering the development of personalised therapeutic strategies. To address this, we perform genomic-transcriptomic characterizations and AI-aided histopathological image analysis of 120 Chinese ESCC patients. Here we show that ESCC can be categorized into differentiated, metabolic, immunogenic and stemness subtypes based on bulk and single-cell RNA-seq, each exhibiting specific molecular and histopathological features based on an amalgamated deep-learning model. The stemness subgroup with signature genes, such as WFDC2, SFRP1, LGR6 and VWA2, has the poorest prognosis and is associated with downregulated immune activities, a high frequency of EP300 mutation/activation, functional mutation enrichment in Wnt signalling and the highest level of intratumoural heterogeneity. The immune profiling by transcriptomics and immunohistochemistry reveals ESCC cells overexpress natural killer cell markers XCL1 and CD160 as immune evasion. Strikingly, XCL1 expression also affects the sensitivity of ESCC cells to common chemotherapy drugs. This study opens avenues for ESCC treatment and provides a valuable public resource to better understand ESCC.
Glucose metabolism controls monocyte homeostasis and migration but has no impact on atherosclerosis development in mice
Authors: Gallerand Alexandre , Dolfi Bastien , Stunault Marion I. , Caillot Zakariya , Castiglione Alexia , Strazzulla Axelle , Chen Chuqiao , Heo Gyu Seong , Luehmann Hannah , Batoul Flora , Vaillant Nathalie , Dumont Adélie , Pilot Thomas , Merlin Johanna , Zair Fairouz N. , Gilleron Jerome , Bertola Adeline , Carmeliet Peter , Williams Jesse W. , Arguello Rafael J. , Masson David , Dombrowicz David , Yvan-Charvet Laurent , Doyen Denis , Haschemi Arvand , Liu Yongjian , Guinamard Rodolphe R. , Ivanov Stoyan
Published: October 2024

Monocytes directly contribute to atherosclerosis development by their recruitment to plaques in which they differentiate into macrophages. In the present study, we ask how modulating monocyte glucose metabolism could affect their homeostasis and their impact on atherosclerosis. Here we investigate how circulating metabolites control monocyte behavior in blood, bone marrow and peripheral tissues of mice. We find that serum glucose concentrations correlate with monocyte numbers. In diet-restricted mice, monocytes fail to metabolically reprogram from glycolysis to fatty acid oxidation, leading to reduced monocyte numbers in the blood. Mechanistically, Glut1-dependent glucose metabolism helps maintain CD115 membrane expression on monocytes and their progenitors, and regulates monocyte migratory capacity by modulating CCR2 expression. Results from genetic models and pharmacological inhibitors further depict the relative contribution of different metabolic pathways to the regulation of CD115 and CCR2 expression. Meanwhile, Glut1 inhibition does not impact atherosclerotic plaque development in mouse models despite dramatically reducing blood monocyte numbers, potentially due to the remaining monocytes having increased migratory capacity. Together, these data emphasize the role of glucose uptake and intracellular glucose metabolism in controlling monocyte homeostasis and functions.
Transient nicotine exposure in early adolescent male mice freezes their dopamine circuits in an immature state
Authors: Reynolds Lauren M. , Gulmez Aylin , Fayad Sophie L. , Campos Renan Costa , Rigoni Daiana , Nguyen Claire , Le Borgne Tinaïg , Topilko Thomas , Rajot Domitille , Franco Clara , Fernandez Sebastian P. , Marti Fabio , Heck Nicolas , Mourot Alexandre , Renier Nicolas , Barik Jacques , Faure Philippe
Published: October 2024

How nicotine acts on developing neurocircuitry in adolescence to promote later addiction vulnerability remains largely unknown, but may hold the key for informing more effective intervention efforts. We found transient nicotine exposure in early adolescent (PND 21-28) male mice was sufficient to produce a marked vulnerability to nicotine in adulthood (PND 60 + ), associated with disrupted functional connectivity in dopaminergic circuits. These mice showed persistent adolescent-like behavioral and physiological responses to nicotine, suggesting that nicotine exposure in adolescence prolongs an immature, imbalanced state in the function of these circuits. Chemogenetically resetting the balance between the underlying dopamine circuits unmasked the mature behavioral response to acute nicotine in adolescent-exposed mice. Together, our results suggest that the perseverance of a developmental imbalance between dopamine pathways may alter vulnerability profiles for later dopamine-dependent psychopathologies.
Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma
Authors: Karlsson Jenny , Yasui Hiroaki , Mañas Adriana , Andersson Natalie , Hansson Karin , Aaltonen Kristina , Jansson Caroline , Durand Geoffroy , Ravi Naveen , Ferro Michele , Yang Minjun , Chattopadhyay Subhayan , Paulsson Kajsa , Spierings Diana , Foijer Floris , Valind Anders , Bexell Daniel , Gisselsson David
Published: October 2024

Neuroblastoma (NB) is one of the most lethal childhood cancers due to its propensity to become treatment resistant. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicate these two contrasting scenarios and show branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.
Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales
Authors: Graf Fabrice E. , Goodman Richard N. , Gallichan Sarah , Forrest Sally , Picton-Barlow Esther , Fraser Alice J. , Phan Minh-Duy , Mphasa Madalitso , Hubbard Alasdair T. M. , Musicha Patrick , Schembri Mark A. , Roberts Adam P. , Edwards Thomas , Lewis Joseph M. , Feasey Nicholas A.
Published: October 2024

Infections with Enterobacterales (E) are increasingly difficult to treat due to antimicrobial resistance. After ceftriaxone replaced chloramphenicol (CHL) as empiric therapy for suspected sepsis in Malawi in 2004, extended-spectrum beta-lactamase (ESBL)-E rapidly emerged. Concurrently, resistance to CHL in Escherichia coli and Klebsiella spp. decreased, raising the possibility of CHL re-introduction. However, many phenotypically susceptible isolates still carry CHL acetyltransferase (cat) genes. To understand the molecular mechanisms and stability of this re-emerging CHL susceptibility we use a combination of genomics, phenotypic susceptibility assays, experimental evolution, and functional assays for CAT activity. Here, we show that of 840 Malawian E. coli and Klebsiella spp. isolates, 31% have discordant CHL susceptibility genotype–phenotype, and we select a subset of 42 isolates for in-depth analysis. Stable degradation of cat genes by insertion sequences leads to re-emergence of CHL susceptibility. Our study suggests that CHL could be reintroduced as a reserve agent for critically ill patients with ESBL-E infections in Malawi and similar settings and highlights the ongoing challenges in inferring antimicrobial resistance from sequence data.
Population variability in X-chromosome inactivation across 10 mammalian species
Authors: Werner Jonathan M. , Hover John , Gillis Jesse
Published: October 2024

One of the two X-chromosomes in female mammals is epigenetically silenced in embryonic stem cells by X-chromosome inactivation. This creates a mosaic of cells expressing either the maternal or the paternal X allele. The X-chromosome inactivation ratio, the proportion of inactivated parental alleles, varies widely among individuals, representing the largest instance of epigenetic variability within mammalian populations. While various contributing factors to X-chromosome inactivation variability are recognized, namely stochastic and/or genetic effects, their relative contributions are poorly understood. This is due in part to limited cross-species analysis, making it difficult to distinguish between generalizable or species-specific mechanisms for X-chromosome inactivation ratio variability. To address this gap, we measure X-chromosome inactivation ratios in ten mammalian species (9531 individual samples), ranging from rodents to primates, and compare the strength of stochastic models or genetic factors for explaining X-chromosome inactivation variability. Our results demonstrate the embryonic stochasticity of X-chromosome inactivation is a general explanatory model for population X-chromosome inactivation variability in mammals, while genetic factors play a minor role.
Climate justice beliefs related to climate action and policy support around the world
Authors: Ogunbode Charles A. , Doran Rouven , Ayanian Arin H. , Park Joonha , Utsugi Akira , van den Broek Karlijn L. , Ghorayeb Jihane , Aquino Sibele D. , Lins Samuel , Aruta John J. B. R. , Reyes Marc E. S. , Zick Andreas , Clayton Susan
Published: October 2024

Climate justice is increasingly prominent in climate change communication and advocacy but little is known about public understanding of the concept or how widely it resonates with different groups. In our global survey of 5,627 adults in 11 countries spanning the global north and south, most participants (66.2%) had never heard of climate justice. Nonetheless, endorsement of climate justice beliefs was widespread (for example, acknowledging the disproportionate impact of climate change on poor people and the underpinning roles of capitalism and colonialism in the climate crisis). Climate justice beliefs were also associated with various indices of climate action and policy support. These associations tended to be stronger in countries with high GHG emissions and where social inequality is also more politically salient. The results highlight the value of climate justice as a motive for climate action across diverse geographical contexts.
Executive function in children with neurodevelopmental conditions: a systematic review and meta-analysis
Authors: Sadozai Ayesha K. , Sun Carter , Demetriou Eleni A. , Lampit Amit , Munro Martha , Perry Nina , Boulton Kelsie A. , Guastella Adam J.
Published: October 2024

Executive function (EF) delays are well documented in paediatric neurodevelopmental conditions (NDCs). There is no consensus about whether EF delay represents a transdiagnostic feature of NDCs. This systematic review and meta-analysis synthesized 180 studies reporting two or more NDC comparisons on EF, examined differences between NDCs, and the moderating effects of gender, age, publication year, DSM editions and assessment types. Studies using established EF measures across seven domains (attention, fluency, set-shifting, set-switching, response inhibition, planning and working memory) in participants under 18 were included. Summary effects were compared: (1) for all reported NDCs relative to control, (2) for each individual NDC relative to control and (3) between NDC groups. Results confirmed that EF delay was a transdiagnostic feature of neurodevelopmental delay, with a moderate effect size of delay across all NDCs (g = 0.56, 95% confidence interval (CI) 0.49–0.63) compared with control. This effect increased with comorbidities (g = 0.72, 95% CI 0.59–0.86), DSM-5 criteria and informant measures. Comparisons between NDCs revealed few differences: children with tic disorders (TD) showed smaller EF delays, children with attention-deficit/hyperactivity disorder (ADHD) showed larger delays in attention, response inhibition, planning and working memory compared with TD and specific learning disorders, while children with autism spectrum disorders showed greater delays on set-switching compared with ADHD. Findings support transdiagnostic models of neurodevelopment to further a developmentally sensitive science that can reveal how EF delays contribute to brain circuitry, symptom profiles and functioning, and ultimately support early interventions and outcomes for all children with NDCs.
Droplet Hi-C enables scalable, single-cell profiling of chromatin architecture in heterogeneous tissues
Authors: Chang Lei , Xie Yang , Taylor Brett , Wang Zhaoning , Sun Jiachen , Armand Ethan J. , Mishra Shreya , Xu Jie , Tastemel Melodi , Lie Audrey , Gibbs Zane A. , Indralingam Hannah S. , Tan Tuyet M. , Bejar Rafael , Chen Clark C. , Furnari Frank B. , Hu Ming , Ren Bing
Published: October 2024

Current methods for analyzing chromatin architecture are not readily scalable to heterogeneous tissues. Here we introduce Droplet Hi-C, which uses a commercial microfluidic device for high-throughput, single-cell chromatin conformation profiling in droplets. Using Droplet Hi-C, we mapped the chromatin architecture of the mouse cortex and analyzed gene regulatory programs in major cortical cell types. In addition, we used this technique to detect copy number variations, structural variations and extrachromosomal DNA in human glioblastoma, colorectal and blood cancer cells, revealing clonal dynamics and other oncogenic events during treatment. We refined the technique to allow joint profiling of chromatin architecture and transcriptome in single cells, facilitating exploration of the links between chromatin architecture and gene expression in both normal tissues and tumors. Thus, Droplet Hi-C both addresses critical gaps in chromatin analysis of heterogeneous tissues and enhances understanding of gene regulation.
Mechanism of polyadenylation-independent RNA polymerase II termination
Authors: Rengachari Srinivasan , Hainthaler Thomas , Oberthuer Christiane , Lidschreiber Michael , Cramer Patrick
Published: October 2024

The mechanisms underlying the initiation and elongation of RNA polymerase II (Pol II) transcription are well-studied, whereas termination remains poorly understood. Here we analyze the mechanism of polyadenylation-independent Pol II termination mediated by the yeast Sen1 helicase. Cryo-electron microscopy structures of two pretermination intermediates show that Sen1 binds to Pol II and uses its adenosine triphosphatase activity to pull on exiting RNA in the 5′ direction. This is predicted to push Pol II forward, induce an unstable hypertranslocated state and destabilize the transcription bubble, thereby facilitating termination. This mechanism of transcription termination may be widely used because it is conceptually conserved in the bacterial transcription system.
Rational design and synthesis of new pyrrolone candidates as prospective insecticidal agents against Culex pipiens L. Larvae
Authors: Hekal Mohamed H. , Hashem Ahmed I. , El-Azm Fatma S.M. Abu , Abdel-Haleem Doaa R. , Rafat El-Hady , Ali Yasmeen M.
Published: October 2024

As a result of its high reactivity, furan-2(3H)-one derivative 2 can be selected as a versatile and suitable candidate for building of novel nitrogen heterocyclic compounds. Consequently, furan-2(3H)-one derivative 2 and some nitrogen nucleophiles were utilized as starting materials for the formation of new pyridazinone and pyrrolone derivatives bearing naphthalene moiety. The continuous buildup of insecticide resistance is the main obstacle facing pest control measures. Pyrrole-based insecticides are a favourable choice due to their unique mode of action and no cross-resistance with traditional neurotoxic insecticides. The larvicidal activities of pyrrolone derivatives were assessed against field and laboratory strains of Culex pipiens larvae in comparison with chlorfenapyr (pyrrole insecticide). Compounds 17 (21.05 µg/mL) > 9 (22.81 µg/mL) > 15 (24.39 µg/mL) > 10 (26.76 µg/mL) > 16 (32.09 µg/mL) were most effective against lab strain of C. pipiens larvae relative to chlorfenapyr (25.43 µg/mL). While in field strain, 17 and 15 were the most toxic compounds followed by 9 > 10 > 16 > 2 with LC50 of 9.87, 10.76, 11.52, 12.68, 15.32 and 18.37 µg/mL, respectively, compared with chlorfenapyr with 14.03 µg/mL. The cytochrome P-450 monooxygenase activities were significantly increased in treated larvae of lab and field strains relative to untreated. The great variations in toxicity of the synthesized compounds were interpreted by structure-activity relationship study. The pyrrolone derivatives are effective against field and insecticide-resistant strains. Therefore, they are considered promising compounds to be integrated into pest management programs.
Loss of Stim2 in zebrafish induces glaucoma-like phenotype
Authors: Baranykova Sofiia , Gupta Rishikesh Kumar , Kajdasz Arkadiusz , Wasilewska Iga , Macias Matylda , Szybinska Aleksandra , Węgierski Tomasz , Nahia Karim Abu , Mondal Shamba S. , Winata Cecilia L. , Kuźnicki Jacek , Majewski Lukasz
Published: October 2024

Calcium is involved in vision processes in the retina and implicated in various pathologies, including glaucoma. Rod cells rely on store-operated calcium entry (SOCE) to safeguard against the prolonged lowering of intracellular calcium ion concentrations. Zebrafish that lacked the endoplasmic reticulum Ca2+ sensor Stim2 (stim2 knockout [KO]) exhibited impaired vision and lower light perception-related gene expression. We sought to understand mechanisms that are responsible for vision impairment in stim2 KO zebrafish. The single-cell RNA (scRNA) sequencing of neuronal cells from brains of 5 days postfertilization larvae distinguished 27 cell clusters, 10 of which exhibited distinct gene expression patterns, including amacrine and γ-aminobutyric acid (GABA)ergic retinal interneurons and GABAergic optic tectum cells. Five clusters exhibited significant changes in cell proportions between stim2 KO and controls, including GABAergic diencephalon and optic tectum cells. Transmission electron microscopy of stim2 KO zebrafish revealed decreases in width of the inner plexiform layer, ganglion cells, and their dendrites numbers (a hallmark of glaucoma). GABAergic neuron densities in the inner nuclear layer, including amacrine cells, as well as photoreceptors significantly decreased in stim2 KO zebrafish. Our study suggests a novel role for Stim2 in the regulation of neuronal insulin expression and GABAergic-dependent vision causing glaucoma-like retinal pathology.
Glyceroniosomes for enhanced intestinal absorption of hydrochlorothiazide and lisinopril in their fixed dose combination
Authors: Elbasuony Aya R. , Abdelaziz Abdelaziz E. , Mazyed Eman A. , El Maghraby Gamal M.
Published: October 2024

The objective was to investigate the effect of co-administration of hydrochlorothiazide and lisinopril as fixed dose combination on their intestinal absorption. The scope was extended to enhance intestinal absorption of both drugs. In situ rabbit intestinal absorption through the duodenum and jejuno-ileum was used to monitor membrane permeability of both drugs when perfused alone or in combination. Niosomes containing glycerols (glyceroniosomes) were loaded with both drugs. Glyceroniosomes comprised Span 60 or Tween 40 in combination with cholesterol and glycerol were prepared by bath sonication. Glyceroniosomes were characterized with respect to vesicle size, drug entrapment efficiency and were examined using transmission electron microscope (TEM). The prepared vesicles were nanosized spherical vesicles with average size of 202.4 nm and 108.8 nm for span free and span containing glyceroniosomes, respectively. The recorded Zeta potential values suggested good stability of the prepared formulations. Intestinal absorption studies reflected incomplete absorption of hydrocholothiazide and lisinopril correlating with their categorization as class IV and III drugs, respectively. Co-perfusion of both drugs reduced the intestinal absorption of lisinopril. Simultaneous encapsulation in glyceroniosomes enhanced the intestinal absorption of both drugs. Tween based systems were more efficient. The study introduced glyceroniosomes as carriers of simultaneous delivery of hydrochlorothiazide and lisinopril.
Computed tomography for the detection of myocardial hypoperfusion in acute myocardial infarction and the associated CT-to-catheter time
Authors: Mostafa Karim , Seoudy Hatim , Aludin Schekeb , Schunk Domagoj , Peckolt Hannes , Wolf Carmen , Saad Mohammed , Both Marcus , Jansen Olav , Frank Derk , Langguth Patrick
Published: October 2024

Emergency computed tomography (CT) often does not allow for comprehensive coronary artery assessment. However, CT may reveal pathological myocardial hypoperfusion suggestive of acute myocardial infarction (AMI), especially in patients presenting with a different diagnostic hypothesis. CT hypoperfusion is known to be associated with myocardial infarction, however the diagnostic value of CT hypoperfusion for the detection of AMI is still not well evaluated. This was a single-centre retrospective study including patients who underwent invasive coronary angiography (ICA) due to suspected AMI based on incidental perfusion defects upon emergency CT imaging between 2018 and 2023. A total of 22 patients (mean age 66.3 ± 10.8 years, 11 female) were included in this analysis. The diagnosis of AMI was established in all cases leading to ICA. Culprit coronary artery lesions with an indication of percutaneous coronary intervention were detected in all patients who underwent ICA. Spearmann correlation for hypoperfused segments on CT imaging and the corresponding vascular territory upon ICA was significantly substantial (ρ = 0.73, p = < 0.001). The higher the number of affected myocardial segments, the faster ICA was initiated. Mean time between the suspicion of AMI on CT imaging and ICA was 196 (29–4044) minutes. Myocardial hypoperfusion on emergency CT imaging should be considered as AMI until proven otherwise, independent of the clinical scenario leading to performance of CT imaging and whether imaging was performed for the exclusion of non-cardiac pathologies. Early initiation of further diagnostic workup may potentially avoid delays to invasive treatment and reduce the CT-to-catheter-time. Our study explicitly underlines that myocardial hypoperfusion upon contrast enhanced CT imaging needs to be considered as sign of acute myocardial infarction and indicates targeted clinical workup to rule out this diagnosis and to shorten the timeframe from imaging diagnosis to interventional treatment.
The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer’s disease
Authors: Xiong Wandi , Xu Kaiyu , Sun Jacquelyne Ka-Li , Liu Siling , Zhao Baizhen , Shi Jie , Herrup Karl , Chow Hei-Man , Lu Lin , Li Jiali
Published: October 2024

Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer’s disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3’UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer’s pathogenesis