bluuebunny/crossref_metadata_2025 huggingface dataset:
Overcoming the relative bandwidth limitations of single VCO frequency synthesizers by implementing a novel PLL architecture
Authors: Braun Tobias T. , Schoepfel Jan , Marquez M. Aldo J. , Pohl Nils
Published: February 2024

Frequency-modulated continuous-wave radar systems profit from increasing the absolute bandwidths of the generated frequency chirps to improve range resolution. As the relative bandwidth of SiGe-voltage-controlled oscillators (VCOs) is limited to about 80%, increasing the center frequency fundamentally or via frequency multiplication is the most direct way to increase that absolute bandwidth. However, as some applications require penetration depth, which dramatically decreases with frequency, other solutions are necessary. Therefore, state-of-the-art concepts rely on the down-conversion of generated frequency chirps via two separately stabilized frequency sources. This article implements a novel architecture, offering relative bandwidths of >100% within a single phase-locked loop (PLL). Therefore, two VCOs at different center frequencies are fed into a down-conversion mixer, whose output is directly stabilized via that PLL with one loop filter generating both tuning voltages. Those circuit blocks can be summarized as one equivalent VCO, offering a higher relative bandwidth and a significantly more linear tuning curve. Thereby, a solution to limited relative bandwidths with high VCO gain variation of single VCO synthesizers is offered while substantially reducing the hardware and implementation effort compared to the state-of-the-art.
Seeing Is Believing
Authors: Silver Elisabeth R. , Ng Linnea C. , Corrington Abby , Hebl Mikki , Braam Janet
Published: February 2024

Abstract: We investigate how visual cues in universities discourage women from pursuing STEM. We extend research on ambient sexism (i.e., witnessing sexist mistreatment of others) to include environmental cues that women do not belong. Men were pictured in STEM buildings (Pilot Study 1) and described in university-sponsored STEM news articles (Pilot Study 2) twice as often as women. In an experiment, undergraduate women who read about male scientists reported less positive STEM attitudes relative to men who read about male scientists and women who read about female scientists. Women who read about and saw images of female scientists reported more positive STEM attitudes than women who simply read about female scientists. Depicting predominantly male scientists in universities negatively impacts female students.
Analyzing the Causation Between Conspiracy Mentality and Belief in Conspiracy Theories
Authors: Nera Kenzo
Published: February 2024

Abstract: The dispositional approach to conspiracy mentality suggests that it causally precedes belief in conspiracy theories. I identify two potential pitfalls when analyzing this causal relationship: circular reasoning (in which the two constructs are conflated and interchangeable) and black box explanations (in which conspiracy mentality is merely defined as a disposition to believe in conspiracy theories). I argue that avoiding black box explanations requires theoretical and empirical works to clarify the content and antecedents of conspiracy mentality. To guide future research, I formulate two hypotheses based on a philosophical analysis of conspiracy thinking and empirical research. In doing so, I question common assumptions on conspiracy mentality. First, against the assumption that conspiracy mentality is unidimensional, I propose that it may be better conceptualized as a multidimensional construct. Second, against the assumption that conspiracy mentality unidirectionally causes conspiracy theory beliefs, I propose that this relationship might be bidirectional.
The Victimizing Effects of Conspiracy Beliefs
Authors: Bertin Paul
Published: February 2024

Abstract: Victimhood has been linked to conspiracy beliefs in various contexts. However, the causal relationship between these constructs remains unclear. Following previous work, conspiracy beliefs could be described as victimized beliefs that are consequences of perceiving one’s ingroup as especially suffering from a situation (i.e., exclusive forms of collective victimhood, comprising competitive victimhood). However, in the absence of causal examination, it might also be that conspiracy beliefs are victimizing beliefs that increase perceptions of victimhood. In Studies 1 and 2, which experimentally tested the widespread victimized beliefs interpretation ( Ntotal = 730), induced exclusive victimhood increased neither specific nor generic conspiracy beliefs. In Study 3 ( N = 335), I tested the reversed causal relations and found that exposure to specific or generic conspiracy theories in a fictitious society increased neither individual nor collective forms of victimhood. However, in Study 4 ( N = 465), exposure to a specific conspiracy theory about a real-world conflict, compared to a generic conspiracy theory, increased exclusive forms of collective victimhood. By contrast, individual-level victimhood about systemic issues increased in both conspiratorial conditions. The goal of Study 5 ( N = 561) was to distinguish the victimizing effects of exposure to a specific conspiracy theory from those of an intergroup conflict situation. Exposure to a conspiracy theory and to an intergroup conflict increased exclusive victimhood to the same extent, but the conspiracy condition again triggered more individual-level victimhood. Together, these results document that conspiracy beliefs have a self-oriented victimizing effect and that it is crucial to account for intergroup conflicts when studying the link between these beliefs and collective-level victimhood. Victimizing one’s status through conspiracy allegations might seek to gain advantages in crisis situations.
Enemies Inside and Out
Authors: Bogatyreva Natalia
Published: February 2024

Abstract: Several popular conspiracy theories hold the government as one of the main figures of power, accusing it of various bad deeds. However, in authoritarian regimes or weak democracies, the state itself creates and exploits conspiracies about external and internal enemies of the nation. This paper explores the relationship between specific prostate conspiracy theory beliefs and conspiracy mentality in the context of Russia ( N = 819), a country, where the government currently leverages conspiracy theories for its own purposes. These findings suggest interesting ways forward for the study of conspiracy theories in nondemocratic states. A discussion about the influence of institutional trust on conspiracy theory beliefs is provided.
On the Usefulness of the Conspiracy Mentality Concept
Authors: Imhoff Roland
Published: February 2024

Abstract: The current commentary aims at defending the usefulness of the conspiracy mentality construct and emphasize its advantages over other ways to conceptualize and measure conspiracy beliefs. In contrast to specific conspiracy theories, items tapping into conspiracy mentality are typically not ideologically laden and are typically neither true nor false. They thus provide a purer measure of endorsing a conspiracy worldview – independent of ideological leaning or concerns of accuracy. Responding to Nera’s complaint about a Black Box definition of conspiracy mentality, the current commentary argues that the current state of the literature goes beyond that. Far from defining conspiracy mentality only in terms of agreeing with specific conspiracy theories, scholars have postulated its constituents (e.g., anti-elitism) and established some associates (e.g., generalized distrust). Whether a more fine-grained approach to conspiracy mentality as a multi-faceted construct will provide more useful is to be conceptually argued and empirically demonstrated instead of merely claimed.
The Greenhouse Gas Budget of Terrestrial Ecosystems in East Asia Since 2000
Authors: Wang Xuhui , Gao Yuanyi , Jeong Sujong , Ito Akihiko , Bastos Ana , Poulter Benjamin , Wang Yilong , Ciais Philippe , Tian Hanqin , Yuan Wenping , Chandra Naveen , Chevallier Frédéric , Fan Lei , Hong Songbai , Lauerwald Ronny , Li Wei , Lin Zhengyang , Pan Naiqing , Patra Prabir K. , Peng Shushi , Ran Lishan , Sang Yuxing , Sitch Stephen , Takashi Maki , Thompson Rona Louise , Wang Chenzhi , Wang Kai , Wang Tao , Xi Yi , Xu Liang , Yan Yanzi , Yun Jeongmin , Zhang Yao , Zhang Yuzhong , Zhang Zhen , Zheng Bo , Zhou Feng , Tao Shu , Canadell Josep G. , Piao Shilong
Published: February 2024

East Asia (China, Japan, Koreas, and Mongolia) has been the world's economic engine over at least the past two decades, exhibiting a rapid increase in fossil fuel emissions of greenhouse gases (GHGs) and has expressed the recent ambition to achieve climate neutrality by mid‐century. However, the GHG balance of its terrestrial ecosystems remains poorly constrained. Here, we present a synthesis of the three most important long‐lived greenhouse gases (CO2, CH4, and N2O) budgets over East Asia during the decades of 2000s and 2010s, following a dual constraint approach. We estimate that terrestrial ecosystems in East Asia is close to neutrality of GHGs, with a magnitude of between −46.3 ± 505.9 Tg CO2eq yr−1(the top‐down approach) and −36.1 ± 207.1 Tg CO2eq yr−1(the bottom‐up approach) during 2000–2019. This net GHG sink includes a large land CO2sink (−1229.3 ± 430.9 Tg CO2 yr−1based on the top‐down approach and −1353.8 ± 158.5 Tg CO2 yr−1based on the bottom‐up approach) being offset by biogenic CH4and N2O emissions, predominantly coming from the agricultural sectors. Emerging data sources and modeling capacities have helped achieve agreement between the top‐down and bottom‐up approaches, but sizable uncertainties remain in several flux terms. For example, the reported CO2flux from land use and land cover change varies from a net source of more than 300 Tg CO2 yr−1to a net sink of ∼−700 Tg CO2 yr−1. Although terrestrial ecosystems over East Asia is close to GHG neutral currently, curbing agricultural GHG emissions and additional afforestation and forest managements have the potential to transform the terrestrial ecosystems into a net GHG sink, which would help in realizing East Asian countries' ambitions to achieve climate neutrality.
Influence of Spatial Heterogeneity in Sea Surface Temperature on Tropical Cyclone Intensity Over the Western North Pacific
Authors: Sun Jia , Jin Shanshan , Ju Xia , He Hailun , Ding Ruibin , Hu Xiaomin , Xiong Xuejun
Published: February 2024

This study explores the impact of sea surface temperature (SST) spatial heterogeneity on tropical cyclone (TC) intensity through a combination of observations and simulations, aiming to provide a reference for further improving TC intensity forecasting skills. Two distinct patterns of SST spatial heterogeneity are identified based on a statistical analysis of observational data, when the SST at the TC center is above and below 29.3°C, respectively. One is a warm‐core pattern (WCP) with a warm peak SST at the TC center decreasing centrifugally which favors TC development, and the other one is a poleward‐decreasing pattern (PDP) with a warm SST at the south decreasing poleward which suppresses TC development. The numerical simulations confirm the opposite influence of the WCP and the PDP on TC intensity. The WCP intensifies TC intensity by strengthening TC secondary circulation, increasing the conversion from ocean heat energy to TC kinetic energy, and compacting TC structure. In contrast, the PDP weakens TC intensity by inducing opposing responses of these processes. The magnitude of TC intensity change caused by SST spatial heterogeneity is comparable to those caused by a 1°C change in SST at the TC center. These findings offer valuable insights into the role of SST spatial heterogeneity in TC development and provide a new perspective to improve TC intensity forecasting by incorporating SST spatial heterogeneity into statistical‐dynamic models.
Contrasting Responses of Land Surface Temperature and Soil Temperature to Forest Expansion During the Dormant Season on the Qinghai‐Tibet Plateau
Authors: Qu Zhuoran , Li Xiaoyan , Shi Fangzhong
Published: February 2024

As one of the important ecological responses of ecosystem to global climate change, forest expansion can alter land surface energy budget and local microclimate. Land surface temperature (LST) and soil temperature (ST) indicate the above‐ and below‐ground thermal state, respectively. However, the lack of studies on the relationships between LST and ST changes after forest expansion hinders our understanding of the vegetation‐microclimate interactions, especially during the dormant season. We quantified the change of LST (∆LST) and ST (∆ST) after forest expansion in the dormant season on the Qinghai‐Tibet Plateau (QTP), and then explored their differences and linkages. The results showed that forest expansion significantly decreased LST by 0.75 ± 0.20°C, while significantly increased ST in three layers (0–7, 7–28, and 28–100 cm) by 0.31 ± 0.06, 0.29 ± 0.05, and 0.20 ± 0.04°C, respectively. The decreased LST was conducive to the preservation of snow, leading to larger snow depth, larger fractional snow cover and more snow cover days in forests than grasslands, which further promoted the increased ST through enhanced thermal insulation. Furthermore, it is suggested that the cooling impact of forest expansion on LST and warming impact on ST would both be stronger at humid sites than at dry sites. These findings will contribute to understand the vegetation‐microclimate‐snow interactions and the decoupling phenomenon between LST and ST in the dormant season influenced by vegetation change.
Radar Attenuation Characteristics of Low Reflectivity Zones in the Martian South Polar Layered Deposits
Authors: Abu Hashmeh N. , Whitten J. L. , Russell A. T. , Putzig N. E.
Published: February 2024

Both sets of Martian polar layered deposits (PLDs) display semi‐rhythmic reflector stratigraphy in radargrams. The southern PLDs (SPLD), among other peculiarities, also contain widespread, distinctive deposits with few to no reflections that commonly occur at or near the top of the stratigraphic column. Here, we study the low reflectivity zones (LRZs) to determine whether they exhibit radar properties indicative of non‐water ice. We find that the previously reported CO2‐ice LRZ exhibits a distinct radar signature compared to all other LRZs. We also found behavior that suggests that the other LRZs may contribute to increased radar signal attenuation, which does not support a CO2 ice composition. We observe many instances of LRZs comprising the entire SPLD column and find that the radar attenuation varies across different LRZs, suggesting unique properties within each of these deposits. Variable radar attenuation of LRZs may be connected to differences in bulk compositions, radar‐sensitive roughness characteristics, and/or distributions of stratigraphic materials.
Climate and Vegetation of the Miocene of Tierra del Fuego: Filaret Formation
Authors: Sandoval C. A. , Yabe A. , Nishida H. , Hinojosa L. F.
Published: February 2024

The changing climate during the Cenozoic affected the diversity of plants in Patagonia, as species richness tends to increase during warm periods and decrease during cold periods. Precipitation is a significant factor shaping diversity, as shown in the case of central Chile during the Miocene. This study presents a reconstruction of the climate and vegetation in Tierra del Fuego Island, located approximately 52°S, using fossil flora recovered from the Filaret Formation to understand the Miocene epoch, characterized by contrasting global climatic changes. Filaret flora comprises twenty‐seven morpho‐taxa, including nine Nothofagus species and other Gondwanan and Neotropical families, such as Atherospermataceae and Anacardiaceae, in agreement with a forest habitat. Leaf physiognomy climate reconstruction suggests microthermal conditions, with a mean annual temperature of 9.4–11°C and annual precipitation ranging from 985 to 1,130 mm. These conditions are warmer and wetter than the modern record of the area, with a MAT of 6°C and mean annual precipitation of 300 mm. As the Filaret fossil record suggests, the forest habitat under a microthermal climate is consistent with the global climatic reconstruction of the Early Miocene. This Miocene landscape on Tierra del Fuego was possible because the Andes could not rain‐shadow humid westerly winds by this timeframe.
The evolution of preclinical models for myelodysplastic neoplasms
Authors: Mina Alain , Pavletic Steven , Aplan Peter D.
Published: February 2024

Myelodysplastic Neoplasms (MDS) are a group of clonal disorders characterized by ineffective hematopoiesis and morphologic dysplasia. Clinical manifestations of MDS vary widely and are dictated in large part by a range of genetic aberrations. The lack of robust in vitro models for MDS has limited the ability to conduct high throughput drug screens, which in turn has hampered the development of novel therapies for MDS. There are very few well-characterized MDS cell lines, and the available cell lines expand poorly in vitro. Conventional xenograft mouse models can provide an in vivo vessel to provide growth of cancer cells, but human MDS cells engraft poorly. Three-dimensional (3D) scaffold models that form human “ossicles” represent a promising new approach and can reproduce the intricate communication between hematopoietic stem and progenitor cells and their environment. Genetically engineered mice utilize specific mutations and may not represent the entire array of human MDS; however, genetically engineered mice provided in vivo proof of principle for novel agents such as luspatercept, demonstrating the clinical utility of this approach. This review offers an overview of available preclinical MDS models and potential approaches to accelerate accurate clinical translation.
Combining thermal scanning probe lithography and dry etching for grayscale nanopattern amplification
Authors: Erbas Berke , Conde-Rubio Ana , Liu Xia , Pernollet Joffrey , Wang Zhenyu , Bertsch Arnaud , Penedo Marcos , Fantner Georg , Banerjee Mitali , Kis Andras , Boero Giovanni , Brugger Juergen
Published: February 2024

Grayscale structured surfaces with nanometer-scale features are used in a growing number of applications in optics and fluidics. Thermal scanning probe lithography achieves a lateral resolution below 10 nm and a vertical resolution below 1 nm, but its maximum depth in polymers is limited. Here, we present an innovative combination of nanowriting in thermal resist and plasma dry etching with substrate cooling, which achieves up to 10-fold amplification of polymer nanopatterns into SiO2 without proportionally increasing surface roughness. Sinusoidal nanopatterns in SiO2 with 400 nm pitch and 150 nm depth are fabricated free of shape distortion after dry etching. To exemplify the possible applications of the proposed method, grayscale dielectric nanostructures are used for scalable manufacturing through nanoimprint lithography and for strain nanoengineering of 2D materials. Such a method for aspect ratio amplification and smooth grayscale nanopatterning has the potential to find application in the fabrication of photonic and nanoelectronic devices.
The prognostic role of diet quality in patients with MAFLD and physical activity: data from NHANES
Authors: Huang Jiaofeng , Wu Yinlian , Zheng Jiaping , Wang Mingfang , Goh George Boon-Bee , Lin Su
Published: February 2024

Background and objectives

Dietary control and increased physical activity (PA) are recommended for patients with metabolic (dysfunction-) associated fatty liver disease (MAFLD). However, not all patients can sustain both exercise and a healthy diet. This study explored the interaction between dietary quality, PA levels, and mortality in MAFLD patients.

Methods

The Third National Health and Nutrition Examination Survey and linked mortality data were used in this study. Diet quality was assessed with the Healthy Eating Index (HEI). PA level was calculated by multiply self-reported exercise frequency and its Metabolic Equivalent A high-quality diet was associated. A Cox proportional hazard model was used to explore risk factors for mortality in MAFLD patients.

Results

In total, 3709 participants with MAFLD were included in the final analysis. The median follow-up time was 26.2 (interquartile range 19.3–28.1) years and 1549 (41.8%) deaths were recorded over follow-up. Cox multivariate regression was used to adjust for potential confounders of mortality. The results showed both HEI score and PA level were inversely correlated with all-cause mortality (P < 0.05). In the subgroup analysis stratified by PA level, higher diet quality decreased all-cause mortality, cardiovascular-related mortality and cancer-related mortality in PA inactive of MAFLD patients (P < 0.05), but these correlations were not present in active PA groups.

Conclusion

Healthy diet and physical activity may have different impact as lifestyle interventions for MAFLD. A high-quality diet is associated less mortality in inactive individuals with MAFLD but not in those with active PA levels. Sedentary individuals require healthier diet.
miR-147b mediated suppression of DUSP8 promotes lung cancer progression
Authors: Turkowski Kati , Herzberg Frederik , Günther Stefan , Weigert Andreas , Haselbauer Tamara , Fink Ludger , Brunn David , Grimminger Friedrich , Seeger Werner , Sültmann Holger , Stiewe Thorsten , Pullamsetti Soni S. , Savai Rajkumar
Published: February 2024

Dual-specificity phosphatase 8 (DUSP8) plays an important role as a selective c-Jun N-terminal kinase (JNK) phosphatase in mitogen-activated protein kinase (MAPK) signaling. In this study, we found that DUSP8 is silenced by miR-147b in patients with lung adenocarcinoma (LUAD), which correlates with poor overall survival. Overexpression of DUSP8 resulted in a tumor-suppressive phenotype in vitro and in vivo experimental models, whereas silencing DUSP8 with a siRNA approach abrogated the tumor-suppressive properties. We found that miR-147b is a posttranscriptional regulator of DUSP8 that is highly expressed in patients with LUAD and is associated with lower survival. NanoString analysis revealed that the MAPK signaling pathway is mainly affected by overexpression of miR-147b, leading to increased proliferation and migration and decreased apoptosis in vitro. Moreover, induction of miR-147b promotes tumor progression in vitro and in vivo experimental models. Knockdown of miR-147b restored DUSP8, decreased tumor progression in vitro, and increased apoptosis via JNK phosphorylation. These results suggest that miR-147b plays a key role in regulating MAPK signaling in LUAD. The link between DUSP8 and miR-147b may provide novel approaches for the treatment of lung cancer.
Coexpression network analysis of the adult brain sheds light on the pathogenic mechanism of DDR1 in schizophrenia and bipolar disorder
Authors: Aranda Selena , Muntané Gerard , Vilella Elisabet
Published: February 2024

DDR1 has been linked to schizophrenia (SCZ) and bipolar disorder (BD) in association studies. DDR1 encodes 58 distinct transcripts, which can be translated into five isoforms (DDR1a-e) and are expressed in the brain. However, the transcripts expressed in each brain cell type, their functions and their involvement in SCZ and BD remain unknown. Here, to infer the processes in which DDR1 transcripts are involved, we used transcriptomic data from the human brain dorsolateral prefrontal cortex of healthy controls (N = 936) and performed weighted gene coexpression network analysis followed by enrichment analyses. Then, to explore the involvement of DDR1 transcripts in SCZ (N = 563) and BD (N = 222), we studied the association of coexpression modules with disease and performed differential expression and transcript significance analyses. Some DDR1 transcripts were distributed across five coexpression modules identified in healthy controls (MHC). MHC1 and MHC2 were enriched in the cell cycle and proliferation of astrocytes and OPCs; MHC3 and MHC4 were enriched in oligodendrocyte differentiation and myelination; and MHC5 was enriched in neurons and synaptic transmission. Most of the DDR1 transcripts associated with SCZ and BD pertained to MHC1 and MHC2. Altogether, our results suggest that DDR1 expression might be altered in SCZ and BD via the proliferation of astrocytes and OPCs, suggesting that these processes are relevant in psychiatric disorders.
Task-state skin potential abnormalities can distinguish major depressive disorder and bipolar depression from healthy controls
Authors: Lyu Hailong , Huang Huimin , He Jiadong , Zhu Sheng , Hong Wanchu , Lai Jianbo , Gao Tongsheng , Shao Jiamin , Zhu Jianfeng , Li Yubo , Hu Shaohua
Published: February 2024

Early detection of bipolar depression (BPD) and major depressive disorder (MDD) has been challenging due to the lack of reliable and easily measurable biological markers. This study aimed to investigate the accuracy of discriminating patients with mood disorders from healthy controls based on task state skin potential characteristics and their correlation with individual indicators of oxidative stress. A total of 77 patients with BPD, 53 patients with MDD, and 79 healthy controls were recruited. A custom-made device, previously shown to be sufficiently accurate, was used to collect skin potential data during six emotion-inducing tasks involving video, pictorial, or textual stimuli. Blood indicators reflecting individual levels of oxidative stress were collected. A discriminant model based on the support vector machine (SVM) algorithm was constructed for discriminant analysis. MDD and BPD patients were found to have abnormal skin potential characteristics on most tasks. The accuracy of the SVM model built with SP features to discriminate MDD patients from healthy controls was 78% (sensitivity 78%, specificity 82%). The SVM model gave an accuracy of 59% (sensitivity 59%, specificity 79%) in classifying BPD patients, MDD patients, and healthy controls into three groups. Significant correlations were also found between oxidative stress indicators in the blood of patients and certain SP features. Patients with depression and bipolar depression have abnormalities in task-state skin potential that partially reflect the pathological mechanism of the illness, and the abnormalities are potential biological markers of affective disorders.
Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects
Authors: DelaCuesta-Barrutia Jon , Martínez-Peula Oihane , Rivero Guadalupe , Santas-Martín Jon A. , Munarriz-Cuezva Eva , Brocos-Mosquera Iria , Miranda-Azpiazu Patricia , Diez-Alarcia Rebeca , Morentin Benito , Honer William G. , Callado Luis F. , Erdozain Amaia M. , Ramos-Miguel Alfredo
Published: February 2024

Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu2R and mGlu3R) in brains of schizophrenia patients may explain the limited efficacy of mGlu2/3R ligands in clinical trials. Studies evaluating mGlu2/3R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu2R and mGlu3R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu2R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu3R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D2 and serotonin 5HT2A receptors correlated with higher density of mGlu3R, but not mGlu2R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu2R, but not mGlu3R regulation observed in schizophrenia brains. mGlu2R and mGlu3R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu2R and mGlu3R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu3R, but not mGlu2R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu3R expression are activated to counterbalance mGluR loss of function is described.
Tumor Treating Fields (TTFields) combined with the drug repurposing approach CUSP9v3 induce metabolic reprogramming and synergistic anti-glioblastoma activity in vitro
Authors: Cao Qiyu , Hajosch Annika , Kast Richard Eric , Loehmann Christopher , Hlavac Michal , Fischer-Posovszky Pamela , Strobel Hannah , Westhoff Mike-Andrew , Siegelin Markus D. , Wirtz Christian Rainer , Halatsch Marc-Eric , Karpel-Massler Georg
Published: February 2024

Background

Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric fields that are continuously delivered to the brain through non-invasive arrays. On a different note, CUSP9v3 represents a drug repurposing strategy that includes 9 repurposed drugs plus metronomic temozolomide. Here, we examined whether TTFields enhance the antineoplastic activity of CUSP9v3 against this disease.

Methods

We performed preclinical testing of a multimodal approach of TTFields and CUSP9v3 in different glioblastoma models.

Results

TTFields had predominantly synergistic inhibitory effects on the cell viability of glioblastoma cells and non-directed movement was significantly impaired when combined with CUSP9v3. TTFields plus CUSP9v3 significantly enhanced apoptosis, which was associated with a decreased mitochondrial outer membrane potential (MOMP), enhanced cleavage of effector caspase 3 and reduced expression of Bcl-2 and Mcl-1. Moreover, oxidative phosphorylation and expression of respiratory chain complexes I, III and IV was markedly reduced.

Conclusion

TTFields strongly enhance the CUSP9v3-mediated anti-glioblastoma activity. TTFields are currently widely used for the treatment of glioblastoma patients and CUSP9v3 was shown to have a favorable safety profile in a phase Ib/IIa trial (NCT02770378) which facilitates transition of this multimodal approach to the clinical setting.
Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer
Authors: Eberlein Cath , Williamson Stuart C. , Hopcroft Lorna , Ros Susana , Moss Jennifer I. , Kerr James , van Weerden Wytske M. , de Bruin Elza C. , Dunn Shanade , Willis Brandon , Ross Sarah J. , Rooney Claire , Barry Simon T.
Published: February 2024

Background/objective

To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null and WT prostate tumours.

Methods

Mechanisms associated with docetaxel capivasertib treatment activity in prostate cancer were examined using a panel of in vivo tumour models and cell lines.

Results

Combining docetaxel and capivasertib had increased activity in PTEN null and WT prostate tumour models in vivo. In vitro short-term docetaxel treatment caused cell cycle arrest in the majority of cells. However, a sub-population of docetaxel-persister cells did not undergo G2/M arrest but upregulated phosphorylation of PI3K/AKT pathway effectors GSK3β, p70S6K, 4E-BP1, but to a lesser extent AKT. In vivo acute docetaxel treatment induced p70S6K and 4E-BP1 phosphorylation. Treating PTEN null and WT docetaxel-persister cells with capivasertib reduced PI3K/AKT pathway activation and cell cycle progression. In vitro and in vivo it reduced proliferation and increased apoptosis or DNA damage though effects were more marked in PTEN null cells. Docetaxel-persister cells were partly reliant on GSK3β as a GSK3β inhibitor AZD2858 reversed capivasertib-induced apoptosis and DNA damage.

Conclusion

Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3β.
Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy
Authors: Saunders Tahnee L. , Windley Simon P. , Gervinskas Gediminas , Balka Katherine R. , Rowe Caitlin , Lane Rachael , Tailler Maximilien , Nguyen Thanh Ngoc , Ramm Georg , Lazarou Michael , De Nardo Dominic , Kile Benjamin T. , McArthur Kate
Published: February 2024

During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.
Structural control of corneal transparency, refractive power and dynamics
Authors: Meek Keith M. , Knupp Carlo , Lewis Philip N. , Morgan Siân R. , Hayes Sally
Published: February 2024

The cornea needs to be transparent to visible light and precisely curved to provide the correct refractive power. Both properties are governed by its structure. Corneal transparency arises from constructive interference of visible light due to the relatively ordered arrangement of collagen fibrils in the corneal stroma. The arrangement is controlled by the negatively charged proteoglycans surrounding the fibrils. Small changes in fibril organisation can be tolerated but larger changes cause light scattering. Corneal keratocytes do not scatter light because their refractive index matches that of the surrounding matrix. When activated, however, they become fibroblasts that have a lower refractive index. Modelling shows that this change in refractive index significantly increases light scatter. At the microscopic level, the corneal stroma has a lamellar structure, the parallel collagen fibrils within each lamella making a large angle with those of adjacent lamellae. X-ray scattering has shown that the lamellae have preferred orientations in the human cornea: inferior-superior and nasal-temporal in the central cornea and circumferential at the limbus. The directions at the centre of the cornea may help withstand the pull of the extraocular muscles whereas the pseudo-circular arrangement at the limbus supports the change in curvature between the cornea and sclera. Elastic fibres are also present; in the limbus they contain fibrillin microfibrils surrounding an elastin core, whereas at the centre of the cornea, they exist as thin bundles of fibrillin-rich microfibrils. We present a model based on the structure described above that may explain how the cornea withstands repeated pressure changes due to the ocular pulse.
Immune signature of Chlamydia vaccine CTH522/CAF®01 translates from mouse-to-human and induces durable protection in mice
Authors: Olsen Anja W. , Rosenkrands Ida , Jacobsen Christina S. , Cheeseman Hannah M. , Kristiansen Max P. , Dietrich Jes , Shattock Robin J. , Follmann Frank
Published: February 2024

The clinical development of an effective Chlamydia vaccine requires in-depth understanding of how well protective pre-clinical immune signatures translate to humans. Here, we report a comparative immunological characterization of CTH522/CAF®01 in female mice and humans. We find a range of immune signatures that translate from mouse to human, including a Th1/Th17 cytokine profile and antibody functionality. We identify vaccine-induced T cell epitopes, conserved among Chlamydia serovars, and previously found in infected individuals. Using the mouse model, we show that the common immune signature protected against ascending infection in mice, and vaccine induced antibodies could delay bacterial ascension to the oviduct, as well as development of pathology, in a T cell depleted mouse model. Finally, we demonstrate long-lasting immunity and protection of mice one year after vaccination. Based on the results obtained in the present study, we propose to further investigate CTH522/CAF®01 in a phase IIb study.
Efficient direct repairing of lithium- and manganese-rich cathodes by concentrated solar radiation
Authors: Wang Hailong , Geng Xin , Hu Linyu , Wang Jun , Xu Yunkai , Zhu Yudong , Liu Zhimeng , Lu Jun , Lin Yuanjing , He Xin
Published: February 2024

Lithium- and manganese-rich layered oxide cathode materials have attracted extensive interest because of their high energy density. However, the rapid capacity fading and serve voltage decay over cycling make the waste management and recycling of key components indispensable. Herein, we report a facile concentrated solar radiation strategy for the direct recycling of Lithium- and manganese-rich cathodes, which enables the recovery of capacity and effectively improves its electrochemical stability. The phase change from layered to spinel on the particle surface and metastable state structure of cycled material provides the precondition for photocatalytic reaction and thermal reconstruction during concentrated solar radiation processing. The inducement of partial inverse spinel phase is identified after concentrated solar radiation treatment, which strongly enhances the redox activity of transition metal cations and oxygen anion, and reversibility of lattice structure. This study sheds new light on the reparation of spent cathode materials and designing high-performance compositions to mitigate structural degradation.
Dipterocarpoidae genomics reveal their demography and adaptations to Asian rainforests
Authors: Wang Rong , Liu Chao-Nan , Segar Simon T. , Jiang Yu-Ting , Zhang Kai-Jian , Jiang Kai , Wang Gang , Cai Jing , Chen Lu-Fan , Chen Shan , Cheng Jing , Compton Stephen G. , Deng Jun-Yin , Ding Yuan-Yuan , Du Fang K. , Hu Xiao-Di , Hu Xing-Hua , Kang Ling , Li Dong-Hai , Lu Ling , Li Yuan-Yuan , Tang Liang , Tong Xin , Wang Zheng-Shi , Xu Wei-Wei , Yang Yang , Zang Run-Guo , Zu Zhuo-Xin , Zhang Yuan-Ye , Chen Xiao-Yong
Published: February 2024

Dipterocarpoideae species form the emergent layer of Asian rainforests. They are the indicator species for Asian rainforest distribution, but they are severely threatened. Here, to understand their adaptation and population decline, we assemble high-quality genomes of seven Dipterocarpoideae species including two autotetraploid species. We estimate the divergence time between Dipterocarpoideae and Malvaceae and within Dipterocarpoideae to be 108.2 (97.8‒118.2) and 88.4 (77.7‒102.9) million years ago, and we identify a whole genome duplication event preceding dipterocarp lineage diversification. We find several genes that showed a signature of selection, likely associated with the adaptation to Asian rainforests. By resequencing of two endangered species, we detect an expansion of effective population size after the last glacial period and a recent sharp decline coinciding with the history of local human activities. Our findings contribute to understanding the diversification and adaptation of dipterocarps and highlight anthropogenic disturbances as a major factor in their endangered status.
Dynamic root microbiome sustains soybean productivity under unbalanced fertilization
Authors: Wang Mingxing , Ge An-Hui , Ma Xingzhu , Wang Xiaolin , Xie Qiujin , Wang Like , Song Xianwei , Jiang Mengchen , Yang Weibing , Murray Jeremy D. , Wang Yayu , Liu Huan , Cao Xiaofeng , Wang Ertao
Published: February 2024

Root-associated microbiomes contribute to plant growth and health, and are dynamically affected by plant development and changes in the soil environment. However, how different fertilizer regimes affect quantitative changes in microbial assembly to effect plant growth remains obscure. Here, we explore the temporal dynamics of the root-associated bacteria of soybean using quantitative microbiome profiling (QMP) to examine its response to unbalanced fertilizer treatments (i.e., lacking either N, P or K) and its role in sustaining plant growth after four decades of unbalanced fertilization. We show that the root-associated bacteria exhibit strong succession during plant development, and bacterial loads largely increase at later stages, particularly for Bacteroidetes. Unbalanced fertilization has a significant effect on the assembly of the soybean rhizosphere bacteria, and in the absence of N fertilizer the bacterial community diverges from that of fertilized plants, while lacking P fertilizer impedes the total load and turnover of rhizosphere bacteria. Importantly, a SynCom derived from the low-nitrogen-enriched cluster is capable of stimulating plant growth, corresponding with the stabilized soybean productivity in the absence of N fertilizer. These findings provide new insights in the quantitative dynamics of the root-associated microbiome and highlight a key ecological cluster with prospects for sustainable agricultural management.
Protective effects of Pt-N-C single-atom nanozymes against myocardial ischemia-reperfusion injury
Authors: Ye Tianbao , Chen Cheng , Wang Di , Huang Chengjie , Yan Zhiwen , Chen Yu , Jin Xian , Wang Xiuyuan , Ding Xianting , Shen Chengxing
Published: February 2024

Effective therapeutic strategies for myocardial ischemia/reperfusion (I/R) injury remain elusive. Targeting reactive oxygen species (ROS) provides a practical approach to mitigate myocardial damage following reperfusion. In this study, we synthesize an antioxidant nanozyme, equipped with a single-Platinum (Pt)-atom (PtsaN-C), for protecting against I/R injury. PtsaN-C exhibits multiple enzyme-mimicking activities for ROS scavenging with high efficiency and stability. Mechanistic studies demonstrate that the excellent ROS-elimination performance of the single Pt atom center precedes that of the Pt cluster center, owing to its better synergistic effect and metallic electronic property. Systematic in vitro and in vivo studies confirm that PtsaN-C efficiently counteracts ROS, restores cellular homeostasis and prevents apoptotic progression after I/R injury. PtsaN-C also demonstrates good biocompatibility, making it a promising candidate for clinical applications. Our study expands the scope of single-atom nanozyme in combating ROS-induced damage and offers a promising therapeutic avenue for the treatment of I/R injury.
In situ modulating coordination fields of single-atom cobalt catalyst for enhanced oxygen reduction reaction
Authors: Liu Meihuan , Zhang Jing , Su Hui , Jiang Yaling , Zhou Wanlin , Yang Chenyu , Bo Shuowen , Pan Jun , Liu Qinghua
Published: February 2024

Single-atom catalysts, especially those with metal−N4 moieties, hold great promise for facilitating the oxygen reduction reaction. However, the symmetrical distribution of electrons within the metal−N4 moiety results in unsatisfactory adsorption strength of intermediates, thereby limiting their performance improvements. Herein, we present atomically coordination-regulated Co single-atom catalysts that comprise a symmetry-broken Cl−Co−N4 moiety, which serves to break the symmetrical electron distribution. In situ characterizations reveal the dynamic evolution of the symmetry-broken Cl−Co−N4 moiety into a coordination-reduced Cl−Co−N2 structure, effectively optimizing the 3d electron filling of Co sites toward a reduced d-band electron occupancy (d5.8 → d5.28) under reaction conditions for a fast four-electron oxygen reduction reaction process. As a result, the coordination-regulated Co single-atom catalysts deliver a large half-potential of 0.93 V and a mass activity of 5480 A gmetal−1. Importantly, a Zn-air battery using the coordination-regulated Co single-atom catalysts as the cathode also exhibits a large power density and excellent stability.
Strong interactions between solitons and background light in Brillouin-Kerr microcombs
Authors: Zhang Menghua , Ding Shulin , Li Xinxin , Pu Keren , Lei Shujian , Xiao Min , Jiang Xiaoshun
Published: February 2024

Dissipative Kerr-soliton combs are laser pulses regularly sustained by a localized solitary wave on top of a continuous-wave background inside a nonlinear resonator. Usually, the intrinsic interactions between the background light and solitons are weak and localized. Here, we demonstrate a strong interaction between the generated soliton comb and the background light in a Brillouin-Kerr microcomb system. This strong interaction enables the generation of a monostable single-soliton microcomb on a silicon chip. Also, new phenomena related to soliton physics including solitons hopping between different states as well as controlling the formations of the soliton states by the pump power, are observed owing to such strong interaction. Utilizing this monostable single-soliton microcomb, we achieve the 100% deterministic turnkey operation successfully without any feedback controls. Importantly, it allows to output turnkey ultra-low-noise microwave signals using a free-running pump.
Bacteria employ lysine acetylation of transcriptional regulators to adapt gene expression to cellular metabolism
Authors: Kremer Magdalena , Schulze Sabrina , Eisenbruch Nadja , Nagel Felix , Vogt Robert , Berndt Leona , Dörre Babett , Palm Gottfried J. , Hoppen Jens , Girbardt Britta , Albrecht Dirk , Sievers Susanne , Delcea Mihaela , Baumann Ulrich , Schnetz Karin , Lammers Michael
Published: February 2024

The Escherichia coli TetR-related transcriptional regulator RutR is involved in the coordination of pyrimidine and purine metabolism. Here we report that lysine acetylation modulates RutR function. Applying the genetic code expansion concept, we produced site-specifically lysine-acetylated RutR proteins. The crystal structure of lysine-acetylated RutR reveals how acetylation switches off RutR-DNA-binding. We apply the genetic code expansion concept in E. coli in vivo revealing the consequences of RutR acetylation on the transcriptional level. We propose a model in which RutR acetylation follows different kinetic profiles either reacting non-enzymatically with acetyl-phosphate or enzymatically catalysed by the lysine acetyltransferases PatZ/YfiQ and YiaC. The NAD+-dependent sirtuin deacetylase CobB reverses enzymatic and non-enzymatic acetylation of RutR playing a dual regulatory and detoxifying role. By detecting cellular acetyl-CoA, NAD+ and acetyl-phosphate, bacteria apply lysine acetylation of transcriptional regulators to sense the cellular metabolic state directly adjusting gene expression to changing environmental conditions.
Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation
Authors: van den Bosch Aletta M. R. , van der Poel Marlijn , Fransen Nina L. , Vincenten Maria C. J. , Bobeldijk Anneleen M. , Jongejan Aldo , Engelenburg Hendrik J. , Moerland Perry D. , Smolders Joost , Huitinga Inge , Hamann Jörg
Published: February 2024

Microglia nodules (HLA-DR+ cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation.