bluuebunny/crossref_metadata_2025 huggingface dataset:
Forging of PM Ti–6Al–4V alloy at the temperature above β-transus and high strain rate: modeling and trials in industrial conditions
Authors: Wojtaszek Marek , Zyguła Krystian , Łukaszek-Sołek Aneta , Jabłońska Magdalena , Stanik Rafał , Gude Maik
Published: March 2023

The results of the forging process in open dies of the powder metallurgy (PM) Ti–6Al–4V alloy, carried out at the temperature above β-transus and at a high strain rate were presented. As an initial material for the research relatively cheap elemental powders were used. This approach gives a real chance for the implementation of the developed technologies. As the range of phase transition temperature in titanium alloys is influenced also by the technology of their production, the β-transus temperature was estimated for the PM Ti–6Al–4V alloy. Finite element method (FEM) numerical analysis of the forging process at the temperature of 1000 °C and high strain rate was performed. The results obtained by the FEM modeling were verified under industrial conditions. The forging trials were made at the temperature of 1000 °C on a screw press operating at a speed of 250 mm s−1. For comparison, the alloy was also studied in as-cast and hot-rolled conditions, which is widely used as a feedstock. The influence of the method of manufacturing feedstock on the microstructure and selected properties of the forgings was determined. This approach allowed for a qualitative assessment of the PM material. The forging process in open dies of two different feedstocks led to the production of forgings with a uniform and similar lamellar microstructure. Thus, it was shown that the heating conditions, the parameters of the forging process, and the method of cooling the product after forging have a decisive influence on the microstructure condition of the forgings shaped in the temperature range of the β phase.
Nazi Cinema as Enchantment
Authors: O'Brien Mary-Elizabeth
Published: March 2023

A study of thirteen Nazi-era films that explores how entertainment cinema served everyday fascism.
The Music of Luigi Dallapiccola
Authors: Fearn Raymond
Published: March 2023

The first English work dealing in detail with the life and musical influences of the Italian composer Luigi Dallapiccola (1904-1975).
Propaganda and Zionist Education
Authors: Bar-Gal Yoram
Published: March 2023

A history of the Jewish National Fund and the ways it encouraged Jews around the world to buy land in Palestine in the years 1924-1947.
Great Britain, Germany and the Soviet Union
Authors: Salzmann Stephanie C.
Published: March 2023

Germany and the Soviet Union concluded the treaty of Rapallo together within five years of their defeat in the First World War. The resulting fear of Soviet-German co-operation cast a long shadow over British foreign policy; this book traces its influence.
Medieval Allegory and the Building of the New Jerusalem
Authors: Meyer Ann R.
Published: March 2023

The concept of the New Jerusalem, the City of God, as realised in architecture and literature, especially Pearl.
Mental Health Care in Modern England
Authors: Cherry Steven
Published: March 2023

This history of one particular place for 'madness' covers changing approaches to insanity and treatments over two centuries.
Rural Conflict, Crime and Protest
Authors: Shakesheff Timothy
Published: March 2023

Evidence from the west of England balances that already available from the eastern regions of England.
Alabaster Images of Medieval England
Authors: Cheetham Francis
Published: March 2023

The fullest catalogue available on English medieval alabasters - 2,400 entries, with historical and art historical contextual material.
Influence of Solar Wind Dynamic Pressure on Distribution of Whistler Mode Waves Based on Van Allen Probe Observations
Authors: Tang Rongxin , Yuan An , Li Haimeng , Ouyang Zhihai , Deng Xiaohua
Published: March 2023

In this study, the effect of solar wind dynamic pressure (PSW) on the global distribution of whistler mode waves (including chorus and hiss waves) while the absence of substorm activity is investigated using the data originating from the Van Allen Probes for nearly 5 years. After the effect of substorm activity is excluded, our statistical results indicate that the hiss and chorus waves exhibit different characteristics with the increase of PSW. The amplitudes of chorus waves increase on the dayside with the PSW strengthen, which can be explained through the local enhanced electron temperature anisotropy and more intense emission for the chorus in the inner magnetosphere. Interestingly, the amplitudes of hiss wave are reduced with the increase of PSW. The weakness of hiss waves can be attributed to electrons at high L‐shells which drift out of the magnetosphere on the dayside when the magnetopause's position decreases. It can significantly result in a reduced chorus inside the magnetopause that will evolve into hiss waves. In addition, the upper and lower cutoff frequencies of hiss waves will increase. This new finding is critical for understanding the generation and evolution of whistler mode waves and its responses to the intensity of PSW.
Evidence of Vertical Slab Tearing in the Late Triassic Qinling Orogen (Central China) From Multiproxy Geochemical and Isotopic Imaging
Authors: Qiu Kun‐Feng , Deng Jun , He Deng‐Yang , Rosenbaum Gideon , Zheng Xi , Williams‐Jones Anthony E. , Yu Hao‐Cheng , Balen Dražen
Published: March 2023

The process of slab tearing profoundly affects interchanges of material and energy between the lithosphere and asthenosphere and has been invoked as a trigger of magmatism in modern and ancient subduction‐collision systems. Horizontal slab tears may occur after continental collision and subsequent slab break‐off, whereas vertical slab tears may occur in response to along‐strike variations in rollback velocity, thereby ripping the subducting lithosphere. Previous studies have documented tearing of subducting slabs in modern convergent settings using geophysical methods, but in ancient collisional belts, where these methods cannot be applied, detection of slab tearing is more difficult, particularly if the oceanic plate was fully subducted and the geological evidence for subduction is limited. Here, we employ multiproxy element‐isotope imaging, as well as zircon petrochronology and whole‐rock geochemistry, to assess evidence of vertical tearing of the Mianlue slab in the Triassic Qinling Orogen in central China. Our results show evidence of anomalous, inferred tear‐related magmatism east of 107°E, at 225–210 Ma. Vertical tearing of the northward subducting Mianlue slab is recorded by geochemically anomalous igneous rocks, and the recognition of N–S to NE–SW trending boundaries defined by Sr‐Nd‐Hf isotopes, elemental ratios (Nb/Ta, and Ca/Al), Mg#, and reduced crustal thickness between 107° and 108°E. The inferred vertical tear may have been driven by slab rollback of the Mianlue slab at 225–210 Ma. The results show that multiproxy element‐isotope imaging (e.g., of εNd(t), εHf(t), (87Sr/86Sr)i, Nb/Ta, Mg#, and Ca/Al) can be used to reconstruct the evolution of fossil subduction systems.
Declining O2 in the Canada Basin Halocline Consistent With Physical and Biogeochemical Effects of Pacific Summer Water Warming
Authors: Arroyo Ashley , Timmermans Mary‐Louise , Le Bras Isabela , Williams William , Zimmermann Sarah
Published: March 2023

The Arctic Ocean's Canada Basin (CB) has seen significant changes in ocean properties in the past two decades. A prominent change has been a warming of the Pacific Summer Water (PSW) layer in the central CB. The corresponding change in dissolved oxygen (O2) is analyzed here to provide additional insight into PSW physics and biology, pathways, and evolution. O2 observations are analyzed between 2003 and 2021 from the Joint Ocean Ice Study/Beaufort Gyre Observing System (JOIS/BGOS) field program, which samples CB hydrographic and biogeochemical properties. In the central CB, warming of the PSW layer over 2003–2021 has been accompanied by O2 decreases over this time in the layer. Nutrients and other biogeochemical properties are analyzed to quantify the combined influences of both physical changes and biological changes on the evolution of O2 concentrations in the CB PSW. In the upper portion of the PSW, O2 decreases can be entirely accounted for by surface warming (and corresponding decrease in O2 solubility) of its source waters in the Chukchi Sea region. In the deeper portion of the PSW layer, the observed O2 changes are larger, and are accounted for by a combination of the decreased solubility effect due to warming, and increased organic matter breakdown in warmer waters. Decreasing O2 in a warming Arctic Ocean is consonant with O2 trends in the warming global oceans, and highlights the need for continued observations and analyses.
The Benefits of Using State‐Of‐The‐Art Digital Soil Properties Maps to Improve the Modeling of Soil Moisture in Land Surface Models
Authors: Xu Chengcheng , Torres‐Rojas Laura , Vergopolan Noemi , Chaney Nathaniel W.
Published: March 2023

This study assesses the added value of using emerging maps of soil properties to improve surface soil moisture simulations using the HydroBlocks land surface model with different soil hydraulic parameterization schemes. Simulations were run at an hourly 30‐m resolution between 2012 and 2019 and evaluated against U.S. Climate Reference Network measurements. The results show that state‐of‐the‐art soil properties maps (POLARIS and SoilGrids250m V2.0) improve the accuracy of simulated surface soil moisture when compared to the STATSGO‐derived CONUS‐SOIL map. Contemporary pedotransfer functions (multi‐linear regression and Artificial Neural Networks‐based) also improve model performance in comparison to the lookup table‐derived soil parameterization schemes. The addition of vertical heterogeneity to the soil properties further improves the mean Kling‐Gupta efficiency by 0.04 and lowers the mean Root mean square error by 0.003 over the CONUS. This study demonstrates that land surface modeling can be improved by using state‐of‐the‐art maps of soil properties, accounting for the vertical heterogeneity of soils, and advancing the use of contemporary pedotransfer functions.
LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway
Authors: Lu Jun , Fu Liang-min , Cao Yun , Fang Yong , Cao Jia-zheng , Pan Yi-hui , Cen Jun-jie , Liang Yan-ping , Chen Zhen-hua , Wei Jin-huan , Huang Yong , Mumin Mukhtar Adan , Xu Quan-hui , Wang Ying-han , Zhu Jiang-quan , Liang Hui , Wang Zhu , Deng Qiong , Chen Wei , Jin Xiao-han , Liu Zhi-ping , Luo Jun-hang
Published: March 2023

LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients’ tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.
Medication adherence and cognitive performance in schizophrenia-spectrum and bipolar disorder: results from the PsyCourse Study
Authors: Senner Fanny , Hiendl Lena , Bengesser Susanne , Adorjan Kristina , Anghelescu Ion-George , Baune Bernhardt T. , Budde Monika , Dannlowski Udo , Dietrich Detlef E. , Falkai Peter , Fallgatter Andreas J. , Hasan Alkomiet , Heilbronner Maria , Jäger Markus , Juckel Georg , Kalman Janos L. , Konrad Carsten , Kohshour Mojtaba Oraki , Papiol Sergi , Reich-Erkelenz Daniela , Reimer Jens , Schaupp Sabrina K. , Schmauß Max , Senner Simon , Spitzer Carsten , Vogl Thomas , Zimmermann Jörg , Heilbronner Urs , Schulte Eva C. , Schulze Thomas G. , Reininghaus Eva Z. , Kirchner Sophie-Kathrin , Dalkner Nina
Published: March 2023

Existing guidelines recommend psychopharmacological treatment for the management of schizophrenia and bipolar disorder as part of holistic treatment concepts. About half of the patients do not take their medication regularly, although treatment adherence can prevent exacerbations and re-hospitalizations. To date, the relationship between medication adherence and cognitive performance is understudied. Therefore, this study investigated the relationship between medication adherence and cognitive performance by analyzing the data of 862 participants with schizophrenia-spectrum and bipolar disorders (mean [SD] age, 41.9 [12.48] years; 44.8% female) from a multicenter study (PsyCourse Study). Z-scores for three cognitive domains were calculated, global functioning was measured with the Global Assessment of Functioning Scale, and adherence was assessed by a self-rating questionnaire. We evaluated four multiple linear regression models and built three clusters with hierarchical cluster analyses. Higher adherence behavior (p < 0.001) was associated with better global functioning but showed no impact on the cognitive domains learning and memory, executive function, and psychomotor speed. The hierarchical cluster analysis resulted in three clusters with different cognitive performances, but patients in all clusters showed similar adherence behavior. The study identified cognitive subgroups independent of diagnoses, but no differences were found in the adherence behavior of the patients in these new clusters. In summary, medication adherence was associated with global but not cognitive functioning in patients with schizophrenia-spectrum and bipolar disorders. In both diagnostic groups, cognitive function might be influenced by various factors but not medication adherence.
Pathological regression of primary tumour and metastatic lymph nodes following chemotherapy in resectable OG cancer: pooled analysis of two trials
Authors: Athauda Avani , Nankivell Matthew , Langer Rupert , Pritchard Susan , Langley Ruth E. , von Loga Katharina , Starling Naureen , Chau Ian , Cunningham David , Grabsch Heike I.
Published: March 2023

Background

No definitive largescale data exist evaluating the role of pathologically defined regression changes within the primary tumour and lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma following neoadjuvant chemotherapy and the impact on survival.

Methods

Data and samples from two large prospective randomised trials (UK MRC OE05 and ST03) were pooled. Stained slides were available for central pathology review from 1619 patients. Mandard tumour regression grade (TRG) and regression of tumour within LNs (LNR: scored as present/absent) were assessed and correlated with overall survival (OS) using a Cox regression model. An exploratory analysis to define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis.

Results

Neither trial demonstrated a relationship between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG, lower ypN stage, lower ypT stage, presence of LNR, presence of well/moderate tumour differentiation, and absence of tumour at resection margin were all associated with better OS. However, the multivariable analysis demonstrated that only ypN, ypT, grade of differentiation and resection margin (R0) were independent indicators of prognosis. Exploratory CART analysis identified six subgroups with 3-year OS ranging from 83% to 22%; with ypN stage being the most important single prognostic variable.

Conclusions

Pathological LN stage within the resection specimen was the single most important determiner of survival. Our results suggest that the assessment of regression changes within the primary tumour or LNs may not be necessary to define the prognosis further.
SIM2s directed Parkin-mediated mitophagy promotes mammary epithelial cell differentiation
Authors: Sanchez Lilia , Epps Jessica , Wall Steven , McQueen Cole , Pearson Scott J. , Scribner Kelly , Wellberg Elizabeth A. , Giles Erin D. , Rijnkels Monique , Porter Weston W.
Published: March 2023

The functionally differentiated mammary gland adapts to extreme levels of stress from increased demand for energy by activating specific protective mechanisms to support neonatal health. Here, we identify the breast tumor suppressor gene, single-minded 2 s (SIM2s) as a novel regulator of mitophagy, a key component of this stress response. Using tissue-specific mouse models, we found that loss ofSim2reduced lactation performance, whereas gain (overexpression) ofSim2senhanced and extended lactation performance and survival of mammary epithelial cells (MECs). Using an in vitro model of MEC differentiation, we observed SIM2s is required for Parkin-mediated mitophagy, which we have previously shown as necessary for functional differentiation. Mechanistically, SIM2s localizes to mitochondria to directly mediate Parkin mitochondrial loading. Together, our data suggest that SIM2s regulates the rapid recycling of mitochondria via mitophagy, enhancing the function and survival of differentiated MECs.
Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma
Authors: Cai Jiayang , Ye Zhang , Hu Yuanyuan , Ye Liguo , Gao Lun , Wang Yixuan , sun Qian , Tong Shiao , Zhang Shenqi , Wu Liquan , Yang Ji’an , Chen Qianxue
Published: March 2023

Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.
Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation
Authors: Chirita Daria , Bronnec Pauline , Magnotti Flora , Dalmon Sarah , Martin Amandine , Popoff Michel , Gerfaud-Valentin Mathieu , Sève Pascal , Belot Alexandre , Contis Anne , Duquesne Agnes , Nocturne Gaetane , Lemelle Irene , Georgin-Lavialle Sophie , Boursier Guilaine , Touitou Isabelle , Jamilloux Yvan , Henry Thomas
Published: March 2023

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disorder. FMF is caused by mutations in the MEFV gene, encoding pyrin, an inflammasome sensor. The best characterized pathogenic mutations associated with FMF cluster in exon 10. Yet, mutations have been described along the whole MEFV coding sequence. Exon 10 encodes the B30.2 domain of the pyrin protein, but the function of this human-specific domain remains unclear. Pyrin is an inflammasome sensor detecting RhoA GTPase inhibition following exposure to bacterial toxins such as TcdA. Here, we demonstrate that the B30.2 domain is dispensable for pyrin inflammasome activation in response to this toxin. Deletion of the B30.2 domain mimics the most typical FMF-associated mutation and confers spontaneous inflammasome activation in response to pyrin dephosphorylation. Our results indicate that the B30.2 domain is a negative regulator of the pyrin inflammasome that acts independently from and downstream of pyrin dephosphorylation. In addition, we identify the central helical scaffold (CHS) domain of pyrin, which lies immediately upstream of the B30.2 domain as a second regulatory domain. Mutations affecting the CHS domain mimic pathogenic mutations in the B30.2 domain and render the pyrin inflammasome activation under the sole control of the dephosphorylation. In addition, specific mutations in the CHS domain strongly increase the cell susceptibility to steroid catabolites, recently described to activate pyrin, in both a cell line model and in monocytes from genotype-selected FMF patients. Taken together, our work reveals the existence of two distinct regulatory regions at the C-terminus of the pyrin protein, that act in a distinct manner to regulate positively or negatively inflammasome activation. Furthermore, our results indicate that different mutations in pyrin regulatory domains have different functional impacts on the pyrin inflammasome which could contribute to the diversity of pyrin-associated autoinflammatory diseases.
The effects of MYC on tumor immunity and immunotherapy
Authors: Li Jiajin , Dong Tingyu , Wu Zhen , Zhu Dacheng , Gu Hao
Published: March 2023

The oncogene MYC is dysregulated in a host of human cancers, and as an important point of convergence in multitudinous oncogenic signaling pathways, it plays a crucial role in tumor immune regulation in the tumor immune microenvironment (TIME). Specifically, MYC promotes the expression of immunosuppressive factors and inhibits the expression of immune activation regulators. Undoubtedly, a therapeutic strategy that targets MYC can initiate a new era of cancer treatment. In this review, we summarize the essential role of the MYC signaling pathway in tumor immunity and the development status of MYC-related therapies, including therapeutic strategies targeting MYC and combined MYC-based immunotherapy. These studies have reported extraordinary insights into the translational application of MYC in cancer treatment and are conducive to the emergence of more effective immunotherapies for cancer.
Arene C–H borylation strategy enabled by a non-classical boron cluster-based electrophile
Authors: Kim Sangmin , Treacy Joseph W. , Nelson Yessica A. , Gonzalez Jordan A. M. , Gembicky Milan , Houk K. N. , Spokoyny Alexander M.
Published: March 2023

Introducing a tri-coordinate boron-based functional group (e.g., boronic ester) into an unactivated C–H bond in the absence of directing groups is an ongoing challenge in synthetic chemistry. Despite previous developments in transition metal-catalyzed and -free approaches, C–H borylation of sterically hindered arenes remains a largely unsolved problem to date. Here, we report a synthetic strategy of a two-step, precious metal-free electrophilic C–H borylation of sterically hindered alkyl- and haloarenes to generate aryl boronic esters. The first step relies on electrophilic aromatic substitution (EAS) induced by cage-opening of Cs2[closo-B10H10], forming a 6-Ar-nido-B10H13product containing a B–C bond, followed by a cage deconstruction of arylated decaboranes promoted by diols. The combination of these two steps allows for the preparation of aryl boronic esters that are hardly accessible by current direct C–H borylation approaches. This reaction does not require any precious metals, highly-engineered ligands, pre-functionalized boron reagents, or inert conditions. In addition, the unique properties of a non-classical boron cluster electrophile intermediate, B10H13+, afford a regioselectivity with unique steric and electronic control without the undesirable side reactions.
Equilibrium shift, poisoning prevention, and selectivity enhancement in catalysis via dehydration of polymeric membranes
Authors: Hyeon Myeong-Hun , Park Hae-Gu , Lee Jongmyeong , Kong Chang-In , Kim Eun-Young , Kim Jong Hak , Moon Su-Young , Kim Seok Ki
Published: March 2023

Generation of water as a byproduct in chemical reactions is often detrimental because it lowers the yield of the target product. Although several water removal methods, using absorbents, inorganic membranes, and additional dehydration reactions, have been proposed, there is an increasing demand for a stable and simple system that can selectively remove water over a wide range of reaction temperatures. Herein we report a thermally rearranged polybenzoxazole hollow fiber membrane with good water permselectivity and stability at reaction temperatures of up to 400 °C. Common reaction engineering challenges, such as those due to equilibrium limits, catalyst deactivation, and water-based side reactions, have been addressed using this membrane in a reactor.
Determinants of functional synaptic connectivity among amygdala-projecting prefrontal cortical neurons in male mice
Authors: Printz Yoav , Patil Pritish , Mahn Mathias , Benjamin Asaf , Litvin Anna , Levy Rivka , Bringmann Max , Yizhar Ofer
Published: March 2023

The medial prefrontal cortex (mPFC) mediates a variety of complex cognitive functions via its vast and diverse connections with cortical and subcortical structures. Understanding the patterns of synaptic connectivity that comprise the mPFC local network is crucial for deciphering how this circuit processes information and relays it to downstream structures. To elucidate the synaptic organization of the mPFC, we developed a high-throughput optogenetic method for mapping large-scale functional synaptic connectivity in acute brain slices. We show that in male mice, mPFC neurons that project to the basolateral amygdala (BLA) display unique spatial patterns of local-circuit synaptic connectivity, which distinguish them from the general mPFC cell population. When considering synaptic connections between pairs of mPFC neurons, the intrinsic properties of the postsynaptic cell and the anatomical positions of both cells jointly account for ~7.5% of the variation in the probability of connection. Moreover, anatomical distance and laminar position explain most of this fraction in variation. Our findings reveal the factors determining connectivity in the mPFC and delineate the architecture of synaptic connections in the BLA-projecting subnetwork.
Bacterial outer membrane vesicle based versatile nanosystem boosts the efferocytosis blockade triggered tumor-specific immunity
Authors: Zhuang Wan-Ru , Wang Yunfeng , Nie Weidong , Lei Yao , Liang Chao , He Jiaqi , Zuo Liping , Huang Li-Li , Xie Hai-Yan
Published: March 2023

Efferocytosis inhibition is emerging as an attractive strategy for antitumor immune therapy because of the subsequent leak of abundant immunogenic contents. However, the practical efficacy is seriously impeded by the immunosuppressive tumor microenvironments. Here, we construct a versatile nanosystem that can not only inhibit the efferocytosis but also boost the following antitumor immunity. MerTK inhibitor UNC2025 is loaded into the bacterial outer membrane vesicles (OMVs), which are then modified with maleimide (mU@OMVs). The prepared mU@OMVs effectively inhibits the efferocytosis by promoting the uptake while preventing the MerTK phosphorylation of tumor associated macrophages, and then captures the released antigens through forming universal thioether bonds. The obtained in situ vaccine effectively transfers to lymph nodes by virtue of the intrinsic features of OMVs, and then provokes intense immune responses that can efficiently prevent the growth, metastasis and recurrence of tumors in mice, providing a generalizable strategy for cancer immunotherapy.
Multi-modal quantification of pathway activity with MAYA
Authors: Landais Yuna , Vallot Céline
Published: March 2023

Signaling pathways can be activated through various cascades of genes depending on cell identity and biological context. Single-cell atlases now provide the opportunity to inspect such complexity in health and disease. Yet, existing reference tools for pathway scoring resume activity of each pathway to one unique common metric across cell types. Here, we present MAYA, a computational method that enables the automatic detection and scoring of the diverse modes of activation of biological pathways across cell populations. MAYA improves the granularity of pathway analysis by detecting subgroups of genes within reference pathways, each characteristic of a cell population and how it activates a pathway. Using multiple single-cell datasets, we demonstrate the biological relevance of identified modes of activation, the robustness of MAYA to noisy pathway lists and batch effect. MAYA can also predict cell types starting from lists of reference markers in a cluster-free manner. Finally, we show that MAYA reveals common modes of pathway activation in tumor cells across patients, opening the perspective to discover shared therapeutic vulnerabilities.
Small data machine learning in materials science
Authors: Xu Pengcheng , Ji Xiaobo , Li Minjie , Lu Wencong
Published: March 2023

This review discussed the dilemma of small data faced by materials machine learning. First, we analyzed the limitations brought by small data. Then, the workflow of materials machine learning has been introduced. Next, the methods of dealing with small data were introduced, including data extraction from publications, materials database construction, high-throughput computations and experiments from the data source level; modeling algorithms for small data and imbalanced learning from the algorithm level; active learning and transfer learning from the machine learning strategy level. Finally, the future directions for small data machine learning in materials science were proposed.
High-performance non-Fermi-liquid metallic thermoelectric materials
Authors: Dong Zirui , Zhang Yubo , Luo Jun , Jiang Ying , Yu Zhiyang , Zhao Nan , Wu Liusuo , Ruan Yurong , Zhang Fang , Guo Kai , Zhang Jiye , Zhang Wenqing
Published: March 2023

Searching for high-performance thermoelectric (TE) materials in the paradigm of narrow-bandgap semiconductors is hampered by a bottleneck. Here we report on the discovery of metallic compounds, TiFexCu2x−1Sb and TiFe1.33Sb, showing the thermopower exceeding many TE semiconductors and the dimensionless figure of merits zTs comparable with the state-of-the-art TE materials. A quasi-linear temperature (T) dependent electrical resistivity in 2–700 K and the logarithmic T-dependent electronic specific heat at low temperature coexist with the high thermopower, highlighting the strong intercoupling of the non-Fermi-liquid (NFL) quantum critical behavior of electrons with TE transports. Electronic structure analysis reveals a competition between the antiferromagnetic (AFM) ordering and Kondo-like spin compensation as well as a parallel two-channel Kondo effect. The T-dependent magnetic susceptibility agrees with the quantum critical scenario of strong local correlation. Our work demonstrates the correlation among high TE performance, NFL quantum criticality, and magnetic fluctuation, which opens up directions for future research.
Toward the utilisation of resources in space: knowledge gaps, open questions, and priorities
Authors: Cilliers Jan , Hadler Kathryn , Rasera Joshua
Published: March 2023

There are many open science questions in space resource utilisation due to the novelty and relative immaturity of the field. While many potential technologies have been proposed to produce usable resources in space, high confidence, large-scale design is limited by gaps in the knowledge of the local environmental conditions, geology, mineralogy, and regolith characteristics, as well as specific science questions intrinsic to each process. Further, the engineering constraints (e.g. energy, throughput, efficiency etc.) must be incorporated into the design. This work aims to summarise briefly recent activities in the field of space resource utilisation, as well as to identify key knowledge gaps, and to present open science questions. Finally, future exploration priorities to enable the use of space resources are highlighted.
DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease
Authors: Masato Anna , Plotegher Nicoletta , Terrin Francesca , Sandre Michele , Faustini Gaia , Thor Andrea , Adams Stephen , Berti Giulia , Cogo Susanna , De Lazzari Federica , Fontana Camilla Maria , Martinez Paul Anthony , Strong Randy , Bandopadhyay Rina , Bisaglia Marco , Bellucci Arianna , Greggio Elisa , Dalla Valle Luisa , Boassa Daniela , Bubacco Luigi
Published: March 2023

Dopamine dyshomeostasis has been acknowledged among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn accumulation and hampers αSyn clearance in primary neurons. DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways in neurites. The progressive decline of neuronal homeostasis further leads to dopaminergic neuron loss and motor impairment, as showed in in vivo models. Finally, we developed a specific antibody which detected increased DOPAL-modified αSyn in human striatal tissues from idiopathic PD patients, corroborating the translational relevance of αSyn-DOPAL interplay in PD neurodegeneration.
Asthma medication adherence and exacerbations and lung function in children managed in Leicester primary care
Authors: Paracha Razi , Lo David K. H. , Montgomery Ursula , Ryan Louise , Varakantam Vivek , Gaillard Erol A.
Published: March 2023

Poor adherence to asthma preventer medication is associated with life-threatening asthma attacks. The quality and outcomes framework mandated primary care annual asthma review does not include adherence monitoring and the effect of poor adherence on lung function in paediatric primary care patients is unknown. The aim was to investigate the link between inhaled corticosteroid (ICS) adherence and spirometry, fraction of exhaled nitric oxide (FeNO) and asthma control in asthmatic school-age children in this cross-sectional observational study involving three Leicestershire general practices. Children 5–16 years on the practice’s asthma registers, were invited for a routine annual asthma review between August 2018 and August 2019. Prescription and clinical data were extracted from practice databases. Spirometry, bronchodilator reversibility (BDR) and FeNO testing were performed as part of the review. 130 of 205 eligible children (63.4%) attended their review. Mean adherence to ICS was 36.2% (SEM 2.1%) and only 14.6% of children had good adherence (≥75% prescriptions issued). We found no differences in asthma exacerbations in the preceding 12 months between the adherence quartiles. 28.6% of children in the lowest and 5.6% in the highest adherence quartile had BDR ≥ 12% but this was not statistically significant (p = 0.55). A single high FeNO value did not predict adherence to ICS. Adherence to ICS in children with asthma in primary care is poor. The link between adherence to ICS and asthma exacerbations, spirometry and FeNO is complex but knowledge of adherence to ICS is critical in the management of children with asthma.
Neurotrophin signaling is a central mechanism of salivary dysfunction after irradiation that disrupts myoepithelial cells
Authors: Chibly Alejandro M. , Patel Vaishali N. , Aure Marit H. , Pasquale Mary C. ,   NIDCD/NIDCR Genomics and Computational Biology Core, Morell Robert J. , Izquierdo Daniel Martin , Boger Erich , Martin Gemma E. , Ghannam Mousa , Andrade Julianne , Denegre Noah G. , Simpson Colleen , Goldstein David P. , Liu Fei-Fei , Lombaert Isabelle M. A. , Hoffman Matthew P.
Published: March 2023

The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk RNAseq of IR versus non-IR human salivary glands showed that neurotrophin signaling is highly disrupted post-radiation. Neurotrophin receptors (NTRs) were significantly upregulated in myoepithelial cells (MECs) post-IR, and single cell RNAseq revealed that MECs pericytes, and duct cells are the main sources of neurotrophin ligands. Using two ex vivo models, we show that nerve growth factor (NGF) induces expression of MEC genes during development, and upregulation of NTRs in adult MECs is associated with stress-induced plasticity and morphological abnormalities in IR human glands. As MECs are epithelial progenitors after gland damage and are required for proper acinar cell contraction and secretion, we propose that MEC-specific upregulation of NTRs post-IR disrupts MEC differentiation and potentially impedes the ability of the gland to regenerate.
Reference proteomes of five wheat species as starting point for future design of cultivars with lower allergenic potential
Authors: Afzal Muhammad , Sielaff Malte , Distler Ute , Schuppan Detlef , Tenzer Stefan , Longin C. Friedrich H.
Published: March 2023

Wheat is an important staple food and its processing quality is largely driven by proteins. However, there is a sizable number of people with inflammatory reactions to wheat proteins, namely celiac disease, wheat allergy and the syndrome of non-celiac wheat sensitivity. Thus, proteome profiles should be of high importance for stakeholders along the wheat supply chain. We applied liquid chromatography-tandem mass spectrometry-based proteomics to establish the flour reference proteome for five wheat species, ancient to modern, each based on 10 cultivars grown in three diverse environments. We identified at least 2540 proteins in each species and a cluster analyses clearly separated the species based on their proteome profiles. Even more, >50% of proteins significantly differed between species - many of them implicated in products’ quality, grain-starch synthesis, plant stress regulation and proven or potential allergic reactions in humans. Notably, the expression of several important wheat proteins was found to be mainly driven by genetics vs. environmental factors, which enables selection and refinement of improved cultivars for the wheat supply chain as long as rapid test methods will be developed. Especially einkorn expressed 5.4 and 7.2-fold lower quantities of potential allergens and immunogenic amylase trypsin inhibitors, respectively, than common wheat, whereas potential allergen content was intermediate in tetraploid wheat species. This urgently warrants well-targeted clinical studies, where the developed reference proteomes will help to design representative test diets.
Healthy Cities, A comprehensive dataset for environmental determinants of health in England cities
Authors: Han Zhenyu , Xia Tong , Xi Yanxin , Li Yong
Published: March 2023

This paper presents a fine-grained and multi-sourced dataset for environmental determinants of health collected from England cities. We provide health outcomes of citizens covering physical health (COVID-19 cases, asthma medication expenditure, etc.), mental health (psychological medication expenditure), and life expectancy estimations. We present the corresponding environmental determinants from four perspectives, including basic statistics (population, area, etc.), behavioural environment (availability of tobacco, health-care services, etc.), built environment (road density, street view features, etc.), and natural environment (air quality, temperature, etc.). To reveal regional differences, we extract and integrate massive environment and health indicators from heterogeneous sources into two unified spatial scales, i.e., at the middle layer super output area (MSOA) and the city level, via big data processing and deep learning. Our data holds great promise for diverse audiences, such as public health researchers and urban designers, to further unveil the environmental determinants of health and design methodology for a healthy, sustainable city.
The first full host plant dataset of Curculionidae Scolytinae of the world: tribe Xyleborini LeConte, 1876
Authors: Ruzzier Enrico , Ortis Giacomo , Vallotto Davide , Faccoli Massimo , Martinez-Sañudo Isabel , Marchioro Matteo
Published: March 2023

Xyleborini is the largest tribe of Scolytinae accounting for about 1300 species worldwide; all species are primarily xylomycetophagous, developing on symbiotic fungi farmed in plant woody tissues. Xyleborini wood-boring action, associated with the inoculum of symbiotic fungi, can lead, sometimes, to the emergence of host plant dieback, wood damage and death; for this reason, multiple Xyleborini are major pests on both cultivated, forest and ornamental trees. Many Xyleborini are invasive worldwide and great effort is expended to manage their biological invasions or prevent new arrivals. Imports of host plants often have a primary role as a pathway for introduction and are frequently responsible for the establishment of species in non-native environments. In this context, data availability on Xyleborini host plants is a major limiting factor in the development of effective detection and monitoring strategies as well as a fundamental variable to consider in risk assessment of plant pests and invasive species. This contribution provides updated host records and the hosts economic categorization for the 1293 Xyleborini known worldwide to date.
A prospective cohort study assessing the relationship between long-COVID symptom incidence in COVID-19 patients and COVID-19 vaccination
Authors: Abu Hamdh Bayan , Nazzal Zaher
Published: March 2023

Current studies about the long-term effects of COVID-19 show a wide range of symptoms. This prospective cohort study aimed to find the incidence of long-COVID symptoms and the associated risk factors. We followed 669 confirmed COVID-19 patients. Sociodemographic and clinical data were extracted from medical records and collected via semi-structured telephone interviews on days 10, 30, 60, and 90. The incidence of long-COVID symptoms was 41.6% (95% CI 37.8–45.4%). Females [aOR = 1.5 (95% CI 1.1–2.3)], the elderly [aOR = 4.9 (95% CI 2.0–11.3)], and those who required hospitalization [aOR = 5.0 (95% CI 1.3–3.7)] were at a higher risk of developing long-COVID. Patients with dyspnea at day 10 [aOR: 2.4 (95% CI 1.6–3.7] and fatigue at day 60 [aOR: 3.1 (95% CI 1.5–6.3] were also at risk. While non-vaccinated patients were almost seven times more likely to report long-COVID symptoms than vaccinated patients [aOR: 6.9 (95% CI 4.2–11.3)]. In conclusion, long-COVID was common among COVID-19 patients, with higher rates among females, older age groups, hospitalized patients, and those with dyspnea and fatigue, while vaccination provided protection. Interventions should educate health professionals, raise general public awareness about the risks and consequences of Long COVID, and the value of vaccination.
Comparative transcriptome analysis reveals the phosphate starvation alleviation mechanism of phosphate accumulating Pseudomonas putida in Arabidopsis thaliana
Authors: Srivastava Sonal , Ranjan Manish , Bano Nasreen , Asif Mehar Hasan , Srivastava Suchi
Published: March 2023

Phosphate starvation is one of the major factors limiting plant productivity globally. Soil microflora with an inherent trait of phosphate accumulation directly influences soil phosphorus level by regulating its labile form in soil solution. However, the detailed mechanism involved during their interaction with plants under phosphate deficient conditions is still unexplored. Hence, to dissect these complex gene regulatory networks, transcriptome analysis of A. thaliana roots grown under phosphate starved conditions in presence of phosphate accumulating bacteria (Pseudomonas putida; RAR) was performed. Plants grown under phosphate starved conditions showed upregulation of phosphate starvation responsive genes associated with cell biogenesis, stress, photosynthesis, senescence, and cellular transport. Inoculation of RAR upregulated genes linked to defense, cell wall remodeling, and hormone metabolism in stressed plants. Gene ontology analysis indicated the induction of S-glycoside, glucosinolate, and glycosinolate metabolic processes in RAR inoculated plants under phosphate stressed conditions. Further, protein–protein interaction analysis revealed upregulation of root development, cation transport, anion transport, sulfur compound metabolic process, secondary metabolic process, cellular amino metabolic process, and response to salicylic acid in RAR inoculated plants under phosphate starved conditions. These results indicate the potential role of phosphate accumulating bacteria in alleviating phosphate starvation in plants by involving multiple pathways.
Accurate clinical toxicity prediction using multi-task deep neural nets and contrastive molecular explanations
Authors: Sharma Bhanushee , Chenthamarakshan Vijil , Dhurandhar Amit , Pereira Shiranee , Hendler James A. , Dordick Jonathan S. , Das Payel
Published: March 2023

Explainable machine learning for molecular toxicity prediction is a promising approach for efficient drug development and chemical safety. A predictive ML model of toxicity can reduce experimental cost and time while mitigating ethical concerns by significantly reducing animal and clinical testing. Herein, we use a deep learning framework for simultaneously modeling in vitro, in vivo, and clinical toxicity data. Two different molecular input representations are used; Morgan fingerprints and pre-trained SMILES embeddings. A multi-task deep learning model accurately predicts toxicity for all endpoints, including clinical, as indicated by the area under the Receiver Operator Characteristic curve and balanced accuracy. In particular, pre-trained molecular SMILES embeddings as input to the multi-task model improved clinical toxicity predictions compared to existing models in MoleculeNet benchmark. Additionally, our multitask approach is comprehensive in the sense that it is comparable to state-of-the-art approaches for specific endpoints in in vitro, in vivo and clinical platforms. Through both the multi-task model and transfer learning, we were able to indicate the minimal need of in vivo data for clinical toxicity predictions. To provide confidence and explain the model’s predictions, we adapt a post-hoc contrastive explanation method that returns pertinent positive and negative features, which correspond well to known mutagenic and reactive toxicophores, such as unsubstituted bonded heteroatoms, aromatic amines, and Michael receptors. Furthermore, toxicophore recovery by pertinent feature analysis captures more of the in vitro (53%) and in vivo (56%), rather than of the clinical (8%), endpoints, and indeed uncovers a preference in known toxicophore data towards in vitro and in vivo experimental data. To our knowledge, this is the first contrastive explanation, using both present and absent substructures, for predictions of clinical and in vivo molecular toxicity.