bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry
Authors: Liu Qing , Zhao Enyang , Geng Bo , Gao Shan , Yu Hongyang , He Xinyang , Li Xuedong , Dong Guanglu , You Bosen 
Published: April 2022

AbstractPrevious studies have investigated whether tumor-associated macrophages (TAMs) play tumorigenic and immunosuppressive roles to encourage cancer development, but the role of TAMs in regulating vasculogenic mimicry (VM) in clear-cell renal cell carcinoma (ccRCC) cells has not been completely clarified. We conducted immunostaining of the tumor-associated macrophage biomarkers CD68/CD163 and double staining for PAS/CD31 in ccRCC human specimens to find that higher TAM infiltration was positively correlated with VM formation. Then we demonstrated that TAM-derived exosomes downregulate TIMP2 expression in RCC cells to promote VM and invasion by shuttling miR-193a-5p. Mechanistic analysis indicated that HIF-1α upregulation in macrophages could transcriptionally increase miR-193a-5p expression. Exosome-shuttled miR-193a-5p then targeted the 3′ untranslated region (UTR) of TIMP2 mRNA to suppress its translation. A preclinical study using an in vivo orthotopic xenograft model of ccRCC in mice substantiated that TAM-derived exosomes enhance VM and enable tumor progression, which confirmed our in vitro data. Suppressing TAM-derived exosomal miR-193a-5p successfully inhibited tumor progression and metastasis. Overall, miR-193a-5p from TAM-derived exosomes downregulates the TIMP2 gene to facilitate the development of RCC, which provides a novel perspective for developing therapeutic strategies for RCC.
Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer
Authors: Zhao Lin , Liu Yuanyuan , Zhang Simiao , Wei Lingyu , Cheng Hongbing , Wang Jinsheng , Wang Jia 
Published: April 2022

AbstractMetabolic disorders and abnormal immune function changes occur in tumor tissues and cells to varying degrees. There is increasing evidence that reprogrammed energy metabolism contributes to the development of tumor suppressive immune microenvironment and influences the course of gastric cancer (GC). Current studies have found that tumor microenvironment (TME) also has important clinicopathological significance in predicting prognosis and therapeutic efficacy. Novel approaches targeting TME therapy, such as immune checkpoint blockade (ICB), metabolic inhibitors and key enzymes of immune metabolism, have been involved in the treatment of GC. However, the interaction between GC cells metabolism and immune metabolism and how to make better use of these immunotherapy methods in the complex TME in GC are still being explored. Here, we discuss how metabolic reprogramming of GC cells and immune cells involved in GC immune responses modulate anti-tumor immune responses, as well as the effects of gastrointestinal flora in TME and GC. It is also proposed how to enhance anti-tumor immune response by understanding the targeted metabolism of these metabolic reprogramming to provide direction for the treatment and prognosis of GC.
The caspase-2 substrate p54nrb exhibits a multifaceted role in tumor cell death susceptibility via gene regulatory functions
Authors: Eichler Madeleine , Distler Ute , Nasrullah Usman , Krishnan Aswini , Kaulich Manuel , Husnjak Koraljka , Eberhardt Wolfgang , Rajalingam Krishnaraj , Tenzer Stefan , Pfeilschifter Josef , Imre Gergely 
Published: April 2022

AbstractCaspase-2 represents an evolutionary conserved caspase, which plays a role in genotoxic stress-induced apoptosis, ageing-related metabolic changes, and in deleting aneuploid cells in tumors. Genetic deletion of caspase-2 leads to increased tumor susceptibility in vivo. The exact downstream signaling mechanism by which caspase-2 accomplishes its specific tumor suppressor functions is not clear. Caspase-2, uniquely among caspases, resides in the nucleus and other cellular compartments. In this study, we identify a nuclear caspase-2 specific substrate, p54nrb, which is selectively cleaved by caspase-2 at D422, leading to disruption of the C-terminal site, the putative DNA binding region of the protein. P54nrb is an RNA and DNA binding protein, which plays a role in RNA editing, transport, and transcriptional regulation of genes. Overexpression of p54nrb is observed in several human tumor types, such as cervix adenocarcinoma, melanoma, and colon carcinoma. In contrast, the loss of p54nrb in tumor cell lines leads to increased cell death susceptibility and striking decrease in tumorigenic potential. By employing high resolution quantitative proteomics, we demonstrate that the loss/cleavage of p54nrb results in altered expression of oncogenic genes, among which the downregulation of the tumorigenic protease cathepsin-Z and the anti-apoptotic gelsolin can be detected universally across three tumor cell types, including adenocarcinoma, melanoma and colon carcinoma. Finally, we demonstrate that p54nrb interacts with cathepsin-Z and gelsolin DNA, but not RNA. Taken together, this study uncovers a so far not understood mechanism of caspase-2 tumor suppressor function in human tumor cells.
Restoration of ER proteostasis attenuates remote apoptotic cell death after spinal cord injury by reducing autophagosome overload
Authors: Bisicchia Elisa , Mastrantonio Roberta , Nobili Annalisa , Palazzo Claudia , La Barbera Livia , Latini Laura , Millozzi Francesco , Sasso Valeria , Palacios Daniela , D’Amelio Marcello , Viscomi Maria Teresa 
Published: April 2022

AbstractThe pathogenic mechanisms that underlie the progression of remote degeneration after spinal cord injury (SCI) are not fully understood. In this study, we examined the relationship between endoplasmic reticulum (ER) stress and macroautophagy, hereafter autophagy, and its contribution to the secondary damage and outcomes that are associated with remote degeneration after SCI. Using a rat model of spinal cord hemisection at the cervical level, we measured ER stress and autophagy markers in the axotomized neurons of the red nucleus (RN). In SCI animals, mRNA and protein levels of markers of ER stress, such as GRP78, CHOP, and GADD34, increased 1 day after the injury, peaking on Day 5. Notably, in SCI animals, the increase of ER stress markers correlated with a blockade in autophagic flux, as evidenced by the increase in microtubule-associated protein 2 light chain 3 (LC3-II) and p62/SQSTM1 (p62) and the decline in LAMP1 and LAMP2 levels. After injury, treatment with guanabenz protected neurons from UPR failure and increased lysosomes biogenesis, unblocking autophagic flux. These effects correlated with greater activation of TFEB and improved neuronal survival and functional recovery—effects that persisted after suspension of the treatment. Collectively, our results demonstrate that in remote secondary damage, impairments in autophagic flux are intertwined with ER stress, an association that contributes to the apoptotic cell death and functional damage that are observed after SCI.
Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
Authors: Sánchez-Cruz Alonso , Hernández-Pinto Alberto , Lillo Concepción , Isiegas Carolina , Marchena Miguel , Lizasoain Ignacio , Bosch Fátima , de la Villa Pedro , Hernández-Sánchez Catalina , de la Rosa Enrique J. 
Published: April 2022

AbstractSynaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Indeed, deficient insulin receptor signaling has been implicated in several brain neurodegenerative pathologies. We present evidence linking impaired insulin receptor signaling with RP. We describe a selective decrease in the levels of the insulin receptor and its downstream effector phospho-S6 in retinal horizontal cell terminals in the rd10 mouse model of RP, as well as aberrant synapses between rod photoreceptors and the postsynaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin, the insulin precursor, production restored retinal insulin receptor signaling, by increasing S6 phosphorylation, without peripheral metabolic consequences. Moreover, proinsulin preserved photoreceptor synaptic connectivity and prolonged visual function in electroretinogram and optomotor tests. These findings point to a disease-modifying role of insulin receptor and support the therapeutic potential of proinsulin in retinitis pigmentosa.
Heavy footprints of upper-ocean eddies on weakened Arctic sea ice in marginal ice zones
Authors: Manucharyan Georgy E. , Thompson Andrew F. 
Published: April 2022

AbstractArctic sea ice extent continues to decline at an unprecedented rate that is commonly underestimated by climate projection models. This disagreement may imply biases in the representation of processes that bring heat to the sea ice in these models. Here we reveal interactions between ocean-ice heat fluxes, sea ice cover, and upper-ocean eddies that constitute a positive feedback missing in climate models. Using an eddy-resolving global ocean model, we demonstrate that ocean-ice heat fluxes are predominantly induced by localized and intermittent ocean eddies, filaments, and internal waves that episodically advect warm subsurface waters into the mixed layer where they are in direct contact with sea ice. The energetics of near-surface eddies interacting with sea ice are modulated by frictional dissipation in ice-ocean boundary layers, being dominant under consolidated winter ice but substantially reduced under low-concentrated weak sea ice in marginal ice zones. Our results indicate that Arctic sea ice loss will reduce upper-ocean dissipation, which will produce more energetic eddies and amplified ocean-ice heat exchange. We thus emphasize the need for sea ice-aware parameterizations of eddy-induced ice-ocean heat fluxes in climate models.
Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice
Authors: Rizzi M. , Powell K. , Robinson M. R. , Matsuki T. , Hoke J. , Maswood R. N. , Georgiadis A. , Georgiou M. , Jones P. R. , Ripamonti C. , Nadal-Nicolás F. M. , Michaelides M. , Rubin G. S. , Smith A. J. , Ali R. R. 
Published: April 2022

AbstractMacular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3−/− mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.
Seismic precursors to the Whakaari 2019 phreatic eruption are transferable to other eruptions and volcanoes
Authors: Ardid Alberto , Dempsey David , Caudron Corentin , Cronin Shane 
Published: April 2022

AbstractVolcanic eruptions that occur without warning can be deadly in touristic and populated areas. Even with real-time geophysical monitoring, forecasting sudden eruptions is difficult, because their precursors are hard to recognize and can vary between volcanoes. Here, we describe a general seismic precursor signal for gas-driven eruptions, identified through correlation analysis of 18 well-recorded eruptions in New Zealand, Alaska, and Kamchatka. The precursor manifests in the displacement seismic amplitude ratio between medium (4.5–8 Hz) and high (8–16 Hz) frequency tremor bands, exhibiting a characteristic rise in the days prior to eruptions. We interpret this as formation of a hydrothermal seal that enables rapid pressurization of shallow groundwater. Applying this model to the 2019 eruption at Whakaari (New Zealand), we describe pressurization of the system in the week before the eruption, and cascading seal failure in the 16 h prior to the explosion. Real-time monitoring for this precursor may improve short-term eruption warning systems at certain volcanoes.
Molecular communications in complex systems of dynamic supramolecular polymers
Authors: Crippa Martina , Perego Claudio , de Marco Anna L. , Pavan Giovanni M. 
Published: April 2022

AbstractSupramolecular polymers are composed of monomers that self-assemble non-covalently, generating distributions of monodimensional fibres in continuous communication with each other and with the surrounding solution. Fibres, exchanging molecular species, and external environment constitute a sole complex system, which intrinsic dynamics is hard to elucidate. Here we report coarse-grained molecular simulations that allow studying supramolecular polymers at the thermodynamic equilibrium, explicitly showing the complex nature of these systems, which are composed of exquisitely dynamic molecular entities. Detailed studies of molecular exchange provide insights into key factors controlling how assemblies communicate with each other, defining the equilibrium dynamics of the system. Using minimalistic and finer chemically relevant molecular models, we observe that a rich concerted complexity is intrinsic in such self-assembling systems. This offers a new dynamic and probabilistic (rather than structural) picture of supramolecular polymer systems, where the travelling molecular species continuously shape the assemblies that statistically emerge at the equilibrium.
Quantum spins and hybridization in artificially-constructed chains of magnetic adatoms on a superconductor
Authors: Liebhaber Eva , Rütten Lisa M. , Reecht Gaël , Steiner Jacob F. , Rohlf Sebastian , Rossnagel Kai , von Oppen Felix , Franke Katharina J. 
Published: April 2022

AbstractMagnetic adatom chains on surfaces constitute fascinating quantum spin systems. Superconducting substrates suppress interactions with bulk electronic excitations but couple the adatom spins to a chain of subgap Yu-Shiba-Rusinov (YSR) quasiparticles. Using a scanning tunneling microscope, we investigate such correlated spin-fermion systems by constructing Fe chains adatom by adatom on superconducting NbSe2. The adatoms couple entirely via the substrate, retaining their quantum spin nature. In dimers, we observe that the deepest YSR state undergoes a quantum phase transition due to Ruderman-Kittel-Kasuya-Yosida interactions, a distinct signature of quantum spins. Chains exhibit coherent hybridization and band formation of the YSR excitations, indicating ferromagnetic coupling. Longer chains develop separate domains due to coexisting charge-density-wave order of NbSe2. Despite the spin-orbit-coupled substrate, we find no signatures of Majoranas, possibly because quantum spins reduce the parameter range for topological superconductivity. We suggest that adatom chains are versatile systems for investigating correlated-electron physics and its interplay with topological superconductivity.
Genomic and metabolic adaptations of biofilms to ecological windows of opportunity in glacier-fed streams
Authors: Busi Susheel Bhanu , Bourquin Massimo , Fodelianakis Stilianos , Michoud Grégoire , Kohler Tyler J. , Peter Hannes , Pramateftaki Paraskevi , Styllas Michail , Tolosano Matteo , De Staercke Vincent , Schön Martina , de Nies Laura , Marasco Ramona , Daffonchio Daniele , Ezzat Leïla , Wilmes Paul , Battin Tom J. 
Published: April 2022

AbstractIn glacier-fed streams, ecological windows of opportunity allow complex microbial biofilms to develop and transiently form the basis of the food web, thereby controlling key ecosystem processes. Using metagenome-assembled genomes, we unravel strategies that allow biofilms to seize this opportunity in an ecosystem otherwise characterized by harsh environmental conditions. We observe a diverse microbiome spanning the entire tree of life including a rich virome. Various co-existing energy acquisition pathways point to diverse niches and the exploitation of available resources, likely fostering the establishment of complex biofilms during windows of opportunity. The wide occurrence of rhodopsins, besides chlorophyll, highlights the role of solar energy capture in these biofilms while internal carbon and nutrient cycling between photoautotrophs and heterotrophs may help overcome constraints imposed by oligotrophy in these habitats. Mechanisms potentially protecting bacteria against low temperatures and high UV-radiation are also revealed and the selective pressure of this environment is further highlighted by a phylogenomic analysis differentiating important components of the glacier-fed stream microbiome from other ecosystems. Our findings reveal key genomic underpinnings of adaptive traits contributing to the success of complex biofilms to exploit environmental opportunities in glacier-fed streams, which are now rapidly changing owing to global warming.
Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship
Authors: Yu Ya-Hui , Su Hui-Min , Lin Sheng-Hsiang , Hsiao Po-Chang , Lin Yi-Ting , Liu Chih-Min , Hwang Tzung-Jeng , Hsieh Ming H. , Liu Chen-Chung , Chien Yi-Ling , Kuo Chian-Jue , Hwu Hai-Gwo , Chen Wei J. 
Published: April 2022

AbstractDespite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.
Global seasonal forecasts of marine heatwaves
Authors: Jacox Michael G. , Alexander Michael A. , Amaya Dillon , Becker Emily , Bograd Steven J. , Brodie Stephanie , Hazen Elliott L. , Pozo Buil Mercedes , Tommasi Desiree 
Published: April 2022

AbstractMarine heatwaves (MHWs)—periods of exceptionally warm ocean temperature lasting weeks to years—are now widely recognized for their capacity to disrupt marine ecosystems1–3. The substantial ecological and socioeconomic impacts of these extreme events present significant challenges to marine resource managers4–7, who would benefit from forewarning of MHWs to facilitate proactive decision-making8–11. However, despite extensive research into the physical drivers of MHWs11,12, there has been no comprehensive global assessment of our ability to predict these events. Here we use a large multimodel ensemble of global climate forecasts13,14 to develop and assess MHW forecasts that cover the world’s oceans with lead times of up to a year. Using 30 years of retrospective forecasts, we show that the onset, intensity and duration of MHWs are often predictable, with skilful forecasts possible from 1 to 12 months in advance depending on region, season and the state of large-scale climate modes, such as the El Niño/Southern Oscillation. We discuss considerations for setting decision thresholds based on the probability that a MHW will occur, empowering stakeholders to take appropriate actions based on their risk profile. These results highlight the potential for operational MHW forecasts, analogous to forecasts of extreme weather phenomena, to promote climate resilience in global marine ecosystems.
Automated bone marrow cytology using deep learning to generate a histogram of cell types
Authors: Tayebi Rohollah Moosavi , Mu Youqing , Dehkharghanian Taher , Ross Catherine , Sur Monalisa , Foley Ronan , Tizhoosh Hamid R. , Campbell Clinton J. V. 
Published: April 2022

Abstract
Background
Bone marrow cytology is required to make a hematological diagnosis, influencing critical clinical decision points in hematology. However, bone marrow cytology is tedious, limited to experienced reference centers and associated with inter-observer variability. This may lead to a delayed or incorrect diagnosis, leaving an unmet need for innovative supporting technologies.

Methods
We develop an end-to-end deep learning-based system for automated bone marrow cytology. Starting with a bone marrow aspirate digital whole slide image, our system rapidly and automatically detects suitable regions for cytology, and subsequently identifies and classifies all bone marrow cells in each region. This collective cytomorphological information is captured in a representation called Histogram of Cell Types (HCT) quantifying bone marrow cell class probability distribution and acting as a cytological patient fingerprint.

Results
Our system achieves high accuracy in region detection (0.97 accuracy and 0.99 ROC AUC), and cell detection and cell classification (0.75 mean average precision, 0.78 average F1-score, Log-average miss rate of 0.31).

Conclusions
HCT has potential to eventually support more efficient and accurate diagnosis in hematology, supporting AI-enabled computational pathology.
(±)-Spiroganoapplanin A, a complex polycyclic meroterpenoid dimer from Ganoderma applanatum displaying potential against Alzheimer's disease
Authors: Peng Xing-Rong , Luo Rong-Can , Su Hai-Guo , Zhou Lin , Ran Xiao-Qian , Guo Ya-Rong , Yao Yong-Gang , Qiu Ming-Hua 
Published: April 2022

(±)-spiroganoapplanin A (1) with a polycyclic meroterpenoid from Ganoderma applanatum showed potential anti-AD’s effect by reducing Aβ42 production and inhibiting Tau phosphorylation through BACE1, CDK5, and GSK3β-mediated pathways.