bluuebunny/crossref_metadata_2025 huggingface dataset:
Virus–pathogen interactions improve water quality along the Middle Route of the South-to-North Water Diversion Canal
Authors: Chen Tianyi , Liu Tang , Wu Zongzhi , Wang Bingxue , Chen Qian , Zhang Mi , Liang Enhang , Ni Jinren
Published: July 2023

Bacterial pathogens and viruses are the leading causes of global waterborne diseases. Here, we discovered an interesting natural paradigm of water “self-purification” through virus–pathogen interactions over a 1432 km continuum along the Middle Route of the South-to-North Water Diversion Canal (MR-SNWDC) in China, the largest water transfer project in the world. Due to the extremely low total phosphorus (TP) content (ND-0.02 mg/L) in the MR-SNWDC, the whole canal has experienced long-lasting phosphorus (P) limitation since its operation in 2015. Based on 4443 metagenome-assembled genomes (MAGs) and 40,261 nonredundant viral operational taxonomic units (vOTUs) derived from our recent monitoring campaign, we found that residential viruses experiencing extreme P constraints had to adopt special adaptive strategies by harboring smaller genomes to minimize nucleotide replication, DNA repair, and posttranslational modification costs. With the decreasing P supply downstream, bacterial pathogens showed repressed environmental fitness and growth potential, and a weakened capacity to maintain P acquisition, membrane formation, and ribonucleotide biosynthesis. Consequently, the unique viral predation effects under P limitation, characterized by enhanced viral lytic infections and an increased abundance of ribonucleotide reductase (RNR) genes linked to viral nuclear DNA replication cycles, led to unexpectedly lower health risks from waterborne bacterial pathogens in the downstream water-receiving areas. These findings highlighted the great potential of water self-purification associated with virus–pathogen dynamics for water-quality improvement and sustainable water resource management.
N-oleoyl glycine and N-oleoyl alanine attenuate alcohol self-administration and preference in mice
Authors: Shahen-Zoabi Samah , Smoum Reem , Bingor Alexey , Grad Etty , Nemirovski Alina , Shekh-Ahmad Tawfeeq , Mechoulam Raphael , Yaka Rami
Published: July 2023

The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain and has an important role in the neurobiological processes underlying drug addiction. We have previously shown that an elevated ECS response to psychostimulant (cocaine) is involved in regulating the development and expression of cocaine-conditioned reward and sensitization. We therefore hypothesized that drug-induced elevation in endocannabinoids (eCBs) and/or eCB-like molecules (eCB-Ls) may represent a protective mechanism against drug insult, and boosting their levels exogenously may strengthen their neuroprotective effects. Here, we determine the involvement of ECS in alcohol addiction. We first measured the eCBs and eCB-Ls levels in different brain reward system regions following chronic alcohol self-administration using LC–MS. We have found that following chronic intermittent alcohol consumption, N-oleoyl glycine (OlGly) levels were significantly elevated in the prefrontal cortex (PFC), and N-oleoyl alanine (OlAla) was significantly elevated in the PFC, nucleus accumbens (NAc) and ventral tegmental area (VTA) in a region-specific manner. We next tested whether exogenous administration of OlGly or OlAla would attenuate alcohol consumption and preference. We found that systemic administration of OlGly or OlAla (60 mg/kg, intraperitoneal) during intermittent alcohol consumption significantly reduced alcohol intake and preference without affecting the hedonic state. These findings suggest that the ECS negatively regulates alcohol consumption and boosting selective eCBs exogenously has beneficial effects against alcohol consumption and potentially in preventing relapse.
Negative regulation of pro-apoptotic AMPK/JNK pathway by itaconate in mice with fulminant liver injury
Authors: Fan Kerui , Chen Kun , Zan Xinyan , Zhi Ying , Zhang Xue , Zhang Xinyue , Qiu Jinghuan , Liu Gang , Li Longjiang , Tang Li , Hu Kai , Wan Jingyuan , Gong Xianqiong , Yang Yongqiang , Zhang Li
Published: July 2023

Accumulating evidence indicates that metabolic responses are deeply integrated into signal transduction, which provides novel opportunities for the metabolic control of various disorders. Recent studies suggest that itaconate, a highly concerned bioactive metabolite catalyzed by immune responsive gene 1 (IRG1), is profoundly involved in the regulation of apoptosis, but the underlying mechanisms have not been fully understood. In the present study, the molecular mechanisms responsible for the apoptosis-modulatory activities of IRG1/itaconate have been investigated in mice with lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced apoptotic liver injury. The results indicated that LPS/D-Gal exposure upregulated the level of IRG1 and itaconate. Deletion of IRG1 resulted in exacerbated hepatocytes apoptosis and liver injury. The phospho-antibody microarray analysis and immunoblot analysis indicated that IRG1 deletion enhanced the activation of AMP-activated protein kinase (AMPK)/c-jun-N-terminal kinase (JNK) pathway in LPS/D-Gal exposed mice. Mechanistically, IRG1 deficiency impaired the anti-oxidative nuclear factor erythroid-2 related factor 2 (Nrf2) signaling and then enhanced the activation of the redox-sensitive AMPK/JNK pathway that promotes hepatocytes apoptosis. Importantly, post-insult supplementation with 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, resulted in beneficial outcomes in fulminant liver injury. Therefore, IRG1/itaconate might function as a negative regulator that controls AMPK-induced hepatocyte apoptosis in LPS/D-Gal-induced fulminant liver injury.
Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors
Authors: Feng Wenbo , Zhou Qingtong , Chen Xianyue , Dai Antao , Cai Xiaoqing , Liu Xiao , Zhao Fenghui , Chen Yan , Ye Chenyu , Xu Yingna , Cong Zhaotong , Li Hao , Lin Shi , Yang Dehua , Wang Ming-Wei
Published: July 2023

Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin pigmentation through five MCR subtypes (MC1R–MC5R). The structural basis of subtype selectivity of the endogenous agonist γ-MSH and non-selectivity of agonist α-MSH remains elusive, as the two agonists are highly similar with a conserved HFRW motif. Here, we report three cryo-electron microscopy structures of MC3R–Gs in complex with γ-MSH and MC5R–Gs in the presence of α-MSH or a potent synthetic agonist PG-901. The structures reveal that α-MSH and γ-MSH adopt a “U-shape” conformation, penetrate into the wide-open orthosteric pocket and form massive common contacts with MCRs via the HFRW motif. The C-terminus of γ-MSH occupies an MC3R-specific complementary binding groove likely conferring subtype selectivity, whereas that of α-MSH distances itself from the receptor with neglectable contacts. PG-901 achieves the same potency as α-MSH with a shorter length by rebalancing the recognition site and mimicking the intra-peptide salt bridge in α-MSH by cyclization. Solid density confirmed the calcium ion binding in MC3R and MC5R, and the distinct modulation effects of divalent ions were demonstrated. Our results provide insights into ligand recognition and subtype selectivity among MCRs, and expand the knowledge of signal transduction among MCR family members.
A multifunctional soft robotic shape display with high-speed actuation, sensing, and control
Authors: Johnson B. K. , Naris M. , Sundaram V. , Volchko A. , Ly K. , Mitchell S. K. , Acome E. , Kellaris N. , Keplinger C. , Correll N. , Humbert J. S. , Rentschler M. E.
Published: July 2023

Shape displays which actively manipulate surface geometry are an expanding robotics domain with applications to haptics, manufacturing, aerodynamics, and more. However, existing displays often lack high-fidelity shape morphing, high-speed deformation, and embedded state sensing, limiting their potential uses. Here, we demonstrate a multifunctional soft shape display driven by a 10 × 10 array of scalable cellular units which combine high-speed electrohydraulic soft actuation, magnetic-based sensing, and control circuitry. We report high-performance reversible shape morphing up to 50 Hz, sensing of surface deformations with 0.1 mm sensitivity and external forces with 50 mN sensitivity in each cell, which we demonstrate across a multitude of applications including user interaction, image display, sensing of object mass, and dynamic manipulation of solids and liquids. This work showcases the rich multifunctionality and high-performance capabilities that arise from tightly-integrating large numbers of electrohydraulic actuators, soft sensors, and controllers at a previously undemonstrated scale in soft robotics.
Three-dimensional molecular architecture of mouse organogenesis
Authors: Qu Fangfang , Li Wenjia , Xu Jian , Zhang Ruifang , Ke Jincan , Ren Xiaodie , Meng Xiaogao , Qin Lexin , Zhang Jingna , Lu Fangru , Zhou Xin , Luo Xi , Zhang Zhen , Wang Minhan , Wu Guangming , Pei Duanqing , Chen Jiekai , Cui Guizhong , Suo Shengbao , Peng Guangdun
Published: July 2023

Mammalian embryos exhibit sophisticated cellular patterning that is intricately orchestrated at both molecular and cellular level. It has recently become apparent that cells within the animal body display significant heterogeneity, both in terms of their cellular properties and spatial distributions. However, current spatial transcriptomic profiling either lacks three-dimensional representation or is limited in its ability to capture the complexity of embryonic tissues and organs. Here, we present a spatial transcriptomic atlas of all major organs at embryonic day 13.5 in the mouse embryo, and provide a three-dimensional rendering of molecular regulation for embryonic patterning with stacked sections. By integrating the spatial atlas with corresponding single-cell transcriptomic data, we offer a detailed molecular annotation of the dynamic nature of organ development, spatial cellular interactions, embryonic axes, and divergence of cell fates that underlie mammalian development, which would pave the way for precise organ engineering and stem cell-based regenerative medicine.
A Phytophthora receptor-like kinase regulates oospore development and can activate pattern-triggered plant immunity
Authors: Pei Yong , Ji Peiyun , Si Jierui , Zhao Hanqing , Zhang Sicong , Xu Ruofei , Qiao Huijun , Duan Weiwei , Shen Danyu , Yin Zhiyuan , Dou Daolong
Published: July 2023

Plant cell-surface leucine-rich repeat receptor-like kinases (LRR-RLKs) and receptor-like proteins (LRR-RLPs) form dynamic complexes to receive a variety of extracellular signals. LRR-RLKs are also widespread in oomycete pathogens, whereas it remains enigmatic whether plant and oomycete LRR-RLKs could mediate cell-to-cell communications between pathogen and host. Here, we report that an LRR-RLK from the soybean root and stem rot pathogen Phytophthora sojae, PsRLK6, can activate typical pattern-triggered immunity in host soybean and nonhost tomato and Nicotiana benthamiana plants. PsRLK6 homologs are conserved in oomycetes and also exhibit immunity-inducing activity. A small region (LRR5-6) in the extracellular domain of PsRLK6 is sufficient to activate BAK1- and SOBIR1-dependent immune responses, suggesting that PsRLK6 is likely recognized by a plant LRR-RLP. Moreover, PsRLK6 is shown to be up-regulated during oospore maturation and essential for the oospore development of P. sojae. Our data provide a novel type of microbe-associated molecular pattern that functions in the sexual reproduction of oomycete, and a scenario in which a pathogen LRR-RLK could be sensed by a plant LRR-RLP to mount plant immunity.
A photochemical method to evidence directional molecular motions
Authors: Regen-Pregizer Benjamin Lukas , Ozcelik Ani , Mayer Peter , Hampel Frank , Dube Henry
Published: July 2023

Light driven synthetic molecular motors represent crucial building blocks for advanced molecular machines and their applications. A standing challenge is the development of very fast molecular motors able to perform rotations with kHz, MHz or even faster frequencies. Central to this challenge is the direct experimental evidence of directionality because analytical methods able to follow very fast motions rarely deliver precise geometrical insights. Here, a general photochemical method for elucidation of directional motions is presented. In a macrocyclization approach the molecular motor rotations are restricted and forced to proceed in two separate ~180° rotation-photoequilibria. Therefore, all four possible photoinduced rotation steps (clockwise and counterclockwise directions) can be quantified. Comparison of the corresponding quantum yields to the unrestricted motor delivers direct evidence for unidirectionality. This method can be used for any ultrafast molecular motor even in cases where no high energy intermediates are present during the rotation cycle.
Lysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 34
Authors: Sugihara Ryuta , Taneike Manabu , Murakawa Tomokazu , Tamai Takahito , Ueda Hiromichi , Kitazume-Taneike Rika , Oka Takafumi , Akazawa Yasuhiro , Nishida Hiroki , Mine Kentaro , Hioki Ayana , Omi Jumpei , Omiya Shigemiki , Aoki Junken , Ikeda Kazutaka , Nishida Kazuhiko , Arita Makoto , Yamaguchi Osamu , Sakata Yasushi , Otsu Kinya
Published: July 2023

Heart failure is a leading cause of mortality in developed countries. Cell death is a key player in the development of heart failure. Calcium-independent phospholipase A2β (iPLA2β) produces lipid mediators by catalyzing lipids and induces nuclear shrinkage in caspase-independent cell death. Here, we show that lysophosphatidylserine generated by iPLA2β induces necrotic cardiomyocyte death, as well as contractile dysfunction mediated through its receptor, G protein-coupled receptor 34 (GPR34). Cardiomyocyte-specific iPLA2β-deficient male mice were subjected to pressure overload. While control mice showed left ventricular systolic dysfunction with necrotic cardiomyocyte death, iPLA2β-deficient mice preserved cardiac function. Lipidomic analysis revealed a reduction of 18:0 lysophosphatidylserine in iPLA2β-deficient hearts. Knockdown of Gpr34 attenuated 18:0 lysophosphatidylserine-induced necrosis in neonatal male rat cardiomyocytes, while the ablation of Gpr34 in male mice reduced the development of pressure overload-induced cardiac remodeling. Thus, the iPLA2β—lysophosphatidylserine—GPR34—necrosis signaling axis plays a detrimental role in the heart in response to pressure overload.
Late Cambrian geomagnetic instability after the onset of inner core nucleation
Authors: Li Yong-Xiang , Tarduno John A. , Jiao Wenjun , Liu Xinyu , Peng Shanchi , Xu Shihua , Yang Aihua , Yang Zhenyu
Published: July 2023

The Ediacaran Period marks a pivotal time in geodynamo evolution when the geomagnetic field is thought to approach the weak state where kinetic energy exceeds magnetic energy, as manifested by an extremely high frequency of polarity reversals, high secular variation, and an ultralow dipole field strength. However, how the geodynamo transitioned from this state into one with more stable field behavior is unknown. Here, we address this issue through a high-resolution magnetostratigraphic investigation of the ~494.5 million-year-old Jiangshanian Global Standard Stratotype and Point (GSSP) section in South China. Our paleomagnetic results document zones with rapid reversals, stable polarity and a ~80 thousand-year-long interval without a geocentric axial dipole field. From these changes, we suggest that for most of the Cambrian, the solid inner core had not yet grown to a size sufficiently large to stabilize the geodynamo. This unusual field behavior can explain paleomagnetic data used to define paradoxical true polar wander, supporting instead the rotational stability of the solid Earth during the great radiation of life in the Cambrian.
Ionomer-free and recyclable porous-transport electrode for high-performing proton-exchange-membrane water electrolysis
Authors: Lee Jason K. , Anderson Grace , Tricker Andrew W. , Babbe Finn , Madan Arya , Cullen David A. , Arregui-Mena José’ D. , Danilovic Nemanja , Mukundan Rangachary , Weber Adam Z. , Peng Xiong
Published: July 2023

Clean hydrogen production requires large-scale deployment of water-electrolysis technologies, particularly proton-exchange-membrane water electrolyzers (PEMWEs). However, as iridium-based electrocatalysts remain the only practical option for PEMWEs, their low abundance will become a bottleneck for a sustainable hydrogen economy. Herein, we propose high-performing and durable ionomer-free porous transport electrodes (PTEs) with facile recycling features enabling Ir thrifting and reclamation. The ionomer-free porous transport electrodes offer a practical pathway to investigate the role of ionomer in the catalyst layer and, from microelectrode measurements, point to an ionomer poisoning effect for the oxygen evolution reaction. The ionomer-free porous transport electrodes demonstrate a voltage reduction of > 600 mV compared to conventional ionomer-coated porous transport electrodes at 1.8 A cm−2 and <0.1 mgIr cm−2, and a voltage degradation of 29 mV at average rate of 0.58 mV per 1000-cycles after 50k cycles of accelerated-stress tests at 4 A cm−2. Moreover, the ionomer-free feature enables facile recycling of multiple components of PEMWEs, which is critical to a circular clean hydrogen economy.
Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton
Authors: Doolittle Madison L. , Saul Dominik , Kaur Japneet , Rowsey Jennifer L. , Vos Stephanie J. , Pavelko Kevin D. , Farr Joshua N. , Monroe David G. , Khosla Sundeep
Published: July 2023

Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using carefully validated antibodies to analyze senescent cells at single-cell resolution. We use multiple criteria to identify senescent mesenchymal cells that are growth-arrested and resistant to apoptosis. These p16 + Ki67-BCL-2+ cells are highly enriched for senescence-associated secretory phenotype and DNA damage markers, are strongly associated with age, and their percentages are increased in late osteoblasts/osteocytes and CD24high osteolineage cells. Moreover, both late osteoblasts/osteocytes and CD24high osteolineage cells are robustly cleared by genetic and pharmacologic senolytic therapies in aged mice. Following isolation, CD24+ skeletal cells exhibit growth arrest, senescence-associated β-galactosidase positivity, and impaired osteogenesis in vitro. These studies thus provide an approach using multiplexed protein profiling to define senescent mesenchymal cells in vivo and identify specific skeletal cell populations cleared by senolytics.
Enhanced clay formation key in sustaining the Middle Eocene Climatic Optimum
Authors: Krause Alexander J. , Sluijs Appy , van der Ploeg Robin , Lenton Timothy M. , Pogge von Strandmann Philip A. E.
Published: July 2023

The Middle Eocene Climatic Optimum (around 40 million years ago) was a roughly 400,000-year-long global warming phase associated with an increase in atmospheric CO2 concentrations and deep-ocean acidification that interrupted the Eocene’s long-term cooling trend. The unusually long duration, compared with early Eocene global warming phases, is puzzling as temperature-dependent silicate weathering should have provided a negative feedback, drawing down CO2 over this timescale. Here we investigate silicate weathering during this climate warming event by measuring lithium isotope ratios (reported as δ7Li), which are a tracer for silicate weathering processes, from a suite of open-ocean carbonate-rich sediments. We find a positive δ7Li excursion—the only one identified for a warming event so far —of ~3‰. Box model simulations support this signal to reflect a global shift from congruent weathering, with secondary mineral dissolution, to incongruent weathering, with secondary mineral formation. We surmise that, before the climatic optimum, there was considerable soil shielding of the continents. An increase in continental volcanism initiated the warming event, but it was sustained by an increase in clay formation, which sequestered carbonate-forming cations, short-circuiting the carbonate–silicate cycle. Clay mineral dynamics may play an important role in the carbon cycle for climatic events occurring over intermediate (i.e., 100,000 year) timeframes.
Himalayan valley-floor widths controlled by tectonically driven exhumation
Authors: Clubb Fiona J. , Mudd Simon M. , Schildgen Taylor F. , van der Beek Peter A. , Devrani Rahul , Sinclair Hugh D.
Published: July 2023

Himalayan rivers transport around a gigaton of sediment annually to ocean basins. Mountain valleys are an important component of this routing system: storage in these valleys acts to buffer climatic and tectonic signals recorded by downstream sedimentary systems. Despite a critical need to understand the spatial distribution, volume and longevity of these valley fills, controls on valley location and geometry are unknown, and estimates of sediment volumes are based on assumptions of valley-widening processes. Here we extract over 1.5 million valley-floor width measurements across the Himalaya to determine the dominant controls on valley-floor morphology and to assess sediment-storage processes. Using random forest regression, we show that channel steepness, a proxy for rock uplift, is a first-order control on valley-floor width. On the basis of a dataset of 1,148 exhumation rates, we find that valley-floor width decreases as exhumation rate increases. Our results suggest that valley-floor width is controlled by long-term tectonically driven exhumation rather than by water discharge or bedrock erodibility and that valley widening predominantly results from sediment deposition along low-gradient valley floors rather than lateral bedrock erosion.
SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response
Authors: Bland Philip , Saville Harry , Wai Patty T. , Curnow Lucinda , Muirhead Gareth , Nieminuszczy Jadwiga , Ravindran Nivedita , John Marie Beatrix , Hedayat Somaieh , Barker Holly E. , Wright James , Yu Lu , Mavrommati Ioanna , Read Abigail , Peck Barrie , Allen Mark , Gazinska Patrycja , Pemberton Helen N. , Gulati Aditi , Nash Sarah , Noor Farzana , Guppy Naomi , Roxanis Ioannis , Pratt Guy , Oldreive Ceri , Stankovic Tatjana , Barlow Samantha , Kalirai Helen , Coupland Sarah E. , Broderick Ronan , Alsafadi Samar , Houy Alexandre , Stern Marc-Henri , Pettit Stephen , Choudhary Jyoti S. , Haider Syed , Niedzwiedz Wojciech , Lord Christopher J. , Natrajan Rachael
Published: July 2023

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.
Entanglement propagation and dynamics in non-additive quantum systems
Authors: Giachetti Guido , Defenu Nicolò
Published: July 2023

The prominent collective character of long-range interacting quantum systems makes them promising candidates for quantum technological applications. Yet, lack of additivity overthrows the traditional picture for entanglement scaling and transport, due to the breakdown of the common mechanism based on excitations propagation and confinement. Here, we describe the dynamics of the entanglement entropy in many-body quantum systems with a diverging contribution to the internal energy from the long-range two body potential. While in the strict thermodynamic limit entanglement dynamics is shown to be suppressed, a rich mosaic of novel scaling regimes is observed at intermediate system sizes, due to the possibility to trigger multiple resonant modes in the global dynamics. Quantitative predictions on the shape and timescales of entanglement propagation are made, paving the way to the observation of these phases in current quantum simulators. This picture is connected and contrasted with the case of local many body systems subject to Floquet driving.
A neural encoder for earthquake rate forecasting
Authors: Zlydenko Oleg , Elidan Gal , Hassidim Avinatan , Kukliansky Doron , Matias Yossi , Meade Brendan , Molchanov Alexandra , Nevo Sella , Bar-Sinai Yohai
Published: July 2023

Forecasting the timing of earthquakes is a long-standing challenge. Moreover, it is still debated how to formulate this problem in a useful manner, or to compare the predictive power of different models. Here, we develop a versatile neural encoder of earthquake catalogs, and apply it to the fundamental problem of earthquake rate prediction, in the spatio-temporal point process framework. The epidemic type aftershock sequence model (ETAS) effectively learns a small number of parameters to constrain the assumed functional forms for the space and time correlations of earthquake sequences (e.g., Omori-Utsu law). Here we introduce learned spatial and temporal embeddings for point process earthquake forecasting models that capture complex correlation structures. We demonstrate the generality of this neural representation as compared with ETAS model using train-test data splits and how it enables the incorporation additional geophysical information. In rate prediction tasks, the generalized model shows$$>4\%$$>4%improvement in information gain per earthquake and the simultaneous learning of anisotropic spatial structures analogous to fault traces. The trained network can be also used to perform short-term prediction tasks, showing similar improvement while providing a 1000-fold reduction in run-time.
β-Endorphin (an endogenous opioid) inhibits inflammation, oxidative stress and apoptosis via Nrf-2 in asthmatic murine model
Authors: Pandey Vinita , Yadav Vandana , Singh Rashmi , Srivastava Atul , Subhashini
Published: July 2023

Asthma, a chronic respiratory disease is characterized by airway inflammation, remodelling, airflow limitation and hyperresponsiveness. At present, it is considered as an umbrella diagnosis consisting several variable clinical presentations (phenotypes) and distinct pathophysiological mechanisms (endotypes). Recent evidence suggests that oxidative stress participates in airway inflammation and remodelling in chronic asthma. Opioids resembled by group of regulatory peptides have proven to act as an immunomodulator. β-Endorphin a natural and potent endogenous morphine produced in the anterior pituitary gland play role in pain modulation. Therapeutic strategy of many opioids including β-Endorphin as an anti‑inflammatory and antioxidative agent has not been yet explored despite its promising analgesic effects. This is the first study to reveal the role of β-Endorphin in regulating airway inflammation, cellular apoptosis, and oxidative stress via Nrf-2 in an experimental asthmatic model. Asthma was generated in balb/c mice by sensitizing with 1% Toulene Diisocyanate on day 0, 7, 14 and 21 and challenging with 2.5% Toulene Diisocyanate from day 22 to 51 (on every alternate day) through intranasal route. β-Endorphin (5 µg/kg) was administered through the nasal route 1 h prior to sensitization and challenge. The effect of β-Endorphin on pulmonary inflammation and redox status along with parameters of oxidative stress were evaluated. We found that pre-treatment of β-Endorphin significantly reduced inflammatory infiltration in lung tissue and cell counts in bronchoalveolar lavage fluid. Also, pre-treatment of β-Endorphin reduced reactive oxygen species, Myeloperoxidase, Nitric Oxide, Protein and protein carbonylation, Glutathione Reductase, Malondialdehyde, IFN-γ, and TNF-α. Reversely, β-Endorphin significantly increased Superoxide dismutase, Catalase, glutathione, Glutathione-S-Transferase, and activation of NF-E2-related factor 2 (Nrf-2) via Kelch-like ECH-associated protein 1 (Keap1), independent pathway in the lung restoring architectural alveolar and bronchial changes. The present findings reveal the therapeutic potency of β-END in regulating asthma by Keap-1 independent regulation of Nrf-2 activity. The present findings reveal the therapeutic potency of β-Endorphin in regulating asthma.
Demographic and motivational differences between participants in analog and digital citizen science projects for monitoring mosquitoes
Authors: Dekramanjian Berj , Bartumeus Frederic , Kampen Helge , Palmer John R. B. , Werner Doreen , Pernat Nadja
Published: July 2023

Worldwide, citizen scientists help to map the distribution of native and introduced mosquito species in a variety of programs, contributing to environmental research and management decisions. Participant background, behavior, and engagement may vary depending on the project design, especially between those using digital apps and those using physical samples, which in turn may impact the quality and representativeness of the data collected. During the analysis of the responses to a survey directed at citizen scientists participating in  a digital and an analog program, we found significant differences in the respondents’ demographic backgrounds. Diverse participant motivations and varying sentiments towards mosquitoes were observed, indicating differing susceptibility in response to the program messages. The results can be translated into recommendations to further strengthen the appeal of citizen science projects and to promote and sustain public engagement in environmental research.
Multi-omic analyses of triptan-treated migraine attacks gives insight into molecular mechanisms
Authors: Kogelman Lisette J. A. , Falkenberg Katrine , Ottosson Filip , Ernst Madeleine , Russo Francesco , Stentoft-Hansen Valdemar , Demharter Samuel , Tfelt-Hansen Peer , Cohen Arieh S. , Olesen Jes , Hansen Thomas Folkmann
Published: July 2023

Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e. serotonin receptor agonists. However, triptans are effective in ~ 60% of the population, and the mechanisms of triptans are debated. Here, we aim to expose the mechanisms of triptan using metabolomics and transcriptomics in spontaneous migraine attacks. We collected temporal multi-omics profiles on 24 migraine patients, using samples collected at a migraine attack, 2 h after treatment with a triptan, when headache-free, and after a cold-pressor test. Differential metabolomic analysis was performed to find metabolites associated with treatment. Their effect was further investigated using correlation analysis and a machine learning approach. We found three differential metabolites: cortisol, sumatriptan and glutamine. The change in sumatriptan levels correlated with a change inGNAI1andVIPR2gene expression, both known to regulate cAMP levels. Furthermore, we found fatty acid oxidation to be affected, a mechanism known to be involved in migraine but not previously found in relation to triptans. In conclusion, using an integrative approach we find evidence for a role of glutamine, cAMP regulation, and fatty acid oxidation in the molecular mechanisms of migraine and/or the effect of triptans.
Quantifying the relationship between spreading depolarization and perivascular cerebrospinal fluid flow
Authors: Mukherjee Saikat , Mirzaee Mahsa , Tithof Jeffrey
Published: July 2023

Recent studies have linked spreading depolarization (SD, an electro-chemical wave in the brain following stroke, migraine, traumatic brain injury, and more) with increase in cerebrospinal fluid (CSF) flow through the perivascular spaces (PVSs, annular channels lining the brain vasculature). We develop a novel computational model that couples SD and CSF flow. We first use high order numerical simulations to solve a system of physiologically realistic reaction–diffusion equations which govern the spatiotemporal dynamics of ions in the extracellular and intracellular spaces of the brain cortex during SD. We then couple the SD wave with a 1D CSF flow model that captures the change in cross-sectional area, pressure, and volume flow rate through the PVSs. The coupling is modelled using an empirical relationship between the excess potassium ion concentration in the extracellular space following SD and the vessel radius. We find that the CSF volumetric flow rate depends intricately on the length and width of the PVS, as well as the vessel radius and the angle of incidence of the SD wave. We derive analytical expressions for pressure and volumetric flow rates of CSF through the PVS for a given SD wave and quantify CSF flow variations when two SD waves collide. Our numerical approach is very general and could be extended in the future to obtain novel, quantitative insights into how CSF flow in the brain couples with slow waves, functional hyperemia, seizures, or externally applied neural stimulations.
Evaluation of urine dipstick tests in experimental porcine urinary tract infection with uropathogenic Escherichia coli
Authors: Stærk Kristian , Jensen Louise Kruse , Andersen Thomas Emil
Published: July 2023

Urinary tract infection is a common disease in pigs and a major reason for sows to be culled. The disease, however, is difficult to diagnose due to lack of distinct clinical signs in the animals. We evaluated the diagnostic value of two commercial urine dipstick tests in 10 pigs using an experimental model of Escherichia coli urinary tract infection. Urine collected at baseline and 48 h after inoculation were analyzed. We show that dipstick tests positive of blood, leucocytes and particularly nitrite are very specific for E. coli UTI with a 100% positive predictive value.
The immunosuppressive activity of myeloid-derived suppressor cells in murine Paracoccidioidomycosis relies on Indoleamine 2,3-dioxygenase activity and Dectin-1 and TLRs signaling
Authors: Kaminski Valéria de Lima , Preite Nycolas Willian , Borges Bruno Montanari , dos Santos Bianca Vieira , Calich Vera Lucia Garcia , Loures Flávio Vieira
Published: July 2023

Paracoccidioidomycosis (PCM) is a systemic mycosis with a high incidence in Latin America. Prior studies have demonstrated the significance of the enzyme Indoleamine 2,3-dioxygenase (IDO-1) in the immune regulation of PCM as well as the vital role of myeloid-derived suppressor cells (MDSCs) in moderating PCM severity. Additionally, Dectin-1 and Toll-Like Receptors (TLRs) signaling in cancer, infection, and autoimmune diseases have been shown to impact MDSC-IDO-1+ activity. To expand our understanding of MDSCs and the role of IDO-1 and pattern recognition receptors (PRRs) signaling in PCM, we generated MDSCs in vitro and administered an IDO-1 inhibitor before challenging the cells with Paracoccidioides brasiliensis yeasts. By co-culturing MDSCs with lymphocytes, we assessed T-cell proliferation to examine the influence of IDO-1 on MDSC activity. Moreover, we utilized specific antibodies and MDSCs from Dectin-1, TLR4, and TLR2 knockout mice to evaluate the effect of these PRRs on IDO-1 production by MDSCs. We confirmed the importance of these in vitro findings by assessing MDSC-IDO-1+ in the lungs of mice following the fungal infection. Taken together, our data show that IDO-1 expression by MDSCs is crucial for the control of T-cell proliferation, and the production of this enzyme is partially dependent on Dectin-1, TLR2, and TLR4 signaling during murine PCM.
Culture-space control is effective in promoting haploid cell formation and spermiogenesis in vitro in neonatal mice
Authors: Hashimoto Kiyoshi , Odaka Hisakazu , Ishikawa-Yamauchi Yu , Nagata Shino , Nakamura Hiroko , Kimura Hiroshi , Sato Takuya , Makiyama Kazuhide , Ogawa Takehiko
Published: July 2023

The classical organ culture method, in which tissue is placed at the gas‒liquid interphase, is effective at inducing mouse spermatogenesis. However, due to reginal variations in the supply of oxygen and nutrients within a tissue, the progress of spermatogenesis was observed only in limited areas of a tissue. In addition, haploid cell formation and its differentiation to spermatozoon, i.e. spermiogenesis, were infrequent and inefficient. Here, we show that the polydimethylsiloxane (PDMS)-chip ceiling (PC) method, which ensures a uniform supply of nutrients and oxygen throughout the tissue by pressing it into a thin, flat shape, can provide control over the culture space. We used this method to culture testis tissue from neonatal mice, aged 1 to 4 days, and found that modulating the culture space during the experiment by replacing one chip with another that had a higher ceiling effectively increased tissue growth. This adjustment also induced more efficient spermatogenesis, with the process of spermiogenesis being particularly promoted. Meiotic cells were observed from culture day 14 onward, and haploid cells were confirmed at the end of each experiment. This technique was also shown to be a sensitive assay for testicular toxicity. Culture-space control will be a critical regulation parameter for sophisticated tissue culture experiments.
3D smooth path planning of AUV based on improved ant colony optimization considering heading switching pressure
Authors: Meng Ronghua , Sun Aiwen , Wu Zhengjia , Du Xuan , Meng Yongdong
Published: July 2023

A smooth and secure spatial path planning algorithm that integrates the improved ant colony optimization with the corrective connected spatial search strategy is proposed, aiming at heavy heading switching pressure of autonomous underwater vehicles sailing in complex marine environment. On the one hand, to overcome the low-dimensional search domain and inaccurate spatial communication information in traditional spatial path planning, the spatial connectivity adjacency domain search strategy is designed based on grid environment model. On the other hand, to alleviate heading switching pressure due to large path steering angles and redundant path turning points, the heuristic functions and pheromone update criterion based on ant colony optimization are introduced to improve the solution quality of smooth paths. The simulation results show that the space search strategy can improve the success probability of safe path planning without reducing the scope of explorable free space. Additionally, the simulations demonstrate that the improved ant colony optimization using the spatial search strategy can guarantee the shortest path with lowest tortuous degree and fewest turning times in the same grid environment.
Three-dimensional micro-X-ray topography using focused sheet-shaped X-ray beam
Authors: Yoneyama Akio , Ishiji Kotaro , Sakaki Atsushi , Kobayashi Yutaka , Inaba Masayuki , Fukuda Kazunori , Konishi Kumiko , Shima Akio , Takamatsu Daiko
Published: July 2023

X-ray topography is a powerful method for analyzing crystal defects and strain in crystalline materials non-destructively. However, conventional X-ray topography uses simple X-ray diffraction images, which means depth information on defects and dislocations cannot be obtained. We have therefor developed a novel three-dimensional micro-X-ray topography technique (3D μ-XRT) that combines Bragg-case section topography with focused sheet-shaped X-rays. The depth resolution of the 3D μ-XRT depends mainly on the focused X-ray beam size and enables non-destructive observation of internal defects and dislocations with an accuracy on the order of 1 μm. The demonstrative observation of SiC power device chips showed that stacking faults, threading screw, threading edge, and basal plane dislocations were clearly visualized three-dimensionally with a depth accuracy of 1.3 μm. 3D μ-XRT is a promising new approach for highly sensitive and non-destructive analysis of material crystallinity in a three-dimensional manner.
Clinicopathological characteristics of HER2-low breast cancer: a retrospective study
Authors: Yang Man , Sun Jiale , Liu Liqiong , Kong Xiangyi , Lin Dongcai , Zhou Hong , Gao Jidong
Published: July 2023

Human Epidermal Growth Factor Receptor-2 (HER2)-negative breast cancers (BCs) contain HER2-low and HER2-zero ones. HER2-low breast cancer has been receiving wide-spread concerns as the marvelous effect of novel anti-HER2 antibody-drug conjugates, however, the characteristic remains unknown. Our aim was to explore the differences of clinicopathological indicators and survival outcomes between HER2-low and HER2-0 breast cancers. We retrospectively analyzed 501 invasive breast cancer patients with complete data on HER2 status from 2017 to 2021 in our single center, of whom 415 HER2 negative patients were included for subsequent analysis. Each cohort was further divided into hormone receptor (HR) positive and HR negative subgroup. Clinicopathological factors and survival outcomes were collected and compared between HER2-low BCs and HER2-0 BCs. HER2-low BCs was obviously higher in HR positive BCs, with 277 (90.5%) HER2-low HR positive patients, 29 (9.5%) HER2-low HR negative patients, 68 (62.4%) HER2-0 HR positive patients and 41 (37.6%) HER2-0 HR negative patients (P < 0.001). Significant differences between HER2-low BCs and Her2-0 BCs were observed in lymph node ratio (LNR) (mean rank, 215 vs. 188 P = 0.014), estrogen receptor (ER)expression (90.5% vs. 62.4% P < 0.001), progesterone receptor (PR) expression (84.3% vs. 56.9% P < 0.001), Ki-67 expression (46.4% vs. 61.5% P < 0.001), androgen receptor (AR) expression (68% vs. 50.5% P < 0.001), adjuvant chemotherapy (69% vs. 79.8% P = 0.03). HER2-low BCs had lower histological grade than HER2-0 BCs, with grade I–II (68.7% vs. 43.1%) and grade III (22.2% vs. 43.1%) P < 0.01. No statistical differences were detected between the two groups for DFS and DDFS. Our results demonstrated that HR and AR status was closely related to HER2-low breast cancers. Further exploration about survival prognosis of HER2-low breast cancer is badly needed.
A system for monitoring the functional status of older adults in daily life
Authors: Friedrich Björn , Elgert Lena , Eckhoff Daniel , Bauer Jürgen Martin , Hein Andreas
Published: July 2023

Functional decline in older adults can lead to an increased need of assistance or even moving to a nursing home. Utilising home automation, power and wearable sensors, our system continuously keeps track of the functional status of older adults through monitoring their daily life and allows health care professionals to create individualised rehabilitation programmes based on the changes in the older adult’s functional capacity and performance in daily life. The system uses the taxonomy of the International Classification of Functioning, Disability and Health (ICF) by the World Health Organization (WHO). It links sensor data to five ICF items from three ICF categories and measures their change over time. We collected data from 20 (pre-)frail older adults (aged $$\ge$$
≥
75 years) during a 10-month observational randomised pilot intervention study. The system successfully passed the first pre-clinical validation step on the real-world data of the OTAGO study. Furthermore, an initial test with a medical professional showed that the system is intuitive and can be used to design personalised rehabilitation measures. Since this research is in an early stage further clinical studies are needed to fully validate the system.
Mechanical properties of a bioabsorbable magnesium interference screw for anterior cruciate ligament reconstruction in various testing bone materials
Authors: Siroros Nad , Merfort Ricarda , Liu Yu , Praster Maximilian , Migliorini Filippo , Maffulli Nicola , Michalik Roman , Hildebrand Frank , Eschweiler Jörg
Published: July 2023

Tears of the anterior cruciate ligament (ACL) negatively impact the stability and kinematics of the knee. Interference screws (ISs) are used for graft fixation in ACL reconstruction and provide sufficient fixation strength to withstand the patients' activities during the graft-to-bone integration process. Magnesium is a novel material used to manufacture IS given its strength and bioabsorbability. In previous studies, the selected magnesium IS design showed a better fixation performance in comparison to the conventional IS design due to its shape design and surface condition. In this study, bioabsorbable magnesium ISs were tested for their insertion (insertion torque and a number of turns to implement the IS) and fixation performance (pull-out and dynamic test). To obtain a reliable initial assessment of IS performance, ISs were implanted in 15 per cubic foot (PCF) Sawbones polyurethane foam blocks, Sawbones biomechanical tibia models with 17 PCF foam cores, and human cadaveric tibiae. Porcine tendons were used in the foam block pull-out test, and nylon ropes were used in all other test setups to prevent influences of the ligament graft material itself. In the pull-out test, the graft was subjected to tensile stress at a rate of 6 mm/min. For the dynamic test, 1000 cycles between 0 and 200 N were performed, followed by a final pull-out test. After each test, the tunnel widening pattern was observed by measuring the aspect ratio of the tunnel at the insertion site. The insertion torque lies within the normal insertion torque of the ISs as well as the average ligament tension before the insertion. In the foam block setup, the nylon rope showed a higher pull-out force than the porcine tendon. The comparison of each setup using nylon rope for both pull-out and pull-out after the dynamic test showed no significant difference between the foam block and cadaver setup. However, all tibia model setup shows unexpectedly high pull-out force due to the influence of its cortical layer. There were no statistically significant differences in tunnel widening between foam block-porcine tendon and foam block-nylon rope constructs. The pull-out resistance of magnesium ISs falls within the typical ACL tension range during daily activities. Even though the test results of the magnesium ISs are different in each bone material, the magnesium IS shows adequate fixation ability and workability during insertion without material failure.