bluuebunny/crossref_metadata_2025 huggingface dataset:
Parallel Electron Beams at Io: Numerical Simulations of the Dense Plasma Wake
Authors: Dols V. , Paterson W. R. , Bagenal F.
Published: March 2024

In 1995, the Galileo spacecraft traversed the wake of Io at ∼900 km altitude. The instruments onboard detected intense bi‐directional field‐aligned electron beams (∼140 eV–150 keV), embedded in a dense, cold and slow plasma wake (Nel ∼ 35,000 cm−3, Ti < 10 eV, V < 3 km/s). Similar electron beams were also detected along subsequent Galileo flybys. Using numerical simulations, we show that these electron beams are responsible for the formation of Io's dense plasma wake. We prescribe the composition of Io's atmosphere in S, O, SO and SO2, compute the atmospheric ionization by the beams with a parameterization adapted from study of auroral electrons at Earth, the plasma flow into Io's atmosphere with a Magneto‐Hydro‐Dynamic code, and the ion composition and temperature with a multi‐species physical chemistry code. Results reveal contrasting chemistries between the upstream and wake regions, leading to different ion compositions. The upstream chemistry is driven by the torus thermal electrons at 5 eV with SO2+ becoming the dominant ion because of electron‐impact ionization of the SO2 atmosphere. The wake chemistry is driven by the high‐energy electrons in the beams with S+ and SO+ becoming the dominant ions produced by dissociative‐ionization of SO2. We show that the wake ion composition is highly sensitive to the atmospheric composition. Juno, in its extended mission, will traverse Io's wake and determine its ion composition, which, compared with our numerical simulations will enable us to infer the detailed composition of the atmosphere.
Passive Optical Observation of Mesosphere and Thermosphere Wind Over Three Stations in China
Authors: Wei Yafei , Gu Sheng‐Yang , Li Na , Qin Yusong , Sun Ruidi , Wang Dong , Hu Guoyuan , Le Huijun , Yuan Wei
Published: March 2024

Fabry Perot interferometer (FPI) is an essential ground‐based passive optical observation device to detect middle and upper atmospheric information. Three FPIs are located at Kunming (103.8°E, 25.6°N), Xinglong (117.4°E, 40.2°N), and Mohe (122.3°E, 53.5°N), China. The diurnal and annual variation of night wind at 87, 97, and 250 km are investigated from 2019 to 2021, compared to Horizontal Wind Model 14 (HWM14) to check the prediction accuracy for the local wind field. Our results are as follows: (a) At 87 km, the zonal winds are similar in Kunming and Xinglong, but the meridional winds are generally stronger in Kunming. The zonal and meridional winds in both locations are dominated by semidiurnal variations. (b) At 97 km, the duration of semidiurnal variation of zonal winds and diurnal variation of meridional winds in Kunming is long, which is opposite to that of Xinglong. (c) At 250 km, the wind speed increases with latitude for both zonal and meridional winds, which are both dominated by diurnal variations for all the three sites. Unlike 87 and 97 km, the entire wind field at 250 km is dominated by annual variation, except for a significant semiannual variation at midnight in Mohe. (d) Overall, the HWM14 predictions are stronger than the FPI measurements at peak wind speeds and similar at 87 and 97 km, which surpasses the performance at 250 km. Especially at 250 km, the model results are worse for the zonal winds of Kunming and the meridional winds of Mohe. These results will help to understand the wind field in the middle and upper atmosphere and improve the accuracy of the model.
Record-Breaking Temperatures Likely as El Ni�o Persists
Authors: van Deelen Grace
Published: March 2024

Global surface air temperatures will likely remain high through early summer because of a continuing El Ni�o event.
Challenges in Measuring Aerosol Cloud-Mediated Radiative Forcing
Authors: Rosenfeld Daniel , Kokhanovsky Alexander , Goren Tom , Gryspeerdt Edward , Hasekamp Otto , Jia Hailing , Lopatin Anton , Quaas Johannes , Pan Zengxin , Sourdeval Odran
Published: March 2024

Satellites are required for the global measurement of aerosol cloud-mediated radiative forcing, but satellite retrievals of aerosols and cloud properties still have challenges to overcome.
Intestinal stem cells: guardians of homeostasis in health and aging amid environmental challenges
Authors: Choi Jiahn , Augenlicht Leonard H.
Published: March 2024

The intestinal epithelium is the first line of defense and acts as an interface between the vast microbial world within the gastrointestinal tract and the body’s internal milieu. The intestinal epithelium not only facilitates nutrient absorption but also plays a key role in defending against pathogens and regulating the immune system. Central to maintaining a healthy epithelium are intestinal stem cells (ISCs), which are essential for replenishing the intestinal epithelium throughout an individual’s lifespan. Recent research has unveiled the intricate interplay between ISCs and their niche, which includes various cell types, extracellular components, and signaling molecules. In this review, we delve into the most recent advances in ISC research, with a focus on the roles of ISCs in maintaining mucosal homeostasis and how ISC functionality is influenced by the niche environment. In this review, we explored the regulatory mechanisms that govern ISC behavior, emphasizing the dynamic adaptability of the intestinal epithelium in the face of various challenges. Understanding the intricate regulation of ISCs and the impact of aging and environmental factors is crucial for advancing our knowledge and developing translational approaches. Future studies should investigate the interactive effects of different risk factors on intestinal function and develop strategies for improving the regenerative capacity of the gut.
Portable dielectrophoresis for biology: ADEPT facilitates cell trapping, separation, and interactions
Authors: Julius Lourdes Albina Nirupa , Akgül Dora , Krishnan Gowri , Falk Fabian , Korvink Jan , Badilita Vlad
Published: March 2024

Dielectrophoresis is a powerful and well-established technique that allows label-free, non-invasive manipulation of cells and particles by leveraging their electrical properties. The practical implementation of the associated electronics and user interface in a biology laboratory, however, requires an engineering background, thus hindering the broader adoption of the technique. In order to address these challenges and to bridge the gap between biologists and the engineering skills required for the implementation of DEP platforms, we report here a custom-built, compact, universal electronic platform termed ADEPT (adaptable dielectrophoresis embedded platform tool) for use with a simple microfluidic chip containing six microelectrodes. The versatility of the open-source platform is ensured by a custom-developed graphical user interface that permits simple reconfiguration of the control signals to address a wide-range of specific applications: (i) precision positioning of the single bacterium/cell/particle in the micrometer range; (ii) viability-based separation by achieving a 94% efficiency in separating live and dead yeast; (iii) phenotype-based separation by achieving a 96% efficiency in separating yeast and Bacillus subtilis; (iv) cell–cell interactions by steering a phagocytosis process where a granulocyte engulfs E. coli RGB-S bacterium. Together, the set of experiments and the platform form a complete basis for a wide range of possible applications addressing various biological questions exploiting the plug-and-play design and the intuitive GUI of ADEPT.
Designing patient-oriented combination therapies for acute myeloid leukemia based on efficacy/toxicity integration and bipartite network modeling
Authors: Mirzaie Mehdi , Gholizadeh Elham , Miettinen Juho J. , Ianevski Filipp , Ruokoranta Tanja , Saarela Jani , Manninen Mikko , Miettinen Susanna , Heckman Caroline A. , Jafari Mohieddin
Published: March 2024

Acute myeloid leukemia (AML), a heterogeneous and aggressive blood cancer, does not respond well to single-drug therapy. A combination of drugs is required to effectively treat this disease. Computational models are critical for combination therapy discovery due to the tens of thousands of two-drug combinations, even with approved drugs. While predicting synergistic drugs is the focus of current methods, few consider drug efficacy and potential toxicity, which are crucial for treatment success. To find effective new drug candidates, we constructed a bipartite network using patient-derived tumor samples and drugs. The network is based on drug-response screening and summarizes all treatment response heterogeneity as drug response weights. This bipartite network is then projected onto the drug part, resulting in the drug similarity network. Distinct drug clusters were identified using community detection methods, each targeting different biological processes and pathways as revealed by enrichment and pathway analysis of the drugs’ protein targets. Four drugs with the highest efficacy and lowest toxicity from each cluster were selected and tested for drug sensitivity using cell viability assays on various samples. Results show that ruxolitinib-ulixertinib and sapanisertib-LY3009120 are the most effective combinations with the least toxicity and the best synergistic effect on blast cells. These findings lay the foundation for personalized and successful AML therapies, ultimately leading to the development of drug combinations that can be used alongside standard first-line AML treatment.
Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases
Authors: Qian Lu , Zhu Yanli , Deng Chao , Liang Zhenxing , Chen Junmin , Chen Ying , Wang Xue , Liu Yanqing , Tian Ye , Yang Yang
Published: March 2024

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators of many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, and inflammation. Accumulating evidence has shown that PGC-1s are implicated in many diseases, such as cancers, cardiac diseases and cardiovascular diseases, neurological disorders, kidney diseases, motor system diseases, and metabolic disorders. Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s. Furthermore, discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods. In this review, we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network, discuss the physio-pathological roles of PGC-1s in human diseases, review the application of PGC-1s, including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies, and suggest several directions for future investigations. This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.
A rapid identification method for soft tissue markers of dentofacial deformities based on heatmap regression
Authors: Zhou Guilong , Zhang Yu , Zhao Jinlong , Tian Lei , Jia Guang , Ma Qin
Published: March 2024

Objective

The purpose of this study was to construct a facial deformity dataset and a network model based on heatmap regression for the recognition of facial soft tissue landmarks to provide a basis for clinicians to perform cephalometric analysis of soft tissue.

Materials and methods

A 34-point face marker detection model, the Back High-Resolution Network (BHR-Net), was constructed based on the heatmap regression algorithm, and a custom dataset of 1780 facial detection images for orthognathic surgery was collected. The mean normalized error (MNE) and 10% failure rate (FR10%) were used to evaluate the performance of BHR-Net, and a test set of 50 patients was used to verify the accuracy of the landmarks and their measurement indicators. The test results were subsequently validated in 30 patients.

Results

Both the MNE and FR10% of BHR-Net were optimal compared with other models. In the test set (50 patients), the accuracy of the markers excluding the nose root was 86%, and the accuracy of the remaining markers reached 94%. In the model validation (30 patients), using the markers detected by BHR-Net, the diagnostic accuracy of doctors was 100% for Class II and III deformities, 100% for the oral angle plane, and 70% for maxillofacial asymmetric deformities.

Conclusions

BHR-Net, a network model based on heatmap regression, can be used to effectively identify landmarks in maxillofacial multipose images, providing a reliable way for clinicians to perform cephalometric measurements of soft tissue objectively and quickly.
AIM2 regulates autophagy to mitigate oxidative stress in aged mice with acute liver injury
Authors: Hu Chao , Li Mengjing , Chen Yongzhen , Cheng Wei , Wang Haining , Zhou Yiming , Teng Fengmeng , Ling Tao , Pan Jinshun , Xu Haozhe , Zheng Yanan , Ji Guozhong , Zhao Ting , You Qiang
Published: March 2024

The cytoplasmic pattern recognition receptor, absent in melanoma 2 (AIM2), detects cytosolic DNA, activating the inflammasome and resulting in pro-inflammatory cytokine production and pyroptotic cell death. Recent research has illuminated AIM2’s contributions to PANoptosis and host defense. However, the role of AIM2 in acetaminophen (APAP)-induced hepatoxicity remains enigmatic. In this study, we unveil AIM2’s novel function as a negative regulator in the pathogenesis of APAP-induced liver damage in aged mice, independently of inflammasome activation. AIM2-deficient aged mice exhibited heightened lipid accumulation and hepatic triglycerides in comparison to their wild-type counterparts. Strikingly, AIM2 knockout mice subjected to APAP overdose demonstrated intensified liver injury, compromised mitochondrial stability, exacerbated glutathione depletion, diminished autophagy, and elevated levels of phosphorylated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Furthermore, our investigation revealed AIM2’s mitochondrial localization; its overexpression in mouse hepatocytes amplified autophagy while dampening JNK phosphorylation. Notably, induction of autophagy through rapamycin administration mitigated serum alanine aminotransferase levels and reduced the necrotic liver area in AIM2-deficient aged mice following APAP overdose. Mechanistically, AIM2 deficiency exacerbated APAP-induced acute liver damage and inflammation in aged mice by intensifying oxidative stress and augmenting the phosphorylation of JNK and ERK. Given its regulatory role in autophagy and lipid peroxidation, AIM2 emerges as a promising therapeutic target for age-related acute liver damage treatment.
SOX2 and OCT4 mediate radiation and drug resistance in pancreatic tumor organoids
Authors: Roy Sanjit , Dukic Tijana , Keepers Zachery , Bhandary Binny , Lamichhane Narottam , Molitoris Jason , Ko Young H. , Banerjee Aditi , Shukla Hem D.
Published: March 2024

Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. In patients with unresectable disease, either FOLFIRINOX, a combination of 5-fluorouracil (5-FU), oxaliplatin and irinotecan, or gemcitabine plus nab-paclitaxel combined with radiation are frontline standard regimens. However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) using OCT4 and SOX2, CSC markers in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 μM of 5-FU (5-Fluorouracil), and 100 μM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as a single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and downregulation following 5-FU treatment. The expression of CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and downregulation to 5-FU chemotherapy drug. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT4 expression, indicating CSC self-renewal inhibition. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant OCT4 and SOX2 expression as compared to normal pancreas, indicating their potential role in pancreatic cancer growth and therapy resistance. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the β-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study emphasizes the crucial role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to explore the impact of CSCs in PC and identify new therapeutic targets.
Coculture with macrophages alters ferroptosis susceptibility of triple-negative cancer cells
Authors: Konishi Hiroto , Haga Yuya , Okumura Moe , Tsujino Hirofumi , Higashisaka Kazuma , Tsutsumi Yasuo
Published: March 2024

Various treatment options, such as molecular targeted drugs and immune checkpoint blockades, are available for patients with cancer. However, some cancer types are refractory to molecular targeted therapies or acquire drug resistance after long-term treatment. Thus, ferroptosis, a newly defined type of programmed cell death caused by the iron-dependent accumulation of lipid peroxidation, has gained attention as a novel cancer treatment strategy. Understanding cell–cell interactions in the tumor microenvironment is important for the clinical application of ferroptosis inducers. However, the effects of cell–cell interactions on ferroptosis sensitivity remain unclear. Thus, we aimed to evaluate the effects of macrophage–cancer cell interactions on ferroptosis induction. Coculture experiments showed that conditioned medium prepared from macrophages did not alter the ferroptosis sensitivity of cancer cells. By contrast, coculture via transwell, which enables cell–cell interactions through secretion, increased the sensitivity of cancer cells to ferroptosis inducers. Additionally, direct coculture increased the susceptibility of cancer cells to RSL3-induced ferroptosis. Mechanistically, coculture with macrophages upregulated the levels of intracellular ferrous ions and lipid peroxidation in cancer cells. These findings provide novel insights into the mechanisms by which cell–cell interactions influence ferroptosis induction and application of ferroptosis inducers as a cancer treatment option.
Optimization of an in vitro Pseudomonas aeruginosa Biofilm Model to Examine Antibiotic Pharmacodynamics at the Air-Liquid Interface
Authors: Tan Xing , Huang Yanqin , Rana Amisha , Singh Nidhi , Abbey Taylor C. , Chen Hui , Toth Peter T. , Bulman Zackery P.
Published: March 2024

Pseudomonas aeruginosa is an important cause of lower respiratory tract infections, such as ventilator-associated bacterial pneumonia (VABP). Using inhaled antibiotics to treat VABP can achieve high drug concentrations at the infection site while minimizing systemic toxicities. Despite the theoretical advantages, clinical trials have failed to show a benefit for inhaled antibiotic therapy in treating VABP. A potential reason for this discordance is the presence of biofilm-embedded bacteria in lower respiratory tract infections. Drug selection and dosing are often based on data from bacteria grown planktonically. In the present study, an in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model was optimized to evaluate the activity of simulated epithelial lining fluid exposures of inhaled and intravenous doses of polymyxin B and tobramycin against two P. aeruginosa strains. Antibiotic activity was also determined against the P. aeruginosa strains grown planktonically. Our study revealed that inhaled antibiotic exposures were more active than their intravenous counterparts across biofilm and planktonic populations. Inhaled exposures of polymyxin B and tobramycin exhibited comparable activity against planktonic P. aeruginosa. Although inhaled polymyxin B exposures were initially more active against P. aeruginosa biofilms (through 6 h), tobramycin was more active by the end of the experiment (48 h). Together, these data slightly favor the use of inhaled tobramycin for VABP caused by biofilm-forming P. aeruginosa that are not resistant to either antibiotic. The optimized in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model may be beneficial for the development of novel anti-biofilm agents or to optimize antibiotic dosing for infections such as VABP.
Effects of plasma treatment on biodegradation of natural and synthetic fibers
Authors: Nyssanbek Marzhan , Kuzina Natalya , Kondrashchenko Valery , Azimov Abdugani
Published: March 2024

This study investigates the application of plasma treatment as a means to enhance biodegradation and modify the structural characteristics of fibrous composites. The methodological component of the study includes the selection of the research object; production of composites; low-temperature plasma treatment, and treatment of biodegradability and mechanical strength of samples. The strengthening of fibers with cellulose leads to a significant improvement in mechanical strength. Such an indicator as mechanical strength increases from 18 to 21 MPa. Treatment of natural fibers with low-temperature plasma led to an increase in mechanical strength from 18 to 25 MPa. Treating reinforced fibers with low-temperature plasma currently results in an even greater enhancement in mechanical strength, increasing from 18 to 29 MPa.The electron microscopy of samples reveals some differences in cell wall microfibrils between plasma-treated and non-treated samples. The non-treated fibres are found to have chips and voids. Meantime, the plasma-treated fibres show structural changes in certain regions which resemble wood charring. Through a comprehensive analysis, this research underscores the substantial impact of plasma treatment on the degradation kinetics and morphological features of cellulose-based composites. The results reveal distinct alterations in the composition and behavior of plasma-treated fibres, signifying a shift towards enhanced biodegradability. The natural fibres examined in this study contained 28–30% lignin, whereas the composites exhibited a lower lignin content of 21–23%. These findings corroborate the inference that plasma treatment induces significant changes in fibre structure, accelerating the biodegradation process by 7 days.
Denervation alters the secretome of myofibers and thereby affects muscle stem cell lineage progression and functionality
Authors: Henze Henriette , Hüttner Sören S. , Koch Philipp , Schüler Svenja C. , Groth Marco , von Eyss Björn , von Maltzahn Julia
Published: March 2024

Skeletal muscle function crucially depends on innervation while repair of skeletal muscle relies on resident muscle stem cells (MuSCs). However, it is poorly understood how innervation affects MuSC properties and thereby regeneration of skeletal muscle. Here, we report that loss of innervation causes precocious activation of MuSCs concomitant with the expression of markers of myogenic differentiation. This aberrant activation of MuSCs after loss of innervation is accompanied by profound alterations on the mRNA and protein level. Combination of muscle injury with loss of innervation results in impaired regeneration of skeletal muscle including shifts in myogenic populations concomitant with delayed maturation of regenerating myofibers. We further demonstrate that loss of innervation leads to alterations in myofibers and their secretome, which then affect MuSC behavior. In particular, we identify an increased secretion of Osteopontin and transforming growth factor beta 1 (Tgfb1) by myofibers isolated from mice which had undergone sciatic nerve transection. The altered secretome results in the upregulation of early activating transcription factors, such as Junb, and their target genes in MuSCs. However, the combination of different secreted factors from myofibers after loss of innervation is required to cause the alterations observed in MuSCs after loss of innervation. These data demonstrate that loss of innervation first affects myofibers causing alterations in their secretome which then affect MuSCs underscoring the importance of proper innervation for MuSC functionality and regeneration of skeletal muscle.
Inflammation-suppressing cornea-in-a-syringe with anti-viral GF19 peptide promotes regeneration in HSV-1 infected rabbit corneas
Authors: Simoliunas Egidijus , Ruedas-Torres Inés , Jiménez-Gómez Yolanda , Edin Elle , Aghajanzadeh-Kiyaseh Mozhgan , Zamani-Roudbaraki Mostafa , Asoklis Rimvydas , Alksne Milda , Thathapudi Neethi C. , Poudel Bijay K. , Rinkunaite Ieva , Asoklis Kasparas , Iesmantaite Monika , Ortega-Llamas Laura , Makselis Almantas , Munoz Marcelo , Baltriukiene Daiva , Bukelskiene Virginija , Gómez-Laguna Jaime , González-Andrades Miguel , Griffith May
Published: March 2024

Pathophysiologic inflammation, e.g., from HSV-1 viral infection, can cause tissue destruction resulting in ulceration, perforation, and ultimately blindness. We developed an injectable Cornea-in-a-Syringe (CIS) sealant-filler to treat damaged corneas. CIS comprises linear carboxylated polymers of inflammation-suppressing 2-methacryloyloxyethyl phosphorylcholine, regeneration-promoting collagen-like peptide, and adhesive collagen-citrate glue. We also incorporated GF19, a modified anti-viral host defense peptide that blocked HSV-1 activity in vitro when released from silica nanoparticles (SiNP-GF19). CIS alone suppressed inflammation when tested in a surgically perforated and HSV-1-infected rabbit corneal model, allowing tissue and nerve regeneration. However, at six months post-operation, only regenerated neocorneas previously treated with CIS with SiNP-GF19 had structural and functional features approaching those of normal healthy corneas and were HSV-1 virus-free. We showed that composite injectable biomaterials can be designed to allow regeneration by modulating inflammation and blocking viral activity in an infected tissue. Future iterations could be optimized for clinical application.
Do calcium channel blockers applied to cardiomyocytes cause increased channel expression resulting in reduced efficacy?
Authors: Jæger Karoline Horgmo , Charwat Verena , Wall Samuel , Healy Kevin E. , Tveito Aslak
Published: March 2024

In the initial hours following the application of the calcium channel blocker (CCB) nifedipine to microtissues consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we observe notable variations in the drug’s efficacy. Here, we investigate the possibility that these temporal changes in CCB effects are associated with adaptations in the expression of calcium ion channels in cardiomyocyte membranes. To explore this, we employ a recently developed mathematical model that delineates the regulation of calcium ion channel expression by intracellular calcium concentrations. According to the model, a decline in intracellular calcium levels below a certain target level triggers an upregulation of calcium ion channels. Such an upregulation, if instigated by a CCB, would then counteract the drug’s inhibitory effect on calcium currents. We assess this hypothesis using time-dependent measurements of hiPSC-CMs dynamics and by refining an existing mathematical model of myocyte action potentials incorporating the dynamic nature of the number of calcium ion channels. The revised model forecasts that the CCB-induced reduction in intracellular calcium concentrations leads to a subsequent increase in calcium ion channel expression, thereby attenuating the drug’s overall efficacy. The data and fit models suggest that dynamic changes in cardiac cells in the presence of CCBs may be explainable by induced changes in protein expression, and that this may lead to challenges in understanding calcium based drug effects on the heart unless timings of applications are carefully considered.
Combinatorial selective ER-phagy remodels the ER during neurogenesis
Authors: Hoyer Melissa J. , Capitanio Cristina , Smith Ian R. , Paoli Julia C. , Bieber Anna , Jiang Yizhi , Paulo Joao A. , Gonzalez-Lozano Miguel A. , Baumeister Wolfgang , Wilfling Florian , Schulman Brenda A. , Harper J. Wade
Published: March 2024

The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis to calcium ion flux and inter-organelle communication. A case in point concerns the process of neurogenesis, where a refined tubular ER network is assembled via ER shaping proteins into the newly formed neuronal projections to create highly polarized dendrites and axons. Previous studies have suggested a role for autophagy in ER remodelling, as autophagy-deficient neurons in vivo display axonal ER accumulation within synaptic boutons, and the membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory and autonomic neuropathy. However, our understanding of the mechanisms underlying selective removal of the ER and the role of individual ER-phagy receptors is limited. Here we combine a genetically tractable induced neuron (iNeuron) system for monitoring ER remodelling during in vitro differentiation with proteomic and computational tools to create a quantitative landscape of ER proteome remodelling via selective autophagy. Through analysis of single and combinatorial ER-phagy receptor mutants, we delineate the extent to which each receptor contributes to both the magnitude and selectivity of ER protein clearance. We define specific subsets of ER membrane or lumenal proteins as preferred clients for distinct receptors. Using spatial sensors and flux reporters, we demonstrate receptor-specific autophagic capture of ER in axons, and directly visualize tubular ER membranes within autophagosomes in neuronal projections by cryo-electron tomography. This molecular inventory of ER proteome remodelling and versatile genetic toolkit provide a quantitative framework for understanding the contributions of individual ER-phagy receptors for reshaping ER during cell state transitions.
Graph states of atomic ensembles engineered by photon-mediated entanglement
Authors: Cooper Eric S. , Kunkel Philipp , Periwal Avikar , Schleier-Smith Monika
Published: March 2024

Graph states are a broad family of entangled quantum states, each defined by a graph composed of edges representing the correlations between subsystems. Such states constitute versatile resources for quantum computation and quantum-enhanced measurement. Their generation and engineering require a high level of control over entanglement. Here we report on the generation of continuous-variable graph states of atomic spin ensembles, which form the nodes of the graph. We program the entanglement structure encoded in the graph edges by combining global photon-mediated interactions in an optical cavity with local spin rotations. By tuning the entanglement between two subsystems, we either localize correlations within each subsystem or enable Einstein–Podolsky–Rosen steering—a strong form of entanglement that enables the extraction of precise information from one subsystem through measurements on the other. We further engineer a four-mode square graph state, highlighting the flexibility of our approach. Our method is scalable to larger and more complex graphs, laying groundwork for measurement-based quantum computation and advanced protocols in quantum metrology.
Biosorption of nickel and cadmium using Pachira aquatica Aubl. peel biochar
Authors: Nascimento Talita L. S. , Oliveira Karine F. S. , Junior Joemil O. D. , Pimenta Alexandre S. , Melo Dulce M. A. , Melo Marcus A. F. , Braga Renata M.
Published: March 2024

This study aimed to assess the value of Pachira aquatica Aubl. fruit peels by exploring their applicability in the biosorption process for the removal of Ni(II) and Cd(II) metal ions. The Pachira aquatica Aubl. fruit peel biochar (PAB) was extensively characterized through various techniques, including proximate analysis, helium pycnometer, XRD, SEM, point of zero charge determination, zeta potential measurement, and Boehm titration. Subsequently, kinetic, isotherm, and thermodynamic batch biosorption studies were conducted, followed by column biosorption tests. The characteristics of PAB, including low moisture content, a neutral point of zero charge, porosity, an irregular and heterogeneous structure, a negatively charged surface, and the presence of functional groups, indicate its remarkable capacity for efficiently binding with heavy metals. Biosorption equilibrium time was achieved at 300 min for both ions, fitting well with a pseudo second-order kinetic model and Langmuir isotherm model. These data suggest that the biosorption process occurred chemically in monolayer. The column C presented an exhaust volume of 1200 mL for Ni(II) and 1080 for Cd(II) and removal of 98% and 99% of removal for Ni(II) and Cd(II), respectively. In summary, PAB demonstrates substantial potential as a biosorbent for effectively removing heavy metals, making a valuable contribution to the valorization of this co-product and the mitigation of environmental pollution.
Evolution mechanism of water-conducting fractures in overburden under the influence of water-rich fault in underground coal mining
Authors: Zhengzheng Cao , Xiangqian Yang , Zhenhua Li , Feng Du
Published: March 2024

Based on the 7618 working face in Yaoqiao coal mine of Datun mining area, the activation mechanism of water-rich faults and the development characteristics of water-conducting fractures in overlying strata under the influence of faults are studied by theoretical analysis, numerical simulation and field measurement in this paper. The research results show that Anderson model and Mohr–Coulomb strength criterion are combined to establish the fault failure mechanical model, and the fault activation criterion under the influence of mining is obtained. FLAC3D numerical simulation results show that with the advance of the working face, the fault begins to be affected by the mining effect of the working face at the distance of 20 ~ 30 m from the fault. Meanwhile, with the advance of the working face, the overburden shear failure range also expands, and the fault fracture gradually expands from top to bottom. The failure zone of the working face roof is connected with the fault fracture zone. Then the fault is "activated" and causes the fault to become a water gushing channel, and finally the water gushing disaster occurs. Through numerical simulation and comparative analysis, the development height of water-conducting fracture is 73.2 m in the absence of fault, and 73.7 m in the presence of fault, indicating that the fault has little influence on the maximum development height of water-conducting fracture. The actual development height of the water-conducting fracture zone in the 7618 working face is 73.97 m and the fracture production ratio is 13.7. The research results can provide theoretical reference for the safe mining of similar working faces across faults.
Glucose values from the same continuous glucose monitoring sensor significantly differ among readers with different generations of algorithm
Authors: Babaya Naru , Noso Shinsuke , Hiromine Yoshihisa , Taketomo Yasunori , Niwano Fumimaru , Yoshida Sawa , Yasutake Sara , Kawabata Yumiko , Maeda Norikazu , Ikegami Hiroshi
Published: March 2024

Continuous glucose monitoring (CGM) values obtained from CGM systems using the same sensor but with different internal algorithms (the first- and third-generation FreeStyle Libre (1st-gen-libre and 3rd-gen-libre, respectively)) were compared. We used 19,819 paired and simultaneously measured CGM values of 13 patients with diabetes. The average CGM value was significantly higher (P < 0.0001) and the time below range (CGM value < 70 mg/dL) was significantly lower (P < 0.0001) with the 3rd-gen-libre than with the 1st-gen-libre. There was a significant correlation (P < 0.0001) between the CGM values of the 3rd-gen-libre (y-axis, mg/dL) and 1st-gen-libre (x-axis, mg/dL) using the following formula: y = 0.9728x + 10.024. On assessing the association between glycated hemoglobin (HbA1c (%), y-axis) and the average CGM values (x-axis, mg/dL) by applying the obtained equation to previously reported 1st-gen-libre data and converting it to 3rd-gen-libre data, we obtained the equation y = 0.02628x + 3.233, indicating that the glucose management indicator reported in the West may be underestimated compared with the laboratory-measured HbA1c in the Japanese population. Glucose values from the same sensor were found to be significantly different between readers with different algorithms, and the calculation of CGM-related indices may need to be individualized for each device.
Risk factors for Echinococcus multilocularis intestinal infections in owned domestic dogs in a North American metropolis (Calgary, Alberta)
Authors: Toews Emilie , Musiani Marco , Smith Anya , Checkley Sylvia , Visscher Darcy , Massolo Alessandro
Published: March 2024

Human alveolar echinococcosis is increasingly documented in Alberta, Canada. Its causative agent, Echinococcus multilocularis (Em), can be transmitted to humans by infected dogs. We assessed the prevalence and associated risk factors for Em infections in domestic dogs in Calgary, Alberta, Canada. In this cross-sectional study that coupled collection and assessment of dog feces with a survey on potential risk factors, 13 of 696 (Bayesian true prevalence, 2.4%; 95% CrI: 1.3–4.0%) individual dogs’ feces collected during August and September 2012 were qPCR positive for Em. Sequencing two of these cases indicated that both were from the same Em European strain responsible for human infections in Alberta. Likelihood of intestinal Em was 5.6-times higher in hounds than other breeds, 4.6-times higher in dogs leashed at dog parks than those allowed off-leash, 3.1-times higher in dogs often kept in the backyard during spring and summer months than those rarely in the yard, and 3.3-times higher in dogs living in neighbourhoods bordering Bowmont park than those in other areas of Calgary. This situation warrants surveillance of dog infections as a preventative measure to reduce infections in North America.
A novel difficult-to-segment samples focusing network for oral CBCT image segmentation
Authors: Hu Fengjun , Chen Zeyu , Wu Fan
Published: March 2024

Using deep learning technology to segment oral CBCT images for clinical diagnosis and treatment is one of the important research directions in the field of clinical dentistry. However, the blurred contour and the scale difference limit the segmentation accuracy of the crown edge and the root part of the current methods, making these regions become difficult-to-segment samples in the oral CBCT segmentation task. Aiming at the above problems, this work proposed a Difficult-to-Segment Focus Network (DSFNet) for segmenting oral CBCT images. The network utilizes a Feature Capturing Module (FCM) to efficiently capture local and long-range features, enhancing the feature extraction performance. Additionally, a Multi-Scale Feature Fusion Module (MFFM) is employed to merge multiscale feature information. To further improve the loss ratio for difficult-to-segment samples, a hybrid loss function is proposed, combining Focal Loss and Dice Loss. By utilizing the hybrid loss function, DSFNet achieves 91.85% Dice Similarity Coefficient (DSC) and 0.216 mm Average Symmetric Surface Distance (ASSD) performance in oral CBCT segmentation tasks. Experimental results show that the proposed method is superior to current dental CBCT image segmentation techniques and has real-world applicability.
An integrated model of the human cornea as a linear biaxial birefringent medium
Authors: Sobczak Marcelina , Jóźwik Agnieszka , Kurzynowski Piotr
Published: March 2024

A novel model of human corneal birefringence is presented. The cornea is treated as a homogeneous biaxial linear birefringent medium in which the values of the binormal axes angle and organization of the main refractive indices vary continuously from the apex to the limbus. In its central part, the angle between binormal axes is 35°, and para centrally, it smoothly increases to 83.7°. The values of the main refractive indices (nx, ny, nz) change, as well as their order, from nx < nz < ny to nz < nx < ny. The transition between these two states was described with a normal distribution (μ = 0.45, σ = 0.1). The presented model corresponds with the experimental results presented in the literature. To our knowledge, it is the first model that presents the anisotropic properties’ distributions of the entire cornea. The presented model facilitates a better understanding of the corneal birefringence phenomenon directly related to its lamellar structure.
A case study on the early stage of Pinus nigra invasion and its impact on species composition and pattern in Pannonic sand grassland
Authors: Bakacsy László , Szepesi Ágnes
Published: March 2024

Alien woody species are successful invaders, frequently used for afforestation in regions like semi-arid lands. Shrubs and trees create important microhabitats in arid areas. Understorey vegetation in these habitats has unique species composition and coexistence. However, the impact of solitary woody species on understorey vegetation is less understood. This study evaluated the effect of native (Juniperus communis) and invasive solitary conifers (Pinus nigra) on surrounding vegetation, where individuals were relatively isolated (referred to as solitary conifers). The field study conducted in Pannonic dry sand grassland in 2018 recorded plant and lichen species presence around six selected solitary conifers. Composition and pattern of understorey vegetation were assessed using 26 m belt transects with 520 units of 5 cm × 5 cm contiguous microquadrats. Compositional diversity (CD) and the number of realized species combinations (NRC) were calculated from the circular transects. Results showed native conifer J. communis created more complex, organized microhabitats compared to alien P. nigra. CD and NRC values were significantly higher under native conifers than invasive ones (p = 0.045 and p = 0.026, respectively). Native species also had more species with a homogeneous pattern than the alien species. Alien conifers negatively affected understorey vegetation composition and pattern: some species exhibited significant gaps and clusters of occurrences along the transects under P. nigra. Based on our study, the removal of invasive woody species is necessary to sustain habitat diversity.
The subseasonal predictability of the western North Pacific subtropical high and the 2020 record-breaking event
Authors: Tseng Kai-Chih , Ho Yun-Hsuan
Published: March 2024

The western North Pacific subtropical high (WNPSH), a prominent feature in the North Pacific during the boreal summer, exerts significant socioeconomic consequences by influencing hydrological extremes such as tropical cyclones, the Meiyu front, and summer heat waves over East Asia. Accurately forecasting the characteristics of the WNPSH over extended timescales is crucial, but subseasonal prediction in this specific context is still in its early stages due to the complex dynamics involved. In this study, we investigate the optimal predictable pattern of the WNPSH using linear stochastic dynamics. Our findings reveal that convection over the Philippine/South China Sea and Japan serves as key precursors, where a dipole vorticity pattern leads to maximum growth of the WNPSH on subseasonal timescales, providing a potential source of predictability. Additionally, we examine the role of optimal predictable patterns in the record-breaking 2020 WNPSH event, and we find that the cumulative effect of stochastic forcing helps explain the sustained features of this extreme case.
Germline determinants of aberrant signaling pathways in cancer
Authors: Dalfovo Davide , Scandino Riccardo , Paoli Marta , Valentini Samuel , Romanel Alessandro
Published: March 2024

Cancer is a complex disease influenced by a heterogeneous landscape of both germline genetic variants and somatic aberrations. While there is growing evidence suggesting an interplay between germline and somatic variants, and a substantial number of somatic aberrations in specific pathways are now recognized as hallmarks in many well-known forms of cancer, the interaction landscape between germline variants and the aberration of those pathways in cancer remains largely unexplored. Utilizing over 8500 human samples across 33 cancer types characterized by TCGA and considering binary traits defined using a large collection of somatic aberration profiles across ten well-known oncogenic signaling pathways, we conducted a series of GWAS and identified genome-wide and suggestive associations involving 276 SNPs. Among these, 94 SNPs revealed cis-eQTL links with cancer-related genes or with genes functionally correlated with the corresponding traits’ oncogenic pathways. GWAS summary statistics for all tested traits were then used to construct a set of polygenic scores employing a customized computational strategy. Polygenic scores for 24 traits demonstrated significant performance and were validated using data from PCAWG and CCLE datasets. These scores showed prognostic value for clinical variables and exhibited significant effectiveness in classifying patients into specific cancer subtypes or stratifying patients with cancer-specific aggressive phenotypes. Overall, we demonstrate that germline genetics can describe patients’ genetic liability to develop specific cancer molecular and clinical profiles.
Phosphorylation regulates tau’s phase separation behavior and interactions with chromatin
Authors: Abasi Lannah S. , Elathram Nesreen , Movva Manasi , Deep Amar , Corbett Kevin D. , Debelouchina Galia T.
Published: March 2024

Tau is a microtubule-associated protein often found in neurofibrillary tangles (NFTs) in the brains of patients with Alzheimer’s disease. Beyond this context, mounting evidence suggests that tau localizes into the nucleus, where it may play a role in DNA protection and heterochromatin regulation. The molecular mechanisms behind these observations are currently unclear. Using in vitro biophysical experiments, here we demonstrate that tau can undergo liquid-liquid phase separation (LLPS) with DNA, mononucleosomes, and reconstituted nucleosome arrays under low salt conditions. Low concentrations of tau promote chromatin compaction and protect DNA from digestion. While the material state of samples at physiological salt is dominated by chromatin oligomerization, tau can still associate strongly and reversibly with nucleosome arrays. These properties are driven by tau’s strong interactions with linker and nucleosomal DNA. In addition, tau co-localizes into droplets formed by nucleosome arrays and phosphorylated HP1α, a key heterochromatin constituent thought to function through an LLPS mechanism. Importantly, LLPS and chromatin interactions are disrupted by aberrant tau hyperphosphorylation. These biophysical properties suggest that tau may directly impact DNA and chromatin accessibility and that loss of these interactions could contribute to the aberrant nuclear effects seen in tau pathology.