bluuebunny/crossref_metadata_2025 huggingface dataset:
Probiotics Attenuate Myopathic Changes in Aging Rats via Activation of the Myogenic Stellate Cells
Authors: Abdel-Halim Nehal H. M. , Farrag Eman A. E. , Hammad Maha O. , Habotta Ola Ali , Hassan Hend M.
Published: December 2023

Aging represents a complex biological process associated with decline in skeletal muscle functions. Aging impairs satellite cells that serve as muscle progenitor cells. Probiotic supplementation may have many beneficial effects via various mechanisms. We examined the possible effects of probiotics in stimulating the proliferation of myogenic stellate cells in aging rats. Twenty-four male albino Sprague–Dawley rats were classified equally into four groups: adult control, old control, adult + probiotics, and old + probiotics. Probiotics (Lactobacillus LB) were administered gavage at a dose of 1 ml (1 × 109 CFU/ml/day) for 4 weeks. A significant increase in the relative gastrocnemius weight ratio and improvement of contractile parameters was detected in the old + probiotics group (0.6 ± 0.01) compared to the old control group (0.47 ± 0.01; P < 0.001). Probiotics significantly upregulated the activities of GSH, while NO and MDA were markedly decreased compared to control groups (P ≤ 0.001). Also, probiotics increased the mRNA and protein expressions of myogenin and CD34 (P < 0.05) as determined by real-time PCR and immunohistochemistry. Moreover, the old + probiotics group showed apparent restoration of the connective tissue spaces, reflecting the all-beneficial effects of probiotics. Our findings indicated that probiotics attenuated myopathic changes in aging rats probably through activation of the myogenic stellate cells. Probiotics improved the muscle weight, function, antioxidant activity, and myogenic transcription factors of the skeletal muscle.
Understanding the fixed pitch RPM-controlled rotor modeling for the conceptual design of UAM vehicles
Authors: Atci Kagan , Weiand Peter , Guner Feyyaz
Published: December 2023

Most of the introduced eVTOL models in the UAM market utilize electrically driven rotors with fixed pitch blades, controlled by their rotational speed. This design approach brings new features and challenges that need to be considered during the conceptual design stage, taking new aspects into account, among them the rotor dynamic response. This paper presents an initial parameterization of the rpm-controlled rotors along with the electric motor, based on the conducted literature research. Several isolated rotor variants are modeled and analyzed in terms of performance, and the dynamic response of the rotor rotational speed. The relations between aerodynamics and inertia are discussed, and their effects on the rotor dynamic response are elaborated on.
The Moral Significance of Privacy Dependencies
Authors: Munch Lauritz Aastrup , Mainz Jakob Thrane
Published: December 2023

Often, when we share information about ourselves, we contribute to people learning personal things about others. This may happen because what we share about ourselves can be used to infer personal information about others. Such dependencies have become known as privacy dependencies in the literature. It is sometimes claimed that the scope of the right to privacy should be expanded in light of such dependencies. For example, some have argued that inferring information about others can violate their right to privacy. Others have argued that sharing personal information about yourself that license such inferences can by itself violate the right to privacy. In this paper, we argue that the latter view should be rejected.
A first look back: model performance under Solvency II
Authors: Korn Ralf , Stahl Gerhard
Published: December 2023

We consider an empirical backtesting for the Solvency Capital Required (SCR) under Solvency II. Based on empirical facts that the Basic own Funds (BoF) can be assumed to evolve log-normally and have a much lower volatility than the corresponding equity for our test data, we make a proposal based on Earnings at Risk (EaR) that can be used to reduce the biases from overshooting SCR estimates in a prudential way.
Towards Full Thickness Small Intestinal Models: Incorporation of Stromal Cells
Authors: Asal Melis , Rep Mila , Bontkes Hetty J. , van Vliet Sandra J. , Mebius Reina E. , Gibbs Susan
Published: December 2023

Introduction

Since small intestine is one of the major barriers of the human body, there is a need to develop reliable in vitro human small intestinal models. These models should incorporate both the epithelial and lamina propria compartments and have similar barrier properties compared to that of the human tissue. These properties are essential for various applications, such as studying cell–cell interaction, intestinal diseases and testing permeability and metabolism of drugs and other compounds. The small intestinal lamina propria contains multiple stromal cell populations with several important functions, such as secretion of extracellular matrix proteins and soluble mediators. In addition, stromal cells influence the intestinal epithelial barrier, support the intestinal stem cell niche and interact with immune cells.

Methods

In this review, we provide an extensive overview on the different types of lamina propria stromal cells found in small intestine and describe a combination of molecular markers that can be used to distinguish each different stromal cell type. We focus on studies that incorporated stromal cells into human representative small intestine models cultured on transwells.

Results and Conclusion

These models display enhanced epithelial morphology, increased cell proliferation and human-like barrier properties, such as low transepithelial electrical resistance (TEER) and intermediate permeability, thus better mimicking the native human small intestine than models only consisting of an epithelium which generally show high TEER and low permeability.
Integrating knowledge representation into traffic prediction: a spatial–temporal graph neural network with adaptive fusion features
Authors: Zhou Yi , Liu Yihan , Ning Nianwen , Wang Li , Zhang Zixing , Gao Xiaozhi , Lu Ning
Published: December 2023

Various external factors that interfere with traffic flow, such as weather conditions, traffic accidents, incidents, and Points of Interest (POIs), need to be considered in performing traffic forecasting tasks. However, the current research methods encounter difficulties in effectively incorporating these factors with traffic characteristics and efficiently updating them, which leads to a lack of dynamics and interpretability. Moreover, capturing temporal dependence and spatial dependence separately and sequentially can result in issues, such as information loss and model errors. To address these challenges, we present a Knowledge Representation learning-actuated spatial–temporal graph neural network (KR-STGNN) for traffic flow prediction. We combine the knowledge embedding with the traffic features via Gated Feature Fusion Module (GFFM), and dynamically update the traffic features adaptively according to the importance of external factors. To conduct the co-capture of spatial–temporal dependencies, we subsequently propose a spatial–temporal feature synchronous capture module (ST-FSCM) combining dilation causal convolution with GRU. Experimental results on a real-world traffic data set demonstrate that KR-STGNN has superior forecasting performances over diverse prediction horizons, especially for short-term prediction. The ablation and perturbation analysis experiments further validate the effectiveness and robustness of the designed method.
Log concavity for unimodal sequences
Authors: Bridges Walter , Bringmann Kathrin
Published: December 2023

In this paper, we prove that the number of unimodal sequences of size n is log-concave. These are coefficients of a mixed false modular form and have a Rademacher-type exact formula due to recent work of the second author and Nazaroglu on false theta functions. Log-concavity and higher Turán inequalities have been well-studied for (restricted) partitions and coefficients of weakly holomorphic modular forms, and analytic proofs generally require precise asymptotic series with error term. In this paper, we proceed from the exact formula for unimodal sequences to carry out this calculation. We expect our method applies to other exact formulas for coefficients of mixed mock/false modular objects.
Allelopathic Potential of Aqueous Extracts and Essential Oils of Rosmarinus officinalis L. and Thymus vulgaris L
Authors: Elghobashy Roufaida M. , El-Darier Salama M. , Atia Adel M. , Zakaria Mohamed
Published: December 2023

Allelopathic effects of essential oils and aqueous extracts from Rosmarinus officinalis (rosemary) and Thymus vulgaris (thyme) have been investigated as a source of new natural herbicidal compounds to suppress two weeds: Chenopodium album and Echinochloa crus-galli associated with two important economic crops, Triticum aestivum (wheat) and Oryza sativa (rice), respectively. A petri-dish experiment was performed, and 10, 20, 50, and 100% aqueous solutions, and doses of 0, 2, 4, 8, and 16 µL of essential oil per petri dish were applied. The number of germinated seeds in each Petri dish was counted daily. After 15 days, germination percentage, the coefficient of velocity of germination, speed of germination, germination energy, germination index, mean germination time, seedling shoot length, root length, shoot–root ratio, and seedling vigour index were recorded. The chemical profiles of both essential oils were identified with GC–MS analysis. Eucalyptol (1,8-cineole), α-pinene, and camphor were identified as the dominant constituents of the rosemary essential oil. The major components detected in thyme essential oil were thymol, o-cymene, caryophyllene, and gamma-terpinene. The results showed that thyme essential oils had the most negative effect by inhibiting the germination of weeds. Both rosemary and thyme essential oils had a generally reducing effect on the growth parameters of weeds. The essential oils of rosemary and thyme have allelopathic potential and should be assessed as allelopathic agents to be used for weed control.
Increased Expression of Neprilysin Is Associated with Inflammation in Preeclampsia
Authors: Atta Sara , Mekky Rehab , Ibrahim Mostafa , Abdallah Mohamed M. , Elbaz Mona A. H. , Radwan Eman
Published: December 2023

Preeclampsia (PE) is associated with a finely tuned equilibrium between trophoblast cell invasion and fetal-maternal immunological tolerance. An imbalance between proinflammatory (IL-6) and anti-inflammatory (IL-10) cytokines is a hallmark of PE. Neprilysin (NEP), a membrane-bound metalloprotease, is vulnerable to the inflammatory environment and plays a significant role in modulating vascular tone. The aim of this study was to determine the correlation between NEP (mRNA and protein) levels and the inflammatory status in PE patients compared to healthy pregnant women and to identify the role of NEP in evaluating the severity of preeclampsia. The study group comprised 52 pregnant women with PE while the control group comprised 47 normotensive pregnant women. After a caesarean section, placental tissue samples from patients and controls were collected to measure the expression levels of IL-6, TGF-β, IL-10, and NEP mRNA. In addition, an enzyme-linked immunosorbent assay was used to assess the quantity of NEP protein in blood samples. Our results revealed a significant positive correlation between NEP (mRNA and protein) and proinflammatory markers IL-6 and TGF-β levels in patients compared to controls and a significant inverse correlation between NEP and anti-inflammatory cytokine IL-10. Moreover, this is the first study to find a strong positive correlation between NEP level and PE severity. In conclusion, in PE patients, there is a substantial relationship between NEP, the degree of inflammation, and PE severity. NEP could act as a potential biomarker for diagnosis and prognosis of PE.
Deep learning-based approach for forecasting intermittent online sales
Authors: Ahmadov Yashar , Helo Petri
Published: December 2023

Deep Neural Networks (DNN’s) present some of the leading applications of Artificial Intelligence (AI) which have proven suitability on various machine-learning use cases. Forecasting demand of intermittent on-line sales is a task which needs to be carried out automatically for a large number of Stock Keeping Units (SKU’s). This paper discusses the intermittent online sales and proposes an AI-based model for forecasting demand. We provide empirical evidence by utilizing data from 17 different sellers with approximately 3000 orders in total. Our findings indicate that thanks to their multi-layered learning structure, the DNN’s can provide up to 35% better accuracy than the classic models such as Moving Average, Exponential Smoothing, Croston’s method and ARIMA. Also, it was revealed that the time between orders’ arrivals follow Exponential distribution and the order sizes also generally follow Exponential distribution. Thus, most of the time, Poisson Exponential distribution can be used for modelling intermittent sales process through online platforms. The analyses show that Poisson Exponential distribution can generate values close to real sales with less than 7% error margin with real data.
Architecture design of a vehicle–road-cloud collaborative automated driving system
Authors: Ran Bin , Zheng Yuan , Luo Kaijie , Ma Haozhan , Rui Yikang , Li Linheng , Li Xiaolong , Hu Jinling , Hu Yanming
Published: December 2023

Transportation systems serve as a crucial foundation for maintaining the normal operation of cities and satisfying the requirements of public life. With the development of next-generation information technologies, automated driving technologies have brought new opportunities to improve the performance of traffic systems and the intelligence level of cities. Currently, significant research efforts have been conducted to develop automated driving systems in three major industries, i.e., automobile, roadway, and telecommunication. However, the collaboration and integration of automated driving systems among automobile, roadway, and telecommunications are still lacking, especially for collaborative development of system architecture and objectives. To address the need, this study first proposes a system architecture of vehicle–road-cloud collaborative automated driving system (VRC-CADS). Three levels of collaborative development, i.e., collaborative sensing, collaborative decision-making, and collaborative control, are designed for the VRC-CADS. Based on that, the typical scenarios of automated driving for each level of the system are further defined and interpreted. Moreover, feasible and systematic suggestions for the collaborative development of the VRC-CADS are provided, considering the cross-cutting collaboration among government agencies, academia, and industry. The proposed system architecture of the VRC-CADS will facilitate the optimization of urban lifelines and the evolution of intelligent cities.
Inertial migration of a sphere in plane Couette flow
Authors: Anand Prateek , Subramanian Ganesh
Published: December 2023

We study the inertial migration of a torque-free neutrally buoyant sphere in wall-bounded plane Couette flow over a wide range of channel Reynolds numbers$Re_c$in the limit of small particle Reynolds number ($Re_p\ll 1$) and confinement ratio ($\lambda \ll 1$). Here,$Re_c = V_{wall}H/\nu$, where$H$denotes the separation between the channel walls,$V_\text {wall}$denotes the speed of the moving wall, and$\nu$is the kinematic viscosity of the Newtonian suspending fluid. Also,$\lambda = a/H$, where$a$is the sphere radius, with$Re_p=\lambda ^2 Re_c$. The channel centreline is found to be the only (stable) equilibrium below a critical$Re_c$($\approx 148$), consistent with the predictions of earlier small-$Re_c$analyses. A supercritical pitchfork bifurcation at the critical$Re_c$creates a pair of stable off-centre equilibria, located symmetrically with respect to the centreline, with the original centreline equilibrium becoming unstable simultaneously. The new equilibria migrate wall-ward with increasing$Re_c$. In contrast to the inference based on recent computations, the aforementioned bifurcation occurs for arbitrarily small$Re_p$provided that$\lambda$is sufficiently small. An analogous bifurcation occurs in the two-dimensional scenario, that is, for a circular cylinder suspended freely in plane Couette flow, with the critical$Re_c$being approximately$110$.
Developmental interactions between peer victimization and depressive symptoms in adolescents: A latent change score analysis
Authors: Wang Chenxu , Xin Guogang , Zhang Libin , Liu Haidong , Yang Yang , Zhang Yunyun
Published: December 2023

Peer victimization and depressive symptoms are highly relevant risks during adolescence. Understanding the dynamic patterns of interactions between peer victimization and depressive symptoms as well as gender differences in these variables can improve intervention strategies for adolescents navigating this critical transition period. In the present study, a large sample of Chinese adolescents reported peer victimization and depressive symptoms in four survey waves at six-month intervals. A total of 2534 adolescents (51.9% boys, M = 12.98 ± 0.60 years) were included in the latent change score (LCS) analysis. The results supported the reciprocal effects model obtained in the full sample. Changes in peer victimization were influenced by prior changes in depressive symptoms over time, and changes in depressive symptoms were influenced by prior levels of peer victimization. There were also gender differences, with boys exhibiting depressive symptom-driven effects on peer victimization, while girls exhibiting peer victimization-induced depressive symptoms. The dynamic relationships between peer victimization and depressive symptoms that promote and constrain each other in adolescents are elucidated in this study. Differentiating effects on boys and girls is crucial for enhancing the effectiveness of practical interventions.
Giant Planets May Be “Agents of Chaos”
Authors: Benningfield Damond
Published: December 2023

Two studies suggest that some giants could make it difficult or even impossible for terrestrial planets to remain in a star’s habitable zone.
When Forests on Land Burn, Forests Underwater Feel the Impact
Authors: Besl J.
Published: December 2023

Kelp is a habitat, a carbon sink, and a binding agent in your ice cream. But new research shows that California’s kelp forests are affected by the fate of their counterparts on land.
Quantifying Diapir Ascent Velocities in Power‐Law Viscous Rock Under Far‐Field Stress: Integrating Analytical Estimates, 3D Numerical Calculations and Geodynamic Applications
Authors: Macherel Emilie , Podladchikov Yuri , Räss Ludovic , Schmalholz Stefan M.
Published: December 2023

Diapirism is crucial for heat and mass transfer in many geodynamic processes. Understanding diapir ascent velocity is vital for assessing its significance in various geodynamic settings. Although analytical estimates exist for ascent velocities of diapirs in power‐law viscous, stress weakening fluids, they lack validation through 3D numerical calculations. Here, we improve these estimates by incorporating combined linear and power‐law viscous flow and validate them using 3D numerical calculations. We focus on a weak, buoyant sphere in a stress weakening fluid subjected to far‐field horizontal simple shear. The ascent velocity depends on two stress ratios: (a) the ratio of buoyancy stress to characteristic stress, controlling the transition from linear to power‐law viscous flow, and (b) the ratio of regional stress associated with far‐field shearing to characteristic stress. Comparing analytical estimates with numerical calculations, we find analytical estimates are accurate within a factor of two. However, discrepancies arise due to the analytical assumption that deviatoric stresses around the diapir are comparable to buoyancy stresses. Numerical results reveal significantly smaller deviatoric stresses. As deviatoric stresses govern stress‐dependent, power‐law viscosity, analytical estimates tend to overestimate stress weakening. We introduce a shape factor to improve accuracy. Additionally, we determine characteristic stresses for representative mantle and lower crustal flow laws and discuss practical implications in natural diapirism, such as sediment diapirs in subduction zones, magmatic plutons or exhumation of ultra‐high‐pressure rocks. Our study enhances understanding of diapir ascent velocities and associated stress conditions, contributing to a thorough comprehension of diapiric processes in geology.
Compound Dry and Wet Extremes Lead to an Increased Risk of Rice Yield Loss
Authors: Chen Huijiao , Wang Shuo
Published: December 2023

Extreme dry and wet events can result in significant crop yield losses. However, the impact of consecutive occurrence of dry and wet extremes on crop yield remains unclear. Here, we investigate the hotspots of compound dry and wet (CDW) extremes across global rice croplands and their impacts on rice yield. We identify a significant increasing trend in the frequency of CDW extremes during 1981–2016. The risk of yield loss caused by CDW extremes can be twice as high as the risk from individual wet and dry extremes. Furthermore, we find that global rice croplands face a 43% higher risk of rice yield loss due to dry‐to‐wet extremes compared to wet‐to‐dry extremes. Our findings provide new insights into the sustainability of global rice production and food security in the face of compound hydrological extremes.
Observational Evidence of Unknown NOx Source and Its Perturbation of Oxidative Capacity in Bermuda's Marine Boundary Layer
Authors: Wang Youfeng , Zhu Yuting , Ye Chunxiang , Zhou Xianliang , Elshorbany Yasin , Hayden Matthew , Peters Andrew J.
Published: December 2023

Nitrogen oxides (NOx) are key intermediates in the atmospheric cycling of reactive nitrogen, the spatiotemporal distribution of which modulates ozone (O3) production. Field campaigns were conducted at the Tudor Hill Marine Atmospheric Observatory, Bermuda, in the spring and summer of 2019 to explore atmospheric cycling of NOx and its modulation of photochemical O3 production in the marine boundary layer. In aged, clean marine air, an atypical NO2 diel profile with a solar noon peak of 69 ± 5 pptv was recorded, challenging the classic U‐shaped diel profile with a solar noon valley characterized by fast photolysis and oxidation consumption in the daytime. This result indicated an unknown daytime NOx source excluded from the current near‐explicit chemical model, which underestimated the solar noon NOx level by 20–56 pptv and source rate by 9.7–33.5 pptv hr−1, considering the upper and lower limits of total OH reactivity and halogen photochemistry in the marine boundary layer. The observed HONO level accounted for ∼56% of the unknown NOx source, implying an unknown NOx regeneration pathway with HONO as an intermediate. The photochemical nature of the unknown NOx source maximized perturbation of photochemical OH and O3 production. The O3 abundance and production rate were underestimated by 2–4 ppbv and 28%–80%, respectively, and the OH abundance and source rate were 7%–55% and 21%–57% lower than the estimated levels with the constraint of NOx, respectively. The unknown NOx source requires urgent revision of the current understanding of reactive nitrogen cycling and the oxidative capacity of the clean marine atmosphere.
Mango‐GPP: A Process‐Based Model for Simulating Gross Primary Productivity of Mangrove Ecosystems
Authors: Tang Yuqi , Li Tingting , Yang Xiu‐Qun , Chao Qingchen , Wang Chunlin , Lai Derrick Y. F. , Liu Jiangong , Zhu Xudong , Zhao Xiaosong , Fan Xingwang , Zhang Yiping , Hu Qiwen , Qin Zhangcai
Published: December 2023

Mangrove ecosystems are becoming increasingly important in global climate mitigation. However, large gaps still exist in evaluating mangroves' gross primary productivity (GPP) due to reasons such as the specific influences, for example, temperature and salt stresses are poorly described in Earth System Models (ESMs). This study developed a process‐based biogeochemical model (Mango‐GPP) to improve the GPP simulation in natural and restored mangroves. The model integrates mangrove‐specific physiological processes, including the response to salt and temperature stresses, as well as the light‐use efficiency at different growing stages. Eddy covariance flux measurements at two natural sites and one restored site in China were used to calibrate and validate Mango‐GPP. The model was calibrated by inverse analysis approach based on two cases and independently validated against the other cases. The validation results showed that it was generally capable of simulating the seasonal and interannual GPP variations at different sites. The simulated daily and annual GPPs agreed well with the observations and yielded R2 of 0.67 and 0.96, with model efficiency of 0.64 and 0.93, respectively. In comparison, Mango‐GPP showed better performances than many current satellite‐based GPP products and ESMs. The model was more sensitive to solar radiation, carbon dioxide concentration, and leaf traits. Future improvements should focus on enhancing Mango‐GPP's descriptive power of key processes, and further simulating other carbon fluxes at regional scales. This work provides a model foundation for further simulating carbon exchanges between the atmosphere, mangrove, and ocean for studying the coastal wetland restoration on regional carbon neutrality.
Advances in high-performance MEMS pressure sensors: design, fabrication, and packaging
Authors: Han Xiangguang , Huang Mimi , Wu Zutang , Gao Yi , Xia Yong , Yang Ping , Fan Shu , Lu Xuhao , Yang Xiaokai , Liang Lin , Su Wenbi , Wang Lu , Cui Zeyu , Zhao Yihe , Li Zhikang , Zhao Libo , Jiang Zhuangde
Published: December 2023

Pressure sensors play a vital role in aerospace, automotive, medical, and consumer electronics. Although microelectromechanical system (MEMS)-based pressure sensors have been widely used for decades, new trends in pressure sensors, including higher sensitivity, higher accuracy, better multifunctionality, smaller chip size, and smaller package size, have recently emerged. The demand for performance upgradation has led to breakthroughs in sensor materials, design, fabrication, and packaging methods, which have emerged frequently in recent decades. This paper reviews common new trends in MEMS pressure sensors, including minute differential pressure sensors (MDPSs), resonant pressure sensors (RPSs), integrated pressure sensors, miniaturized pressure chips, and leadless pressure sensors. To realize an extremely sensitive MDPS with broad application potential, including in medical ventilators and fire residual pressure monitors, the “beam-membrane-island” sensor design exhibits the best performance of 66 μV/V/kPa with a natural frequency of 11.3 kHz. In high-accuracy applications, silicon and quartz RPS are analyzed, and both materials show ±0.01%FS accuracy with respect to varying temperature coefficient of frequency (TCF) control methods. To improve MEMS sensor integration, different integrated “pressure +x” sensor designs and fabrication methods are compared. In this realm, the intercoupling effect still requires further investigation. Typical fabrication methods for microsized pressure sensor chips are also reviewed. To date, the chip thickness size can be controlled to be <0.1 mm, which is advantageous for implant sensors. Furthermore, a leadless pressure sensor was analyzed, offering an extremely small package size and harsh environmental compatibility. This review is structured as follows. The background of pressure sensors is first presented. Then, an in-depth introduction to MEMS pressure sensors based on different application scenarios is provided. Additionally, their respective characteristics and significant advancements are analyzed and summarized. Finally, development trends of MEMS pressure sensors in different fields are analyzed.
Airway epithelial cGAS inhibits LPS-induced acute lung injury through CREB signaling
Authors: Jin Zhangchu , Shao Zhehua , Yang Shiyi , Guo Anyi , Han Yinling , Wu Yinfang , Zhao Yun , Wu Yanping , Shen Jiaxin , Zhang Min , Zhan Xueqin , Diao Wenqi , Ying Songmin , Zhang Chao , Li Wen , Shen Huahao , Chen Zhihua , Yan Fugui
Published: December 2023

Increased levels of cytosolic DNA in lung tissues play an important role in acute lung injury. However, the detailed mechanisms involved remain elusive. Here, we found that cyclic GMP-AMP synthase (cGAS, a cytosolic DNA sensor) expression was increased in airway epithelium in response to increased cytosolic DNA. Conditional deletion of airway epithelial cGAS exacerbated acute lung injury in mice, cGAS knockdown augmented LPS-induced production of interleukin (IL)-6 and IL-8. Mechanically, deletion of cGAS augmented expression of phosphorylated CREB (cAMP response element-binding protein), and cGAS directly interacted with CREB via its C-terminal domain. Furthermore, CREB knockdown rescued the LPS-induced excessive inflammatory response caused by cGAS deletion. Our study demonstrates that airway epithelial cGAS plays a protective role in acute lung injury and confirms a non-canonical cGAS-CREB pathway that regulates the inflammatory responses in airway epithelium to mediate LPS-induced acute lung injury.
Comprehensive genomic profiling of breast cancers characterizes germline-somatic mutation interactions mediating therapeutic vulnerabilities
Authors: Chen Chao , Lin Cai-Jin , Pei Yu-Chen , Ma Ding , Liao Li , Li Si-Yuan , Fan Lei , Di Gen-Hong , Wu Song-Yang , Liu Xi-Yu , Wang Yun-Jin , Hong Qi , Zhang Guo-Liang , Xu Lin-Lin , Li Bei-Bei , Huang Wei , Shi Jin-Xiu , Jiang Yi-Zhou , Hu Xin , Shao Zhi-Ming
Published: December 2023

Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population.
Autoregulation of the LIM kinases by their PDZ domain
Authors: Casanova-Sepúlveda Gabriela , Sexton Joel A. , Turk Benjamin E. , Boggon Titus J.
Published: December 2023

LIM domain kinases (LIMK) are important regulators of actin cytoskeletal remodeling. These protein kinases phosphorylate the actin depolymerizing factor cofilin to suppress filament severing, and are key nodes between Rho GTPase cascades and actin. The two mammalian LIMKs, LIMK1 and LIMK2, contain consecutive LIM domains and a PDZ domain upstream of the C-terminal kinase domain. The roles of the N-terminal regions are not fully understood, and the function of the PDZ domain remains elusive. Here, we determine the 2.0 Å crystal structure of the PDZ domain of LIMK2 and reveal features not previously observed in PDZ domains including a core-facing arginine residue located at the second position of the ‘x-Φ-G-Φ’ motif, and that the expected peptide binding cleft is shallow and poorly conserved. We find a distal extended surface to be highly conserved, and when LIMK1 was ectopically expressed in yeast we find targeted mutagenesis of this surface decreases growth, implying increased LIMK activity. PDZ domain LIMK1 mutants expressed in yeast are hyperphosphorylated and show elevated activity in vitro. This surface in both LIMK1 and LIMK2 is critical for autoregulation independent of activation loop phosphorylation. Overall, our study demonstrates the functional importance of the PDZ domain to autoregulation of LIMKs.
Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy
Authors: Gress Abigail R. , Ronayne Christine E. , Thiede Joshua M. , Meyerholz David K. , Okurut Samuel , Stumpf Julia , Mathes Tailor V. , Ssebambulidde Kenneth , Meya David B. , Cresswell Fiona V. , Boulware David R. , Bold Tyler D.
Published: December 2023

After Mycobacterium tuberculosis (Mtb) infection, many effector T cells traffic to the lungs, but few become activated. Here we use an antigen receptor reporter mouse (Nur77-GFP) to identify recently activated CD4 T cells in the lungs. These Nur77-GFPHI cells contain expanded TCR clonotypes, have elevated expression of co-stimulatory genes such as Tnfrsf4/OX40, and are functionally more protective than Nur77-GFPLO cells. By contrast, Nur77-GFPLO cells express markers of terminal exhaustion and cytotoxicity, and the trafficking receptor S1pr5, associated with vascular localization. A short course of immunotherapy targeting OX40+ cells transiently expands CD4 T cell numbers and shifts their phenotype towards parenchymal protective cells. Moreover, OX40 agonist immunotherapy decreases the lung bacterial burden and extends host survival, offering an additive benefit to antibiotics. CD4 T cells from the cerebrospinal fluid of humans with HIV-associated tuberculous meningitis commonly express surface OX40 protein, while CD8 T cells do not. Our data thus propose OX40 as a marker of recently activated CD4 T cells at the infection site and a potential target for immunotherapy in tuberculosis.
Biophysical basis of filamentous phage tactoid-mediated antibiotic tolerance in P. aeruginosa
Authors: Böhning Jan , Graham Miles , Letham Suzanne C. , Davis Luke K. , Schulze Ulrike , Stansfeld Phillip J. , Corey Robin A. , Pearce Philip , Tarafder Abul K. , Bharat Tanmay A. M.
Published: December 2023

Inoviruses are filamentous phages infecting numerous prokaryotic phyla. Inoviruses can self-assemble into mesoscale structures with liquid-crystalline order, termed tactoids, which protect bacterial cells in Pseudomonas aeruginosa biofilms from antibiotics. Here, we investigate the structural, biophysical, and protective properties of tactoids formed by the P. aeruginosa phage Pf4 and Escherichia coli phage fd. A cryo-EM structure of the capsid from fd revealed distinct biochemical properties compared to Pf4. Fd and Pf4 formed tactoids with different morphologies that arise from differing phage geometries and packing densities, which in turn gave rise to different tactoid emergent properties. Finally, we showed that tactoids formed by either phage protect rod-shaped bacteria from antibiotic treatment, and that direct association with a tactoid is required for protection, demonstrating the formation of a diffusion barrier by the tactoid. This study provides insights into how filamentous molecules protect bacteria from extraneous substances in biofilms and in host-associated infections.
Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration
Authors: Toth Andrea , Kannan Paranthaman , Snowball John , Kofron Matthew , Wayman Joseph A. , Bridges James P. , Miraldi Emily R. , Swarr Daniel , Zacharias William J.
Published: December 2023

Lung epithelial regeneration after acute injury requires coordination cellular coordination to pattern the morphologically complex alveolar gas exchange surface. During adult lung regeneration, Wnt-responsive alveolar epithelial progenitor (AEP) cells, a subset of alveolar type 2 (AT2) cells, proliferate and transition to alveolar type 1 (AT1) cells. Here, we report a refined primary murine alveolar organoid, which recapitulates critical aspects of in vivo regeneration. Paired scRNAseq and scATACseq followed by transcriptional regulatory network (TRN) analysis identified two AT1 transition states driven by distinct regulatory networks controlled in part by differential activity of Nkx2-1. Genetic ablation of Nkx2-1 in AEP-derived organoids was sufficient to cause transition to a proliferative stressed Krt8+ state, and AEP-specific deletion of Nkx2-1 in adult mice led to rapid loss of progenitor state and uncontrolled growth of Krt8+ cells. Together, these data implicate dynamic epigenetic maintenance via Nkx2-1 as central to the control of facultative progenitor activity in AEPs.
A histone demethylase links the loss of plasticity to nongenetic inheritance and morphological change
Authors: Levis Nicholas A. , Ragsdale Erik J.
Published: December 2023

Plasticity is a widespread feature of development, enabling phenotypic change based on the environment. Although the evolutionary loss of plasticity has been linked both theoretically and empirically to increased rates of phenotypic diversification, molecular insights into how this process might unfold are generally lacking. Here, we show that a regulator of nongenetic inheritance links evolutionary loss of plasticity in nature to changes in plasticity and morphology as selected in the laboratory. Across nematodes of Diplogastridae, which ancestrally had a polyphenism, or discrete plasticity, in their feeding morphology, we use molecular evolutionary analyses to screen for change associated with independent losses of plasticity. Having inferred a set of ancestrally polyphenism-biased genes from phylogenetically informed gene-knockouts and gene-expression comparisons, selection signatures associated with plasticity’s loss identify the histone H3K4 di/monodemethylase gene spr-5/LSD1/KDM1A. Manipulations of this gene affect both sensitivity and variation in plastic morphologies, and artificial selection of manipulated lines drive multigenerational shifts in these phenotypes. Our findings thus give mechanistic insight into how traits are modified as they traverse the continuum of greater to lesser environmental sensitivity.
Multicenter evaluation of gut microbiome profiling by next-generation sequencing reveals major biases in partial-length metabarcoding approach
Authors: Roume Hugo , Mondot Stanislas , Saliou Adrien , Le Fresne-Languille Sophie , Doré Joël
Published: December 2023

Next-generation sequencing workflows, using either metabarcoding or metagenomic approaches, have massively contributed to expanding knowledge of the human gut microbiota, but methodological bias compromises reproducibility across studies. Where these biases have been quantified within several comparative analyses on their own, none have measured inter-laboratory reproducibility using similar DNA material. Here, we designed a multicenter study involving seven participating laboratories dedicated to partial- (P1 to P5), full-length (P6) metabarcoding, or metagenomic profiling (MGP) using DNA from a mock microbial community or extracted from 10 fecal samples collected at two time points from five donors. Fecal material was collected, and the DNA was extracted according to the IHMS protocols. The mock and isolated DNA were then provided to the participating laboratories for sequencing. Following sequencing analysis according to the laboratories’ routine pipelines, relative taxonomic-count tables defined at the genus level were provided and analyzed. Large variations in alpha-diversity between laboratories, uncorrelated with sequencing depth, were detected among the profiles. Half of the genera identified by P1 were unique to this partner and two-thirds of the genera identified by MGP were not detected by P3. Analysis of beta-diversity revealed lower inter-individual variance than inter-laboratory variances. The taxonomic profiles of P5 and P6 were more similar to those of MGP than those obtained by P1, P2, P3, and P4. Reanalysis of the raw sequences obtained by partial-length metabarcoding profiling, using a single bioinformatic pipeline, harmonized the description of the bacterial profiles, which were more similar to each other, except for P3, and closer to the profiles obtained by MGP. This study highlights the major impact of the bioinformatics pipeline, and primarily the database used for taxonomic annotation. Laboratories need to benchmark and optimize their bioinformatic pipelines using standards to monitor their effectiveness in accurately detecting taxa present in gut microbiota.
Rapid seasonal changes in phenotypes in a wild Drosophila population
Authors: Ueno Takahisa , Takenoshita Akiko , Hamamichi Kaiya , Sato Mitsuhiko P. , Takahashi Yuma
Published: December 2023

Seasonal environmental change is one of the most rapid and striking environmental variables. Although relatively rapid adaptation to environmental changes over several years or several decades has been described in many taxa, rapid responses to seasonal environments are delicate, and therefore, the detection of the evolutionary responses requires sensitive methods. In this study, we examined seasonal changes in phenotypes related to thermal tolerance and morphological traits of Drosophila lutescens collected at the spring and autumn periods from a single location. We first demonstrated that flies in the two seasonal periods were almost genetically identical using double-digest restriction site-associated DNA sequencing and analysis. Using an experimental design to eliminate the effect of possible confounding factors that influence phenotypes (i.e., maternal effects and the environmental conditions in which each phenotype was analyzed), we showed that the heat tolerance of D. lutescens was significantly higher in the autumn population than in the spring population. Furthermore, cold tolerance was slightly higher in the spring population than in the autumn one. Although wing length and thorax length did not change significantly between seasons, the ratio of wing length to thorax length changed significantly between them. These results suggest that seasonal environmental heterogeneity induces rapid phenotypic changes within a year. Finally, we discuss the possibility of rapid evolutionary responses to seasonal changes.
Effects of donor-specific microvascular anatomy on hemodynamic perfusion in human choriocapillaris
Authors: An Senyou , Yu Huidan , Islam MD Mahfuzul , Zhang Xiaoyu , Zhan Yuting , Olivieri Joseph J. , Ambati Jayakrishna , Yao Jun , Gelfand Bradley D.
Published: December 2023

Evidence from histopathology and clinical imaging suggest that choroidal anatomy and hemodynamic perfusion are among the earliest changes in retinal diseases such as age-related macular degeneration (AMD). However, how inner choroidal anatomy affects hemodynamic perfusion is not well understood. Therefore, we sought to understand the influences of choroidal microvascular architecture on the spatial distribution of hemodynamic parameters in choriocapillaris from human donor eyes using image-based computational hemodynamic (ICH) simulations. We subjected image-based inner choroid reconstructions from eight human donor eyes to ICH simulation using a kinetic-based volumetric lattice Boltzmann method to compute hemodynamic distributions of velocity, pressure, and endothelial shear stress. Here, we demonstrate that anatomic parameters, including arteriolar and venular arrangements and intercapillary pillar density and distribution exert profound influences on inner choroidal hemodynamic characteristics. Reductions in capillary, arteriolar, and venular density not only reduce the overall blood velocity within choriocapillaris, but also substantially increase its spatial heterogeneity. These first-ever findings improve understanding of how choroidal anatomy affects hemodynamics and may contribute to pathogenesis of retinal diseases such as AMD.
Self-supervised MRI denoising: leveraging Stein’s unbiased risk estimator and spatially resolved noise maps
Authors: Pfaff Laura , Hossbach Julian , Preuhs Elisabeth , Wagner Fabian , Arroyo Camejo Silvia , Kannengiesser Stephan , Nickel Dominik , Wuerfl Tobias , Maier Andreas
Published: December 2023

Thermal noise caused by the imaged object is an intrinsic limitation in magnetic resonance imaging (MRI), resulting in an impaired clinical value of the acquisitions. Recently, deep learning (DL)-based denoising methods achieved promising results by extracting complex feature representations from large data sets. Most approaches are trained in a supervised manner by directly mapping noisy to noise-free ground-truth data and, therefore, require extensive paired data sets, which can be expensive or infeasible to obtain for medical imaging applications. In this work, a DL-based denoising approach is investigated which operates on complex-valued reconstructed magnetic resonance (MR) images without noise-free target data. An extension of Stein’s unbiased risk estimator (SURE) and spatially resolved noise maps quantifying the noise level with pixel accuracy were employed during the training process. Competitive denoising performance was achieved compared to supervised training with mean squared error (MSE) despite optimizing the model without noise-free target images. The proposed DL-based method can be applied for MR image enhancement without requiring noise-free target data for training. Integrating the noise maps as an additional input channel further enables the regulation of the desired level of denoising to adjust to the preference of the radiologist.
Online real-time learning of dynamical systems from noisy streaming data
Authors: Sinha S. , Nandanoori S. P. , Barajas-Solano D. A.
Published: December 2023

Recent advancements in sensing and communication facilitate obtaining high-frequency real-time data from various physical systems like power networks, climate systems, biological networks, etc. However, since the data are recorded by physical sensors, it is natural that the obtained data is corrupted by measurement noise. In this paper, we present a novel algorithm for online real-time learning of dynamical systems from noisy time-series data, which employs the Robust Koopman operator framework to mitigate the effect of measurement noise. The proposed algorithm has three main advantages: (a) it allows for online real-time monitoring of a dynamical system; (b) it obtains a linear representation of the underlying dynamical system, thus enabling the user to use linear systems theory for analysis and control of the system; (c) it is computationally fast and less intensive than the popular extended dynamic mode decomposition (EDMD) algorithm. We illustrate the efficiency of the proposed algorithm by applying it to identify the Van der Pol oscillator, the chaotic attractor of the Henon map, the IEEE 68 bus system, and a ring network of Van der Pol oscillators.