bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-chain n-3 PUFA ingestion for the stimulation of muscle protein synthesis in healthy older adults
Authors: Witard Oliver C. , Banic Milena , Rodriguez-Sanchez Nidia , van Dijk Miriam , Galloway Stuart D. R.
Published: November 2023

This review aims to critically evaluate the efficacy of long-chain ո-3 PUFA ingestion in modulating muscle protein synthesis (MPS), with application to maintaining skeletal muscle mass, strength and function into later life. Ageing is associated with a gradual decline in muscle mass, specifically atrophy of type II fibres, that is exacerbated by periods of (in)voluntary muscle disuse. At the metabolic level, in otherwise healthy older adults, muscle atrophy is underpinned by anabolic resistance which describes the impaired MPS response to non-pharmacological anabolic stimuli, namely, physical activity/exercise and amino acid provision. Accumulating evidence implicates a mechanistic role for n-3 PUFA in upregulating MPS under stimulated conditions (post-prandial state or following exercise) via incorporation of EPA and DHA into the skeletal muscle phospholipid membrane. In some instances, these changes in MPS with chronic ո-3 PUFA ingestion have translated into clinically relevant improvements in muscle mass, strength and function; an observation evidently more prevalent in healthy older women than men. This apparent sexual dimorphism in the adaptive response of skeletal muscle metabolism to EPA and DHA ingestion may be related to a greater propensity for females to incorporate ո-3 PUFA into human tissue and/or the larger dose of ingested ո-3 PUFA when expressed relative to body mass or lean body mass. Future experimental studies are warranted to characterise the optimal dosing and duration of ո-3 PUFA ingestion to prescribe tailored recommendations regarding n-3 PUFA nutrition for healthy musculoskeletal ageing into later life.
Maximum Supersaturation in the Marine Boundary Layer Clouds Over the North Atlantic
Authors: Gong Xianda , Wang Yang , Xie Hua , Zhang Jiaoshi , Lu Zheng , Wood Robert , Stratmann Frank , Wex Heike , Liu Xiaohong , Wang Jian
Published: November 2023

The maximum supersaturation (Sx) in clouds is a key parameter affecting the cloud's microphysical and radiative properties. We investigate the Sx of the marine boundary layer clouds by combining airborne and surface observations in the Eastern North Atlantic. The cloud droplet number concentration (Nc) in the least diluted cloud cores agrees well with the number concentration of particles larger than the Hoppel Minimum (HM) (N>HM) below clouds, indicating that the HM represents the average size threshold above which particles are activated to form cloud droplets. The Sx values derived from surface observations vary from 0.10% to 0.50% from June 2017 to June 2018, with a clear seasonal variation exhibiting higher values during winter. Most of the Sx variance (∼60%) can be explained by the cloud condensation nuclei (CCN) concentration and updraft velocity (w), with the CCN concentration playing a more important role than w in explaining the variation of Sx. The influence of CCN concentration on Sx leads to a buffered response of Nc to aerosol perturbations. The response of Nc to low aerosol concentration during winter is further buffered by the high w. The global Community Earth System Model (CESM) simulated Sx values in the Azores have a positive bias compared to measured Sx, likely due to overestimated w and underestimated CCN concentration. The CESM simulated Sx exhibits higher values further north over the North Atlantic Ocean, which is attributed to stronger w. The suppression of Sx by aerosol is also evident in regions with high CCN concentrations.
Natural Vegetation Succession Under Climate Change and the Combined Effects on Net Primary Productivity
Authors: Zhang Sen , Hao Xingming , Zhao Zhuoyi , Zhang Jingjing , Fan Xue , Li Xuewei
Published: November 2023

Climate change and the resulting natural vegetation succession can alter vegetation productivity. However, the mechanisms underlying future productivity changes under the two influences remain unclear. Here, we used the comprehensive sequence classification system to simulate changes in global potential natural vegetation under different climate scenarios (SSP1‐2.6, SSP2‐4.5, SSP3‐7.0, and SSP5‐8.5), and combined the Carnegie–Ames–Stanford Approach model with random forest to assess the response of net primary productivity (NPP) to climate change and vegetation succession from 2020 to 2100. Except for SSP126, terrestrial NPP in 2100 decreased by 0.86, 2.39, and 2.54 Pg C·a−1 versus 2020 under SSP2‐4.5, SSP5‐8.5, and SSP3‐7.0, respectively. Forest was the primary contributor to terrestrial NPP changes. The total forest area was projected to increase under all scenarios, with SSP2‐4.5 showing the largest increase (358.57 × 104 km2). However, expanding forest regions exhibited a relatively low mean NPP, while stable regions demonstrated a declining pattern. Consequently, forest NPP increased under SSP1‐2.6 but decreased by 4.03, 3.43, and 0.82 Pg C·a−1 in 2100 versus 2020 under SSP5‐8.5, SSP3‐7.0, and SSP2‐4.5, respectively. In comparison, grassland and desert exerted minor influence on terrestrial NPP changes, their total NPP decreased only under the SSP1‐2.6 scenario. The grassland area decreased, but the mean NPP increased, whereas the desert area expanded, resulting in consistent changes in both total and mean NPP. Our results analyzed the effects of climate change and vegetation distribution under its influence on the change of NPP, which can deepen our understanding of their relationship.
Arctic Tropospheric Ozone Trends
Authors: Law Kathy S. , Hjorth Jens L. , Pernov Jakob B. , Whaley Cynthia H. , Skov Henrik , Collaud Coen Martine , Langner Joakim , Arnold Stephen R. , Tarasick David , Christensen Jesper , Deushi Makoto , Effertz Peter , Faluvegi Greg , Gauss Michael , Im Ulas , Oshima Naga , Petropavlovskikh Irina , Plummer David , Tsigaridis Kostas , Tsyro Svetlana , Solberg Sverre , Turnock Steven T.
Published: November 2023

Observed trends in tropospheric ozone, an important air pollutant and short‐lived climate forcer (SLCF), are estimated using available surface and ozonesonde profile data for 1993–2019, using a coherent methodology, and compared to modeled trends (1995–2015) from the Arctic Monitoring Assessment Program SLCF 2021 assessment. Increases in observed surface ozone at Arctic coastal sites, notably during winter, and concurrent decreasing trends in surface carbon monoxide, are generally captured by multi‐model median trends. Wintertime increases are also estimated in the free troposphere at most Arctic sites, with decreases during spring months. Winter trends tend to be overestimated by the multi‐model medians. Springtime surface ozone increases in northern coastal Alaska are not simulated while negative springtime trends in northern Scandinavia are not always reproduced. Possible reasons for observed changes and model performance are discussed including decreasing precursor emissions, changing ozone dry deposition, and variability in large‐scale meteorology.
Automatic Characterization of Boulders on Planetary Surfaces From High‐Resolution Satellite Images
Authors: Prieur Nils C. , Amaro Brian , Gonzalez Emiliano , Kerner Hannah , Medvedev Sergei , Rubanenko Lior , Werner Stephanie C. , Xiao Zhiyong , Zastrozhnov Dmitry , Lapôtre Mathieu G. A.
Published: November 2023

Boulders form from a variety of geological processes, which their size, shape, and orientation may help us better understand. Furthermore, they represent potential hazards to spacecraft landing that need to be characterized. However, mapping individual boulders across vast areas is extremely labor‐intensive, often limiting the extent over which they are characterized and the statistical robustness of obtained boulder morphometrics. To automate boulder characterization, we use an instance segmentation neural network, Mask R‐CNN, to detect and outline boulders in high‐resolution satellite and aerial images. Our neural network, BoulderNet, was trained from a data set of >33,000 boulders in >750 image tiles from Earth, the Moon, and Mars. BoulderNet not only correctly detects the majority of boulders in images but also identifies the outline of boulders with high fidelity, achieving average precision and recall values of 72% and 64% relative to manually digitized boulders from the test data set, when only detections with intersection‐over‐union ratios >50% are considered valid. These values are similar to those obtained from human mappers. On Earth, equivalent boulder diameters, aspect ratios, and orientations extracted from predictions were benchmarked against ground measurements and yield values within ±15%, ±0.20, and ±20° of their ground‐truth values, respectively. BoulderNet achieves better boulder detection and characterization performance relative to existing methods, providing a versatile open‐source tool to characterize entire boulder fields on planetary surfaces.
Tumor-mesothelium HOXA11-PDGF BB/TGF β1-miR-181a-5p-Egr1 feedforward amplifier circuity propels mesothelial fibrosis and peritoneal metastasis of gastric cancer
Authors: Wang Chao , Ji Jun , Jin Yangbing , Sun Ying , Cai Qu , Jiang Jinling , Guo Liting , Zhou Chenfei , Zhang Jun
Published: November 2023

A proportion of gastric cancer (GC) patients suffer from peritoneal metastasis (PM) in the late stage of tumor and these patients have a poor prognosis. To provide more care for GC patient with PM, a deeper exploration of the molecular characteristics of GC-PM is needed. Here we performed the in vitro and in vivo study to illustrate the effect of HOXA11 over-expressed GC cells on peritoneal mesothelial cells (HMrSV5), transcriptomics analyses of HMrSV5 cells co-cultured with HOXA11 over-expressed GC cells, counterparts or alone, cytokine array analyses of serum-free culture medium of HOXA11 over-expressed GC cells, we validated our findings through genetic manipulation of HMrSV5 cells and neutralizing antibodies targeting cytokines secreted by HOXA11 over-expressed GC cells in vitro, as well as utilized human peritoneal metastatic lesions to validate expression of potential targets. We identified that HOXA11 over-expressed GC cells strongly propelled mesothelial fibrosis in vivo and in vitro, and HOXA11 regulated paracrine and autocrine of PDGF BB and TGF β1 in GC cells to propel mesothelial fibrosis. Meanwhile, HOXA11 over-expressed GC cells drove PDGF BB and TGF β1 secretion to activate developmental-process related genes in HMrSV5 cells, including Egr1, which processes dependent on miR-181a-5p. Then, Egr1 could mediate peritoneal mesothelial fibrosis. Correspondingly, Egr1 over-expressed HMrSV5 cells supported migration and peritoneal dissemination of GC cells. Together our results suggest that a feedforward amplifier circuity governing GC cells and mesothelial cells in peritoneum contribute to peritoneal metastasis of GC cells.
The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later
Authors: Rivas Juan F. Garcia , Clugston Robin D.
Published: November 2023

Congenital diaphragmatic hernia (CDH) is a severe birth defect and a major cause of neonatal respiratory distress. Impacting ~2–3 in 10,000 births, CDH is associated with a high mortality rate, and long-term morbidity in survivors. Despite the significant impact of CDH, its etiology remains incompletely understood. In 2003, Greer et al. proposed the Retinoid Hypothesis, stating that the underlying cause of abnormal diaphragm development in CDH was related to altered retinoid signaling. In this review, we provide a comprehensive update to the Retinoid Hypothesis, discussing work published in support of this hypothesis from the past 20 years. This includes reviewing teratogenic and genetic models of CDH, lessons from the human genetics of CDH and epidemiological studies, as well as current gaps in the literature and important areas for future research. The Retinoid Hypothesis is one of the leading hypotheses to explain the etiology of CDH, as we continue to better understand the role of retinoid signaling in diaphragm development, we hope that this information can be used to improve CDH outcomes.

Impact

This review provides a comprehensive update on the Retinoid Hypothesis, which links abnormal retinoic acid signaling to the etiology of congenital diaphragmatic hernia.

The Retinoid Hypothesis was formulated in 2003. Twenty years later, we extensively review the literature in support of this hypothesis from both animal models and humans.
Structure and function of the membrane microdomains in osteoclasts
Authors: Hou Jialong , Liu Jian , Huang Zhixian , Wang Yining , Yao Hanbing , Hu Zhenxin , Shi Chengge , Xu Jiake , Wang Qingqing
Published: November 2023

The cell membrane structure is closely related to the occurrence and progression of many metabolic bone diseases observed in the clinic and is an important target to the development of therapeutic strategies for these diseases. Strong experimental evidence supports the existence of membrane microdomains in osteoclasts (OCs). However, the potential membrane microdomains and the crucial mechanisms underlying their roles in OCs have not been fully characterized. Membrane microdomain components, such as scaffolding proteins and the actin cytoskeleton, as well as the roles of individual membrane proteins, need to be elucidated. In this review, we discuss the compositions and critical functions of membrane microdomains that determine the biological behavior of OCs through the three main stages of the OC life cycle.
Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis
Authors: Tamura Ryutaro , Sabu Yusuke , Mizuno Tadahaya , Mizuno Seiya , Nakano Satoshi , Suzuki Mitsuyoshi , Abukawa Daiki , Kaji Shunsaku , Azuma Yoshihiro , Inui Ayano , Okamoto Tatsuya , Shimizu Seiichi , Fukuda Akinari , Sakamoto Seisuke , Kasahara Mureo , Takahashi Satoru , Kusuhara Hiroyuki , Zen Yoh , Ando Tomohiro , Hayashi Hisamitsu
Published: November 2023

Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.
Potential drivers of the recent large Antarctic ozone holes
Authors: Kessenich Hannah E. , Seppälä Annika , Rodger Craig J.
Published: November 2023

The past three years (2020–2022) have witnessed the re-emergence of large, long-lived ozone holes over Antarctica. Understanding ozone variability remains of high importance due to the major role Antarctic stratospheric ozone plays in climate variability across the Southern Hemisphere. Climate change has already incited new sources of ozone depletion, and the atmospheric abundance of several chlorofluorocarbons has recently been on the rise. In this work, we take a comprehensive look at the monthly and daily ozone changes at different altitudes and latitudes within the Antarctic ozone hole. Following indications of early-spring recovery, the October middle stratosphere is dominated by continued, significant ozone reduction since 2004, amounting to 26% loss in the core of the ozone hole. We link the declines in mid-spring Antarctic ozone to dynamical changes in mesospheric descent within the polar vortex, highlighting the importance of continued monitoring of the state of the ozone layer.
HIV-1 Gag targeting to the plasma membrane reorganizes sphingomyelin-rich and cholesterol-rich lipid domains
Authors: Tomishige Nario , Bin Nasim Maaz , Murate Motohide , Pollet Brigitte , Didier Pascal , Godet Julien , Richert Ludovic , Sako Yasushi , Mély Yves , Kobayashi Toshihide
Published: November 2023

Although the human immunodeficiency virus type 1 lipid envelope has been reported to be enriched with host cell sphingomyelin and cholesterol, the molecular mechanism of the enrichment is not well understood. Viral Gag protein plays a central role in virus budding. Here, we report the interaction between Gag and host cell lipids using different quantitative and super-resolution microscopy techniques in combination with specific probes that bind endogenous sphingomyelin and cholesterol. Our results indicate that Gag in the inner leaflet of the plasma membrane colocalizes with the outer leaflet sphingomyelin-rich domains and cholesterol-rich domains, enlarges sphingomyelin-rich domains, and strongly restricts the mobility of sphingomyelin-rich domains. Moreover, Gag multimerization induces sphingomyelin-rich and cholesterol-rich lipid domains to be in close proximity in a curvature-dependent manner. Our study suggests that Gag binds, coalesces, and reorganizes pre-existing lipid domains during assembly.
Myr-Arf1 conformational flexibility at the membrane surface sheds light on the interactions with ArfGAP ASAP1
Authors: Zhang Yue , Soubias Olivier , Pant Shashank , Heinrich Frank , Vogel Alexander , Li Jess , Li Yifei , Clifton Luke A. , Daum Sebastian , Bacia Kirsten , Huster Daniel , Randazzo Paul A. , Lösche Mathias , Tajkhorshid Emad , Byrd R. Andrew
Published: November 2023

ADP-ribosylation factor 1 (Arf1) interacts with multiple cellular partners and membranes to regulate intracellular traffic, organelle structure and actin dynamics. Defining the dynamic conformational landscape of Arf1 in its active form, when bound to the membrane, is of high functional relevance and key to understanding how Arf1 can alter diverse cellular processes. Through concerted application of nuclear magnetic resonance (NMR), neutron reflectometry (NR) and molecular dynamics (MD) simulations, we show that, while Arf1 is anchored to the membrane through its N-terminal myristoylated amphipathic helix, the G domain explores a large conformational space, existing in a dynamic equilibrium between membrane-associated and membrane-distal conformations. These configurational dynamics expose different interfaces for interaction with effectors. Interaction with the Pleckstrin homology domain of ASAP1, an Arf-GTPase activating protein (ArfGAP), restricts motions of the G domain to lock it in what seems to be a conformation exposing functionally relevant regions.
Apparent nonlinear damping triggered by quantum fluctuations
Authors: Gely Mario F. , Sanz Mora Adrián , Yanai Shun , van der Spek Rik , Bothner Daniel , Steele Gary A.
Published: November 2023

Nonlinear damping, the change in damping rate with the amplitude of oscillations plays an important role in many electrical, mechanical and even biological oscillators. In novel technologies such as carbon nanotubes, graphene membranes or superconducting resonators, the origin of nonlinear damping is sometimes unclear. This presents a problem, as the damping rate is a key figure of merit in the application of these systems to extremely precise sensors or quantum computers. Through measurements of a superconducting resonator, we show that from the interplay of quantum fluctuations and the nonlinearity of a Josephson junction emerges a power-dependence in the resonator response which closely resembles nonlinear damping. The phenomenon can be understood and visualized through the flow of quasi-probability in phase space where it reveals itself as dephasing. Crucially, the effect is not restricted to superconducting circuits: we expect that quantum fluctuations or other sources of noise give rise to apparent nonlinear damping in systems with a similar conservative nonlinearity, such as nano-mechanical oscillators or even macroscopic systems.
Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing
Authors: Nguyen Lien D. , Wei Zhiyun , Silva M. Catarina , Barberán-Soler Sergio , Zhang Jiarui , Rabinovsky Rosalia , Muratore Christina R. , Stricker Jonathan M. S. , Hortman Colin , Young-Pearse Tracy L. , Haggarty Stephen J. , Krichevsky Anna M.
Published: November 2023

MicroRNAs (miRNAs) regulate fundamental biological processes by silencing mRNA targets and are dysregulated in many diseases. Therefore, miRNA replacement or inhibition can be harnessed as potential therapeutics. However, existing strategies for miRNA modulation using oligonucleotides and gene therapies are challenging, especially for neurological diseases, and none have yet gained clinical approval. We explore a different approach by screening a biodiverse library of small molecule compounds for their ability to modulate hundreds of miRNAs in human induced pluripotent stem cell-derived neurons. We demonstrate the utility of the screen by identifying cardiac glycosides as potent inducers of miR-132, a key neuroprotective miRNA downregulated in Alzheimer’s disease and other tauopathies. Coordinately, cardiac glycosides downregulate known miR-132 targets, including Tau, and protect rodent and human neurons against various toxic insults. More generally, our dataset of 1370 drug-like compounds and their effects on the miRNome provides a valuable resource for further miRNA-based drug discovery.
PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling
Authors: Lin Yongfang , Yang Jing , Yang Qili , Zeng Sha , Zhang Jiayu , Zhu Yuanxiang , Tong Yuxin , Li Lin , Tan Weiqi , Chen Dahua , Sun Qinmiao
Published: November 2023

TANK-binding kinase 1 (TBK1) is a key kinase in regulating antiviral innate immune responses. While the oligomerization of TBK1 is critical for its full activation, the molecular mechanism of how TBK1 forms oligomers remains unclear. Here, we show that protein tyrosine kinase 2 beta (PTK2B) acts as a TBK1-interacting protein and regulates TBK1 oligomerization. Functional assays reveal that PTK2B depletion reduces antiviral signaling in mouse embryonic fibroblasts, macrophages and dendritic cells, and genetic experiments show that Ptk2b-deficient mice are more susceptible to viral infection than control mice. Mechanistically, we demonstrate that PTK2B directly phosphorylates residue Tyr591 of TBK1, which increases TBK1 oligomerization and activation. In addition, we find that PTK2B also interacts with the stimulator of interferon genes (STING) and can promote its oligomerization in a kinase-independent manner. Collectively, PTK2B enhances the oligomerization of TBK1 and STING via different mechanisms, subsequently regulating STING-TBK1 activation to ensure efficient antiviral innate immune responses.
Cis-trans isomerization of peptoid residues in the collagen triple-helix
Authors: Qiu Rongmao , Li Xiaojing , Huang Kui , Bai Weizhe , Zhou Daoning , Li Gang , Qin Zhao , Li Yang
Published: November 2023

Cis-peptide bonds are rare in proteins, and building blocks less favorable to the trans-conformer have been considered destabilizing. Although proline tolerates the cis-conformer modestly among all amino acids, for collagen, the most prevalent proline-abundant protein, all peptide bonds must be trans to form its hallmark triple-helix structure. Here, using host-guest collagen mimetic peptides (CMPs), we discover that surprisingly, even the cis-enforcing peptoid residues (N-substituted glycines) form stable triple-helices. Our interrogations establish that these peptoid residues entropically stabilize the triple-helix by pre-organizing individual peptides into a polyproline-II helix. Moreover, noting that the cis-demanding peptoid residues drastically reduce the folding rate, we design a CMP whose triple-helix formation can be controlled by peptoid cis-trans isomerization, enabling direct targeting of fibrotic remodeling in myocardial infarction in vivo. These findings elucidate the principles of peptoid cis-trans isomerization in protein folding and showcase the exploitation of cis-amide-favoring residues in building programmable and functional peptidomimetics.
Axion insulator state in hundred-nanometer-thick magnetic topological insulator sandwich heterostructures
Authors: Zhuo Deyi , Yan Zi-Jie , Sun Zi-Ting , Zhou Ling-Jie , Zhao Yi-Fan , Zhang Ruoxi , Mei Ruobing , Yi Hemian , Wang Ke , Chan Moses H. W. , Liu Chao-Xing , Law K. T. , Chang Cui-Zu
Published: November 2023

An axion insulator is a three-dimensional (3D) topological insulator (TI), in which the bulk maintains the time-reversal symmetry or inversion symmetry but the surface states are gapped by surface magnetization. The axion insulator state has been observed in molecular beam epitaxy (MBE)-grown magnetically doped TI sandwiches and exfoliated intrinsic magnetic TI MnBi2Te4 flakes with an even number layer. All these samples have a thickness of ~ 10 nm, near the 2D-to-3D boundary. The coupling between the top and bottom surface states in thin samples may hinder the observation of quantized topological magnetoelectric response. Here, we employ MBE to synthesize magnetic TI sandwich heterostructures and find that the axion insulator state persists in a 3D sample with a thickness of ~ 106 nm. Our transport results show that the axion insulator state starts to emerge when the thickness of the middle undoped TI layer is greater than ~ 3 nm. The 3D hundred-nanometer-thick axion insulator provides a promising platform for the exploration of the topological magnetoelectric effect and other emergent magnetic topological states, such as the high-order TI phase.
Brain metastasis, EGFR mutation subtype and generation of EGFR-TKI jointly influence the treatment outcome of patient with EGFR-mutant NSCLC
Authors: Ju Jia-Shiuan , Huang Allen Chung-Cheng , Tung Pi-Hung , Huang Chi-Hsien , Chiu Tzu-Hsuan , Wang Chin-Chou , Ko How-Wen , Chung Fu-Tsai , Hsu Ping-Chih , Fang Yueh-Fu , Guo Yi-Ke , Kuo Chih-Hsi Scott , Yang Cheng-Ta
Published: November 2023

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients’ outcome. 553 metastatic EGFR-mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99–1.48]; p = 0.053), ECOG PS 0–1 (HR 0.71 [95% CI 0.54–0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66–0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0–1 (HR 0.41 [95% CI 0.31–0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13–1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02–4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12–0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28–1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR-mutant NSCLC, whereas OS was mainly associated with EGFR subtype.
Economic implications of autonomous adaptation of firms and households in a resource-rich coastal city
Authors: Taberna Alessandro , Filatova Tatiana , Hochrainer-Stigler Stefan , Nikolic Igor , Noll Brayton
Published: November 2023

Climate change intensifies the likelihood of extreme flood events worldwide, amplifying the potential for compound flooding. This evolving scenario represents an escalating risk, emphasizing the urgent need for comprehensive climate change adaptation strategies across society. Vital to effective response are models that evaluate damages, costs, and benefits of adaptation strategies, encompassing non-linearities and feedback between anthropogenic and natural systems. While flood risk modeling has progressed, limitations endure, including inadequate stakeholder representation and indirect risks such as business interruption and diminished tax revenues. To address these gaps, we propose an innovative version of the Climate-economy Regional Agent-Based model that integrates a dynamic, rapidly expanding agglomeration economy populated by interacting households and firms with extreme flood events. Through this approach, feedback loops and cascading effects generated by flood shocks are delineated within a socio-economic system of boundedly-rational agents. By leveraging extensive behavioral data, our model incorporates a risk layering strategy encompassing bottom-up and top-down adaptation, spanning individual risk reduction to insurance. Calibrated to resemble a research-rich coastal megacity in China, our model demonstrates how synergistic adaptation actions at all levels effectively combat the mounting climate threat. Crucially, the integration of localized risk management with top-down approaches offers explicit avenues to address both direct and indirect risks, providing significant insights for constructing climate-resilient societies.
A novel code generator for graphical user interfaces
Authors: Cai Bo , Luo Jian , Feng Zhen
Published: November 2023

Graphical user interfaces (GUIs) are widely used in human–computer interaction, providing a convenient interface for operation. Automating the conversion of GUI design images into source code can significantly reduce the coding workload for front-end developers. Detecting elements in GUI images is a key challenge in achieving automatic GUI code generation and is crucial for tasks such as GUI automation and testing. However, current state-of-the-art methods do not fully consider the unique characteristics of GUI images and elements, and they lack the required high localization accuracy, resulting in low detection accuracy for GUI element boxes. In this paper, we propose GUICG, an automatic GUI code generator that combines deep neural networks with image processing techniques to efficiently detect GUI elements from GUI images and generate front-end code. We empirically investigate various deep learning approaches and image processing methods for GUI component detection. Based on a comprehensive understanding of their performance and characteristics, we design GUICG by fusing image processing with a deep learning-based target detection model, achieving state-of-the-art performance. GUICG outperforms existing methods in accuracy and F1 score for component detection tasks, while producing human-readable code with a logical structure. Furthermore, we conduct an ablation study to quantitatively assess the impact of each key element in GUICG.
Burden of diseases attributable to excess body weight in the Middle East and North Africa region, 1990–2019
Authors: Nejadghaderi Seyed Aria , Grieger Jessica A. , Karamzad Nahid , Kolahi Ali-Asghar , Sullman Mark J. M. , Safiri Saeid , Sabour Siamak
Published: November 2023

High body mass index (BMI), or excess body weight (EBW), represents a significant risk factor for a range of diseases, including cardiovascular diseases and cancers. The study sought to determine the burden of diseases attributable to EBW in the Middle East and North Africa (MENA) region from 1990 and 2019. The analysis also included an exploration of this burden by age, sex, underlying cause, and sociodemographic index (SDI). We utilized publicly available data from the Global Burden of Disease (GBD) study 2019 to identify the deaths and disability-adjusted life-years (DALYs) of diseases associated with EBW in MENA, spanning the period from 1990 to 2019. The GBD estimated the mean BMI and the prevalence of EBW using hierarchical mixed-effects regression, followed by spatiotemporal Gaussian process regression to determine the most accurate BMI distribution through comparison with actual data. In 2019, there were an estimated 538.4 thousand deaths (95% UI 369.9–712.3) and 17.9 million DALYs (12.9–23.1) attributable to EBW in the region. The DALYs attributable to EBW were higher in men (9.3 million [6.5–12.4]) than in women (8.5 million [6.4–10.8]). The age-standardized death and DALY rates for the diseases associated with EBW increased by 5.1% (− 9.0–25.9) and 8.3% (− 6.5–28.8), respectively, during the study period which was not significant. Egypt had the highest age-standardized mortality rate due to EBW (217.7 [140.0, 307.8]), while Yemen (88.6 [45.9, 143.5]) had the lowest. In 2019, the highest number of DALYs occurred among individuals aged 60 to 64 years old. Furthermore, we found a positive association between a nation's SDI and the age-standardized DALY rate linked to EBW. Cardiovascular disease emerged as the leading contributor to the EBW burden in MENA. The disease burden attributable to EBW showed a non-significant increase in MENA from 1990 to 2019.
Molecular dynamics of JUNO-IZUMO1 complexation suggests biologically relevant mechanisms in fertilization
Authors: Pacak Paulina , Kluger Carleen , Vogel Viola
Published: November 2023

JUNO-IZUMO1 binding is the first known physical link created between the sperm and egg membranes in fertilization, however, how this initiates sperm-egg fusion remains elusive. As advanced structural insights will help to combat the infertility crisis, or advance fertility control, we employed all-atom Molecular Dynamics (MD) to derive dynamic structural insights that are difficult to obtain experimentally. We found that the hydrated JUNO-IZUMO1 interface is composed of a large set of short-lived non-covalent interactions. The contact interface is destabilized by strategically located point mutations, as well as by Zn2+ ions, which shift IZUMO1 into the non-binding “boomerang” conformation. We hypothesize that the latter might explain how the transient zinc spark, as released after sperm entry into the oocyte, might contribute to block polyspermy. To address a second mystery, we performed another set of simulations, as it was previously suggested that JUNO in solution is unable to bind to folate despite it belonging to the folate receptor family. MD now suggests that JUNO complexation with IZUMO1 opens up the binding pocket thereby enabling folate insertion. Our MD simulations thus provide crucial new hypotheses how the dynamics of the JUNO-IZUMO1 complex upon solvation might regulate fertility.
Solanum lycopersicum heme-binding protein 2 as a potent antimicrobial weapon against plant pathogens
Authors: Farvardin Atefeh , Llorens Eugenio , Liu-Xu Luisa , Sánchez-Giménez Lorena , Wong Aloysius , Biosca Elena G. , Pedra José M. , Falomir Eva , Camañes Gemma , Scalschi Loredana , Vicedo Begonya
Published: November 2023

The rise in antibiotic-resistant bacteria caused by the excessive use of antibiotics has led to the urgent exploration of alternative antimicrobial solutions. Among these alternatives, antimicrobial proteins, and peptides (Apps) have garnered attention due to their wide-ranging antimicrobial effects. This study focuses on evaluating the antimicrobial properties of Solanum lycopersicum heme-binding protein 2 (SlHBP2), an apoplastic protein extracted from tomato plants treated with 1-Methyl tryptophan (1-MT), against Pseudomonas syringae pv. tomato DC3000 (Pst). Computational studies indicate that SlHBP2 is annotated as a SOUL heme-binding family protein. Remarkably, recombinant SlHBP2 demonstrated significant efficacy in inhibiting the growth of Pst within a concentration range of 3–25 μg/mL. Moreover, SlHBP2 exhibited potent antimicrobial effects against other microorganisms, including Xanthomonas vesicatoria (Xv), Clavibacter michiganensis subsp. michiganensis (Cmm), and Botrytis cinerea. To understand the mechanism of action employed by SlHBP2 against Pst, various techniques such as microscopy and fluorescence assays were employed. The results revealed that SlHBP2 disrupts the bacterial cell wall and causes leakage of intracellular contents. To summarize, the findings suggest that SlHBP2 has significant antimicrobial properties, making it a potential antimicrobial agent against a wide range of pathogens. Although further studies are warranted to explore the full potential of SlHBP2 and its suitability in various applications.
Multicenter observational survey on psychosocial and behavioral impacts of COVID-19 in people living with HIV in Northern Vietnam
Authors: Matsumoto Shoko , Nagai Moeko , Tran Linh Khanh , Yamaoka Kazue , Nguyen Hoai Dung Thi , Dinh Van Trang , Tanuma Junko , Pham Thach Ngoc , Oka Shinichi , Van Tran Giang
Published: November 2023

Socially marginalized groups, including people living with HIV/AIDS (PLHIV), could be disproportionately affected by Coronavirus disease 2019 (COVID-19). Following an initial single-center survey conducted in 2020, we conducted a second survey of 11 antiretroviral therapy (ART) sites in Northern Vietnam between June 2021 and January 2022. We tested anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) nucleocapsid IgG antibodies and assessed prevention against COVID-19 and impacts of COVID-19 on access to ART, economic security, risky health behaviors, and mental health using self-reported questionnaires. In total, 7808 PLHIV on ART participated in the second survey. The overall prevalence of SARS-CoV-2 antibody was as low as 1.2%. There was no clear upward trend in COVID-19 infection among PLHIV compared with the rate of infection among the general population. HIV treatment was generally maintained and no increase in risky health behaviors was observed. The economic impacts were significant, with high unemployment rate, poorer economic security, and binge drinking strongly associated with depression. However, the prevalence of depression decreased by 11.2% compared with pre-COVID-19 levels. Social support, including for patients to continue HIV treatment and effective employment/financial assistance, may help to alleviate the negative socioeconomic impacts of COVID-19 and improve mental health among PLHIV.
Survey on chest CT findings in COVID-19 patients in Okinawa, Japan: differences between the delta and omicron variants
Authors: Tsuchiya Nanae , Yonamine Eri , Iraha Shoko , Takara Makoto , Oshiro Yasuji , Tetsuhiro Miyara , Murayama Sadayuki , Kinoshita Ryo , Sato Masaki , Nishikuramori Yukiko , Takara Hiroaki , Akamine Tamaki , Morita Hikaru , Matayoshi Takashi , Chinen Yuma , Nishie Akihiro
Published: November 2023

To investigate the frequency of pneumonia and chest computed tomography (CT) findings in patients with coronavirus disease 2019 (COVID-19) during the fifth Delta variant-predominant and sixth Omicron variant-predominant waves of the COVID-19 pandemic in Okinawa, Japan. A survey on chest CT examinations for patients with COVID-19 was conducted byhospitals with board-certified radiologists who provided treatment for COVID-19 pneumonia in Okinawa Prefecture. Data from 11 facilities were investigated. Indications for chest CT; number of COVID-19 patients undergoing chest CT; number of patients with late-onset pneumonia, tracheal intubation, and number of deaths; and COVID-19 Reporting and Data System classifications of initial chest CT scans were compared by the chi-squared test between the two pandemic waves (Delta vs. Omicron variants). A total of 1944 CT scans were performed during the fifth wave, and 1178 were performed during the sixth wave. CT implementation rates, which were the number of patients with COVID-19 undergoing CT examinations divided by the total number of COVID-19 cases in Okinawa Prefecture during the waves, were 7.1% for the fifth wave and 2.1% for the sixth wave. The rates of tracheal intubation and mortality were higher in the fifth wave. Differences between the distributions of the CO-RADS classifications were statistically significant for the fifth and sixth waves (p < 0.0001). In the fifth wave, CO-RADS 5 (typical of COVID-19) was most common (65%); in the sixth wave, CO-RADS 1 (no findings of pneumonia) was most common (50%). The finding of “typical for other infection but not COVID-19” was more frequent in the sixth than in the fifth wave (13.6% vs. 1.9%, respectively). The frequencies of pneumonia and typical CT findings were higher in the fifth Delta variant-predominant wave, and nontypical CT findings were more frequent in the sixth Omicron variant-predominant wave of the COVID-19 pandemic in Okinawa, Japan.
AePUb promoter length modulates gene expression in Aedes aegypti
Authors: Anderson Michelle A. E. , Leftwich Philip T. , Wilson Ray , Paladino Leonela Z. Carabajal , Basu Sanjay , Rooney Sara , Adelman Zach N. , Alphey Luke
Published: November 2023

Molecular tools for modulating transgene expression in Aedes aegypti are few. Here we demonstrate that adjustments to the AePUb promoter length can alter expression levels of two reporter proteins in Ae. aegypti cell culture and in mosquitoes. This provides a simple means for increasing or decreasing expression of a gene of interest and easy translation from cells to whole insects.
Comparative analysis of four nutritional scores predicting the incidence of MACE in older adults with acute coronary syndromes after PCI
Authors: Zhu Xing-Yu , Yang Dan-Dan , Zhang Kai-Jie , Zhu Hui-Jing , Su Fei-Fei , Tian Jian-Wei
Published: November 2023

To determine the most appropriate nutritional assessment tool for predicting the occurrence of major adverse cardiovascular events (MACE) within 1 year in elderly ACS patients undergoing PCI from four nutritional assessment tools including PNI, GNRI, CONUT, and BMI. Consecutive cases diagnosed with acute coronary syndrome (ACS) and underwent percutaneous coronary intervention (PCI) in the Department of Cardiovascular Medicine of the Air force characteristic medical center from 1 January 2020 to 1 April 2022 were retrospectively collected. The basic clinical characteristics and relevant test and examination indexes were collected uniformly, and the cases were divided into the MACE group (174 cases) and the non-MACE group (372 cases) according to whether a major adverse cardiovascular event (MACE) had occurred within 1 year. Predictive models were constructed to assess the nutritional status of patients with the Prognostic Nutritional Index (PNI), Geriatric Nutritional Risk Index (GNRI), Controlling nutritional status (CONUT) scores, and Body Mass Index (BMI), respectively, and to analyze their relationship with prognosis. The incremental value of the four nutritional assessment tools in predicting risk was compared using the Integrated Discriminant Improvement (IDI) and the net reclassification improvement (NRI). The predictive effect of each model on the occurrence of major adverse cardiovascular events (MACE) within 1 year in elderly ACS patients undergoing PCI was assessed using area under the ROC curve (AUC), calibration curves, decision analysis curves, and clinical impact curves; comparative analyses were performed. Among the four nutritional assessment tools, the area under the curve (AUC) was significantly higher for the PNI (AUC: 0.798, 95%CI 0.755–0.840 P < 0.001) and GNRI (AUC: 0.760, 95%CI 0.715–0.804 P < 0.001) than for the CONUT (AUC: 0.719,95%CI 0.673–0.765 P < 0.001) and BMI (AUC: 0.576, 95%CI 0.522–0.630 P < 0.001). The positive predictive value (PPV) of PNI: 67.67% was better than GNRI, CONUT, and BMI, and the negative predictive value (NPV): of 83.90% was better than CONUT and BMI and similar to the NPV of GNRI. The PNI, GNRI, and CONUT were compared with BMI, respectively. The PNI had the most significant improvement in the Integrated Discriminant Improvement Index (IDI) (IDI: 0.1732, P < 0.001); the PNI also had the most significant improvement in the Net Reclassification Index (NRI) (NRI: 0.8185, P < 0.001). In addition, of the four nutritional assessment tools used in this study, the PNI was more appropriate for predicting the occurrence of major adverse cardiovascular events (MACE) within 1 year in elderly ACS patients undergoing PCI.
Comparison of the effectiveness of integrative immunomodulatory treatments and conventional therapies on the survival of selected gastrointestinal cancer patients
Authors: Kleef Ralf , Dank Magdolna , Herold Magdolna , Agoston Emese Irma , Lohinszky Julia , Martinek Emoke , Herold Zoltan , Szasz Attila Marcell
Published: November 2023

In the last decade, the use of immunomodulating treatments (IMT) at integrative oncology providers (IOP) increased. IMTs are used to modulate the tumor microenvironment, which might lead to increased response-to-treatment, and the indication of immune checkpoint inhibitors might also be widened. The efficacy and safety of IMTs in advanced/metastatic gastrointestinal cancers were compared with conventional chemo(radio)therapy (CT). 21 colorectal– (CRC), 14 pancreatic– (PC), 5 cholangiocellular– (CCC), 5 gastric– (GC) and 4 esophageal cancer (EC) patients received IMT. IMT and CT were compared in CRC and PC. CT was administered at an academic oncology center. After the initiation of IMT, a median survival of ~ 20 (CRC, PC and EC) and ~ 10 months (CCC and GC) was observed. Of the IMTs, locoregional modulated electro-hyperthermia had the most positive effect on overall survival (HR: 0.3055; P = 0.0260), while fever-inducing interleukin-2, and low-dose ipilimumab showed a positive tendency. IMT was superior to CT in PC (HR: 0.1974; P = 0.0013), while modest effect was detected in CRC (HR: 0.7797; P = 0.4710). When the whole study population was analyzed, IMTs showed minimal effect on patient survival, still CT had the greatest effect if introduced as early as possible (HR: 0.0624; P < 0.0001). The integrative IMTs in the presented form have mild impact on gastrointestinal cancer patients’ survival, however, we observed its benefit in PC, which warrants further investigations.
Genotyping and phylogenetic analysis of Coxiella burnetii in domestic ruminant and clinical samples in Iran: insights into Q fever epidemiology
Authors: Mohabati Mobarez Ashraf , Baseri Neda , Khalili Mohammad , Mostafavi Ehsan , Esmaeili Saber
Published: November 2023

Coxiella burnetii, a zoonotic pathogen, is the causative agent of Q fever, an endemic disease in Iran. However, there is currently a lack of available data on the genotypes of C. burnetii in the country. Here, we typed 26 C. burnetii isolates detected in milk, abortion, cotylodon, and cardiac valve samples from various geographical areas and hosts (7 cattle, 8 goats, 10 sheep, and 1 human) using Multilocus Variable Number Tandem Repeat Analysis (MLVA/VNTR) with five loci:ms24, ms27, ms28, ms33, and ms34. As IS1111 was observed to be spontaneously inserted in locus ms23 across all of our examined C. burnetii samples, five loci were employed for MLVA/VNTR genotyping. Among the 26 C. burnetii strains, 22 distinct genotypes (A–V) were identified in the discriminative loci. In silico analysis categorized Iranian C. burnetii strains into five genomic groups along with seven singletons, representing 11 exiting clonal complexes worldwide. Clusters 10 and 11 exclusively consisted of Iranian samples. These findings revealed high genotyping diversity among C. burnetii isolates in Iran. The genotypes circulating in Iran differed significantly from those found in other regions worldwide. To gain a comprehensive understanding of Q fever epidemiology in Iran, it is crucial to conduct large-scale studies that assess the distribution of C. burnetii genotypes across different geographical areas, hosts, and sources.