bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of BRCA2 R3052Q variant in mice supports its functional impact as a low-risk variant
Authors: Mishra Arun Prakash , Hartford Suzanne , Chittela Rajani Kant , Sahu Sounak , Kharat Suhas S. , Alvaro-Aranda Lucia , Contreras-Perez Aida , Sullivan Teresa , Martin Betty K. , Albaugh Mary , Southon Eileen , Burkett Sandra , Karim Baktiar , Carreira Aura , Tessarollo Lino , Sharan Shyam K.
Published: November 2023

Pathogenic variants in BRCA2 are known to significantly increase the lifetime risk of developing breast and ovarian cancers. Sequencing-based genetic testing has resulted in the identification of thousands of BRCA2 variants that are considered to be variants of uncertain significance (VUS) because the disease risk associated with them is unknown. One such variant is p.Arg3052Gln, which has conflicting interpretations of pathogenicity in the ClinVar variant database. Arginine at position 3052 in BRCA2 plays an important role in stabilizing its C-terminal DNA binding domain. We have generated a knock-in mouse model expressing this variant to examine its role on growth and survival in vivo. Homozygous as well as hemizygous mutant mice are viable, fertile and exhibit no overt phenotype. While we did not observe any hematopoietic defects in adults, we did observe a marked reduction in the in vitro proliferative ability of fetal liver cells that were also hypersensitive to PARP inhibitor, olaparib. In vitro studies performed on embryonic and adult fibroblasts derived from the mutant mice showed significant reduction in radiation induced RAD51 foci formation as well as increased genomic instability after mitomycin C treatment. We observed mis-localization of a fraction of R3052Q BRCA2 protein to the cytoplasm which may explain the observed in vitro phenotypes. Our findings suggest that BRCA2 R3052Q should be considered as a hypomorphic variant.
Three-degrees-of-freedom orientation manipulation of small untethered robots with a single anisotropic soft magnet
Authors: Wang Heng , Cui Junhao , Tian Kuan , Han Yuxiang
Published: November 2023

Magnetic actuation has been well exploited for untethered manipulation and locomotion of small-scale robots in complex environments such as intracorporeal lumens. Most existing magnetic actuation systems employ a permanent magnet onboard the robot. However, only 2-DoF orientation of the permanent-magnet robot can be controlled since no torque can be generated about its axis of magnetic moment, which limits the dexterity of manipulation. Here, we propose a new magnetic actuation method using a single soft magnet with an anisotropic geometry (e.g., triaxial ellipsoids) for full 3-DoF orientation manipulation. The fundamental actuation principle of anisotropic magnetization and 3-DoF torque generation are analytically modeled and experimentally validated. The hierarchical orientation stability about three principal axes is investigated, based on which we propose and validate a multi-step open-loop control strategy to alternatingly manipulate the direction of the longest axis of the soft magnet and the rotation about it for dexterous 3-DoF orientation manipulation.
PET/CT based cross-modal deep learning signature to predict occult nodal metastasis in lung cancer
Authors: Zhong Yifan , Cai Chuang , Chen Tao , Gui Hao , Deng Jiajun , Yang Minglei , Yu Bentong , Song Yongxiang , Wang Tingting , Sun Xiwen , Shi Jingyun , Chen Yangchun , Xie Dong , Chen Chang , She Yunlang
Published: November 2023

Occult nodal metastasis (ONM) plays a significant role in comprehensive treatments of non-small cell lung cancer (NSCLC). This study aims to develop a deep learning signature based on positron emission tomography/computed tomography to predict ONM of clinical stage N0 NSCLC. An internal cohort (n = 1911) is included to construct the deep learning nodal metastasis signature (DLNMS). Subsequently, an external cohort (n = 355) and a prospective cohort (n = 999) are utilized to fully validate the predictive performances of the DLNMS. Here, we show areas under the receiver operating characteristic curve of the DLNMS for occult N1 prediction are 0.958, 0.879 and 0.914 in the validation set, external cohort and prospective cohort, respectively, and for occult N2 prediction are 0.942, 0.875 and 0.919, respectively, which are significantly better than the single-modal deep learning models, clinical model and physicians. This study demonstrates that the DLNMS harbors the potential to predict ONM of clinical stage N0 NSCLC.
Precise solid-phase synthesis of CoFe@FeOx nanoparticles for efficient polysulfide regulation in lithium/sodium-sulfur batteries
Authors: Chen Yanping , Yao Yu , Zhao Wantong , Wang Lifeng , Li Haitao , Zhang Jiangwei , Wang Baojun , Jia Yi , Zhang Riguang , Yu Yan , Liu Jian
Published: November 2023

Complex metal nanoparticles distributed uniformly on supports demonstrate distinctive physicochemical properties and thus attract a wide attention for applications. The commonly used wet chemistry methods display limitations to achieve the nanoparticle structure design and uniform dispersion simultaneously. Solid-phase synthesis serves as an interesting strategy which can achieve the fabrication of complex metal nanoparticles on supports. Herein, the solid-phase synthesis strategy is developed to precisely synthesize uniformly distributed CoFe@FeOx core@shell nanoparticles. Fe atoms are preferentially exsolved from CoFe alloy bulk to the surface and then be carburized into a FexC shell under thermal syngas atmosphere, subsequently the formed FexC shell is passivated by air, obtaining CoFe@FeOx with a CoFe alloy core and a FeOx shell. This strategy is universal for the synthesis of MFe@FeOx (M = Co, Ni, Mn). The CoFe@FeOx exhibits bifunctional effect on regulating polysulfides as the separator coating layer for Li-S and Na-S batteries. This method could be developed into solid-phase synthetic systems to construct well distributed complex metal nanoparticles.
Adaptive traits of cysts of the snow alga Sanguina nivaloides unveiled by 3D subcellular imaging
Authors: Ezzedine Jade A. , Uwizeye Clarisse , Si Larbi Grégory , Villain Gaelle , Louwagie Mathilde , Schilling Marion , Hagenmuller Pascal , Gallet Benoît , Stewart Adeline , Petroutsos Dimitris , Devime Fabienne , Salze Pascal , Liger Lucie , Jouhet Juliette , Dumont Marie , Ravanel Stéphane , Amato Alberto , Valay Jean-Gabriel , Jouneau Pierre-Henri , Falconet Denis , Maréchal Eric
Published: November 2023

Sanguina nivaloides is the main alga forming red snowfields in high mountains and Polar Regions. It is non-cultivable. Analysis of environmental samples by X-ray tomography, focused-ion-beam scanning-electron-microscopy, physicochemical and physiological characterization reveal adaptive traits accounting for algal capacity to reside in snow. Cysts populate liquid water at the periphery of ice, are photosynthetically active, can survive for months, and are sensitive to freezing. They harbor a wrinkled plasma membrane expanding the interface with environment. Ionomic analysis supports a cell efflux of K+, and assimilation of phosphorus. Glycerolipidomic analysis confirms a phosphate limitation. The chloroplast contains thylakoids oriented in all directions, fixes carbon in a central pyrenoid and produces starch in peripheral protuberances. Analysis of cells kept in the dark shows that starch is a short-term carbon storage. The biogenesis of cytosolic droplets shows that they are loaded with triacylglycerol and carotenoids for long-term carbon storage and protection against oxidative stress.
Lipases and carboxylesterases affect moth sex pheromone compounds involved in interspecific mate recognition
Authors: de Fouchier Arthur , Fruitet Elise , Lievers Rik , Kuperus Peter , Emerson Jennifer , Gould Fred , Heckel David G. , Groot Astrid T.
Published: November 2023

Moth sex pheromones are a classical model for studying sexual selection. Females typically produce a species-specific pheromone blend that attracts males. Revealing the enzymes involved in the interspecific variation in blend composition is key for understanding the evolution of these sexual communication systems. The nature of the enzymes involved in the variation of acetate esters, which are prominent compounds in moth pheromone blends, remains unclear. We identify enzymes involved in acetate degradation using two closely related moth species: Heliothis (Chloridea) subflexa and H. (C.) virescens, which have different quantities of acetate esters in their sex pheromone. Through comparative transcriptomic analyses and CRISPR/Cas9 knockouts, we show that two lipases and two esterases from H. virescens reduce the levels of pheromone acetate esters when expressed in H. subflexa females. Together, our results show that lipases and carboxylesterases are involved in tuning Lepidoptera pheromones composition.
Morphological evolution of bird wings follows a mechanical sensitivity gradient determined by the aerodynamics of flapping flight
Authors: Rader Jonathan A. , Hedrick Tyson L.
Published: November 2023

The physical principles that govern the function of biological structures also mediate their evolution, but the evolutionary drivers of morphological traits within complex structures can be difficult to predict. Here, we use morphological traits measured from 1096 3-dimensional bird wing scans from 178 species to test the interaction of two frameworks for relating morphology to evolution. We examine whether the evolutionary rate (σ2) and mode is dominated by the modular organization of the wing into handwing and armwing regions, and/or the relationship between trait morphology and functional output (i.e. mechanical sensitivity, driven here by flapping flight aerodynamics). Our results support discretization of the armwing and handwing as morphological modules, but morphological disparity andσ2varied continuously with the mechanical sensitivity gradient and were not modular. Thus, mechanical sensitivity should be considered an independent and fundamental driver of evolutionary dynamics in biomechanical traits, distinct from morphological modularity.
Membrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT
Authors: Khan Farha , Elgeti Matthias , Grandfield Samuel , Paz Aviv , Naughton Fiona B. , Marcoline Frank V. , Althoff Thorsten , Ermolova Natalia , Wright Ernest M. , Hubbell Wayne L. , Grabe Michael , Abramson Jeff
Published: November 2023

Sodium-dependent glucose transporters (SGLTs) couple a downhill Na+ ion gradient to actively transport sugars. Here, we investigate the impact of the membrane potential on vSGLT structure and function using sugar uptake assays, double electron-electron resonance (DEER), electrostatic calculations, and kinetic modeling. Negative membrane potentials, as present in all cell types, shift the conformational equilibrium of vSGLT towards an outward-facing conformation, leading to increased sugar transport rates. Electrostatic calculations identify gating charge residues responsible for this conformational shift that when mutated reduce galactose transport and eliminate the response of vSGLT to potential. Based on these findings, we propose a comprehensive framework for sugar transport via vSGLT, where the cellular membrane potential facilitates resetting of the transporter after cargo release. This framework holds significance not only for SGLTs but also for other transporters and channels.
The TDRD3-USP9X complex and MIB1 regulate TOP3B homeostasis and prevent deleterious TOP3B cleavage complexes
Authors: Saha Sourav , Huang Shar-yin Naomi , Yang Xi , Saha Liton Kumar , Sun Yilun , Khandagale Prashant , Jenkins Lisa M. , Pommier Yves
Published: November 2023

TOP3B is stabilized by TDRD3. Hypothesizing that TDRD3 recruits a deubiquitinase, we find that TOP3B interacts with USP9X via TDRD3. Inactivation of USP9X destabilizes TOP3B, and depletion of both TDRD3 and USP9X does not promote further TOP3B ubiquitylation. Additionally, we observe that MIB1 mediates the ubiquitylation and proteasomal degradation of TOP3B by directly interacting with TOP3B independently of TDRD3. Combined depletion of USP9X, TDRD3 and MIB1 causes no additional increase in TOP3B levels compared to MIB1 knockdown alone indicating that the TDRD3-USP9X complex works downstream of MIB1. To comprehend why cells degrade TOP3B in the absence of TDRD3, we measured TOP3Bccs. Lack of TDRD3 increases TOP3Bccs in DNA and RNA, and induced R-loops, γH2AX and growth defect. Biochemical experiments confirm that TDRD3 increases the turnover of TOP3B. Our work provides molecular insights into the mechanisms by which TDRD3 protect cells from deleterious TOP3Bccs which are otherwise removed by TRIM41.
A primate nigrostriatal atlas of neuronal vulnerability and resilience in a model of Parkinson’s disease
Authors: Tang Lei , Xu Nana , Huang Mengyao , Yi Wei , Sang Xuan , Shao Mingting , Li Ye , Hao Zhao-zhe , Liu Ruifeng , Shen Yuhui , Yue Feng , Liu Xialin , Xu Chuan , Liu Sheng
Published: November 2023

The degenerative process in Parkinson’s disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. Here we generated high-quality profiles for 250,173 cells from the substantia nigra (SN) and putamen (PT) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian macaques and matched controls. Our primate model of parkinsonism recapitulates important pathologic features in nature PD and provides an unbiased view of the axis of neuronal vulnerability and resistance. We identified seven molecularly defined subtypes of nigral DaNs which manifested a gradient of vulnerability and were confirmed by fluorescence-activated nuclei sorting. Neuronal resilience was associated with a FOXP2-centered regulatory pathway shared between PD-resistant DaNs and glutamatergic excitatory neurons, as well as between humans and nonhuman primates. We also discovered activation of immune response common to glial cells of SN and PT, indicating concurrently activated pathways in the nigrostriatal system. Our study provides a unique resource to understand the mechanistic connections between neuronal susceptibility and PD pathophysiology, and to facilitate future biomarker discovery and targeted cell therapy.
Cosmic-void observations reconciled with primordial magnetogenesis
Authors: Hosking David N. , Schekochihin Alexander A.
Published: November 2023

It has been suggested that the weak magnetic field hosted by the intergalactic medium in cosmic voids could be a relic from the early Universe. However, accepted models of turbulent magnetohydrodynamic decay predict that the present-day strength of fields originally generated at the electroweak phase transition (EWPT) without parity violation would be too low to explain the observed scattering ofγ-rays from TeV blazars. Here, we propose that the decay is mediated by magnetic reconnection and conserves the mean square fluctuation level of magnetic helicity. We find that the relic fields would be stronger by several orders of magnitude under this theory than was indicated by previous treatments, which restores the consistency of the EWPT-relic hypothesis with the observational constraints. Moreover, efficient EWPT magnetogenesis would produce relics at the strength required to resolve the Hubble tension via magnetic effects at recombination and seed galaxy-cluster fields close to their present-day strength.
The homeodomain transcriptional regulator DVE-1 directs a program for synapse elimination during circuit remodeling
Authors: Alexander Kellianne D. , Ramachandran Shankar , Biswas Kasturi , Lambert Christopher M. , Russell Julia , Oliver Devyn B. , Armstrong William , Rettler Monika , Liu Samuel , Doitsidou Maria , Bénard Claire , Walker Amy K. , Francis Michael M.
Published: November 2023

The elimination of synapses during circuit remodeling is critical for brain maturation; however, the molecular mechanisms directing synapse elimination and its timing remain elusive. We show that the transcriptional regulator DVE-1, which shares homology with special AT-rich sequence-binding (SATB) family members previously implicated in human neurodevelopmental disorders, directs the elimination of juvenile synaptic inputs onto remodeling C. elegans GABAergic neurons. Juvenile acetylcholine receptor clusters and apposing presynaptic sites are eliminated during the maturation of wild-type GABAergic neurons but persist into adulthood in dve-1 mutants, producing heightened motor connectivity. DVE-1 localization to GABAergic nuclei is required for synapse elimination, consistent with DVE-1 regulation of transcription. Pathway analysis of putative DVE-1 target genes, proteasome inhibitor, and genetic experiments implicate the ubiquitin-proteasome system in synapse elimination. Together, our findings define a previously unappreciated role for a SATB family member in directing synapse elimination during circuit remodeling, likely through transcriptional regulation of protein degradation processes.
Architecture of the baculovirus nucleocapsid revealed by cryo-EM
Authors: Jia Xudong , Gao Yuanzhu , Huang Yuxuan , Sun Linjun , Li Siduo , Li Hongmei , Zhang Xueqing , Li Yinyin , He Jian , Wu Wenbi , Venkannagari Harikanth , Yang Kai , Baker Matthew L. , Zhang Qinfen
Published: November 2023

Baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) has been widely used as a bioinsecticide and a protein expression vector. Despite their importance, very little is known about the structure of most baculovirus proteins. Here, we show a 3.2 Å resolution structure of helical cylindrical body of the AcMNPV nucleocapsid, composed of VP39, as well as 4.3 Å resolution structures of both the head and the base of the nucleocapsid composed of over 100 protein subunits. AcMNPV VP39 demonstrates some features of the HK97-like fold and utilizes disulfide-bonds and a set of interactions at its C-termini to mediate nucleocapsid assembly and stability. At both ends of the nucleocapsid, the VP39 cylinder is constricted by an outer shell ring composed of proteins AC104, AC142 and AC109. AC101(BV/ODV-C42) and AC144(ODV-EC27) form a C14 symmetric inner layer at both capsid head and base. In the base, these proteins interact with a 7-fold symmetric capsid plug, while a portal-like structure is seen in the central portion of head. Additionally, we propose an application of AlphaFold2 for model building in intermediate resolution density.
Comprehensive genomic characterization of HER2-low and HER2-0 breast cancer
Authors: Tarantino Paolo , Gupta Hersh , Hughes Melissa E. , Files Janet , Strauss Sarah , Kirkner Gregory , Feeney Anne-Marie , Li Yvonne , Garrido-Castro Ana C. , Barroso-Sousa Romualdo , Bychkovsky Brittany L. , DiLascio Simona , Sholl Lynette , MacConaill Laura , Lindeman Neal , Johnson Bruce E. , Meyerson Matthew , Jeselsohn Rinath , Qiu Xintao , Li Rong , Long Henry , Winer Eric P. , Dillon Deborah , Curigliano Giuseppe , Cherniack Andrew D. , Tolaney Sara M. , Lin Nancy U.
Published: November 2023

The molecular underpinnings of HER2-low and HER2-0 (IHC 0) breast tumors remain poorly defined. Using genomic findings from 1039 patients with HER2-negative metastatic breast cancer undergoing next-generation sequencing from 7/2013-12/2020, we compare results between HER2-low (n = 487, 47%) and HER2-0 tumors (n = 552, 53%). A significantly higher number of ERBB2 alleles (median copy count: 2.05) are observed among HER2-low tumors compared to HER2-0 (median copy count: 1.79; P = 2.36e-6), with HER2-0 tumors harboring a higher rate of ERBB2 hemideletions (31.1% vs. 14.5%). No other genomic alteration reaches significance after accounting for multiple hypothesis testing, and no significant differences in tumor mutational burden are observed between HER2-low and HER2-0 tumors (median: 7.26 mutations/megabase vs. 7.60 mutations/megabase, p = 0.24). Here, we show that the genomic landscape of HER2-low and HER2-0 tumors does not differ significantly, apart from a higher ERBB2 copy count among HER2-low tumors, and a higher rate of ERBB2 hemideletions in HER2-0 tumors.
Diurnal switches in diazotrophic lifestyle increase nitrogen contribution to cereals
Authors: Tang Yuqian , Qin Debin , Tian Zhexian , Chen Wenxi , Ma Yuanxi , Wang Jilong , Yang Jianguo , Yan Dalai , Dixon Ray , Wang Yi-Ping
Published: November 2023

Uncoupling of biological nitrogen fixation from ammonia assimilation is a prerequisite step for engineering ammonia excretion and improvement of plant-associative nitrogen fixation. In this study, we have identified an amino acid substitution in glutamine synthetase, which provides temperature sensitive biosynthesis of glutamine, the intracellular metabolic signal of the nitrogen status. As a consequence, negative feedback regulation of genes and enzymes subject to nitrogen regulation, including nitrogenase is thermally controlled, enabling ammonia excretion in engineered Escherichia coli and the plant-associated diazotroph Klebsiella oxytoca at 23 °C, but not at 30 °C. We demonstrate that this temperature profile can be exploited to provide diurnal oscillation of ammonia excretion when variant bacteria are used to inoculate cereal crops. We provide evidence that diurnal temperature variation improves nitrogen donation to the plant because the inoculant bacteria have the ability to recover and proliferate at higher temperatures during the daytime.
Asymmetric CRISPR enabling cascade signal amplification for nucleic acid detection by competitive crRNA
Authors: Moon Jeong , Liu Changchun
Published: November 2023

Nucleic acid detection powered by CRISPR technology provides a rapid, sensitive, and deployable approach to molecular diagnostics. While exciting, there remain challenges limiting its practical applications, such as the need for pre-amplification and the lack of quantitative ability. Here, we develop an asymmetric CRISPR assay for cascade signal amplification detection of nucleic acids by leveraging the asymmetric trans-cleavage behavior of competitive crRNA. We discover that the competitive reaction between a full-sized crRNA and split crRNA for CRISPR-Cas12a can induce cascade signal amplification, significantly improving the target detection signal. In addition, we find that CRISPR-Cas12a can recognize fragmented RNA/DNA targets, enabling direct RNA detection by Cas12a. Based on these findings, we apply our asymmetric CRISPR assay to quantitatively detect microRNA without the need for pre-amplification, achieving a detection sensitivity of 856 aM. Moreover, using this method, we analyze and quantify miR-19a biomarker in plasma samples from bladder cancer patients. This asymmetric CRISPR assay has the potential to be widely applied for simple and sensitive nucleic acid detection in various diagnostic settings.
Critical role of electrons in the short lifetime of blue OLEDs
Authors: Kim Jaewook , Kim Joonghyuk , Kim Yongjun , Son Youngmok , Shin Youngsik , Bae Hye Jin , Kim Ji Whan , Nam Sungho , Jung Yongsik , Kim Hyeonsu , Kang Sungwoo , Jung Yoonsoo , Lee Kyunghoon , Choi Hyeonho , Kim Woo Youn
Published: November 2023

Designing robust blue organic light-emitting diodes is a long-standing challenge in the display industry. The highly energetic states of blue emitters cause various degradation paths, leading to collective luminance drops in a competitive manner. However, a key mechanism of the operational degradation of organic light-emitting diodes has yet to be elucidated. Here, we show that electron-induced degradation reactions play a critical role in the short lifetime of blue organic light-emitting diodes. Our control experiments demonstrate that the operational lifetime of a whole device can only be explained when excitons and electrons exist together. We examine the atomistic mechanisms of the electron-induced degradation reactions by analyzing their energetic profiles using computational methods. Mass spectrometric analysis of aged devices further confirm the key mechanisms. These results provide new insight into rational design of robust blue organic light-emitting diodes.
Strong transient magnetic fields induced by THz-driven plasmons in graphene disks
Authors: Han Jeong Woo , Sai Pavlo , But Dmytro B. , Uykur Ece , Winnerl Stephan , Kumar Gagan , Chin Matthew L. , Myers-Ward Rachael L. , Dejarld Matthew T. , Daniels Kevin M. , Murphy Thomas E. , Knap Wojciech , Mittendorff Martin
Published: November 2023

Strong circularly polarized excitation opens up the possibility to generate and control effective magnetic fields in solid state systems, e.g., via the optical inverse Faraday effect or the phonon inverse Faraday effect. While these effects rely on material properties that can be tailored only to a limited degree, plasmonic resonances can be fully controlled by choosing proper dimensions and carrier concentrations. Plasmon resonances provide new degrees of freedom that can be used to tune or enhance the light-induced magnetic field in engineered metamaterials. Here we employ graphene disks to demonstrate light-induced transient magnetic fields from a plasmonic circular current with extremely high efficiency. The effective magnetic field at the plasmon resonance frequency of the graphene disks (3.5 THz) is evidenced by a strong ( ~ 1°) ultrafast Faraday rotation ( ~ 20 ps). In accordance with reference measurements and simulations, we estimated the strength of the induced magnetic field to be on the order of 0.7 T under a moderate pump fluence of about 440 nJ cm−2.
Biofilm heterogeneity-adaptive photoredox catalysis enables red light-triggered nitric oxide release for combating drug-resistant infections
Authors: Cheng Jian , Gan Guihai , Zheng Shaoqiu , Zhang Guoying , Zhu Chen , Liu Shiyong , Hu Jinming
Published: November 2023

The formation of biofilms is closely associated with persistent and chronic infections, and physiological heterogeneity such as pH and oxygen gradients renders biofilms highly resistant to conventional antibiotics. To date, effectively treating biofilm infections remains a significant challenge. Herein, we report the fabrication of micellar nanoparticles adapted to heterogeneous biofilm microenvironments, enabling nitric oxide (NO) release through two distinct photoredox catalysis mechanisms. The key design feature involves the use of tertiary amine (TA) moieties, which function as sacrificial agents to avoid the quenching of photocatalysts under normoxic and neutral pH conditions and proton acceptors at acidic pH to allow deep biofilm penetration. This biofilm-adaptive NO-releasing platform shows excellent antibiofilm activity against ciprofloxacin-resistant Pseudomonas aeruginosa (CRPA) biofilms both in vitro and in a mouse skin infection model, providing a strategy for combating biofilm heterogeneity and biofilm-related infections.
Stemness signature and targeted therapeutic drugs identification for Triple Negative Breast Cancer
Authors: Gul Samina , Pang Jianyu , Yuan Hongjun , Chen Yongzhi , yu Qian , Wang Hui , Tang Wenru
Published: November 2023

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and carries the worst prognosis, characterized by the lack of progesterone, estrogen, and HER2 gene expression. This study aimed to analyze cancer stemness-related gene signature to determine patients’ risk stratification and prognosis feature with TNBC. Here one-class logistic regression (OCLR) algorithm was applied to compute the stemness index of TNBC patients. Cox and LASSO regression analysis was performed on stemness-index related genes to establish 16 genes-based prognostic signature, and their predictive performance was verified in TCGA and METABERIC merged data cohort. We diagnosed the expression level of prognostic genes signature in the tumor immune microenvironment, analyzed the TNBC scRNA-seq GSE176078 dataset, and further validated the expression level of prognostic genes using the HPA database. Finally, the small molecular compounds targeted at the anti-tumor effect of predictive genes were screened by molecular docking; this novel stemness-based prognostic genes signature study could facilitate the prognosis of patients with TNBC and thus provide a feasible therapeutic target for TNBC.
Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer
Authors: Saridogan Turcin , Akcakanat Argun , Zhao Ming , Evans Kurt W. , Yuca Erkan , Scott Stephen , Kirby Bryce P. , Zheng Xiaofeng , Ha Min Jin , Chen Huiqin , Ng Patrick K. S. , DiPeri Timothy P. , Mills Gordon B. , Rodon Ahnert Jordi , Damodaran Senthil , Meric-Bernstam Funda
Published: November 2023

Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib’s efficacy in breast cancer models. Nine breast cancer patient–derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2-amplified model and prolonged regression (> 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%–2.6% and 1.5%–2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.
Spatio-temporal pattern evolution of China’s provincial tourism efficiency and development level based on DEA-MI model
Authors: Liao Zhenjie , Zhang Lijuan , Liang Shan
Published: November 2023

The spatial differences of efficiency and development level of regional tourism are evident, and the dynamic grasp of their spatiotemporal evolution characteristics and coupling coordination relationship is important to promote high-quality sustainable tourism development. Herein, we measured the tourism development level of 31 provincial units in China during 2000–2020, introduced the data envelopment analysis-based Malmquist productivity index to determine tourism efficiency, used exploratory spatiotemporal data analysis methods to explore the spatiotemporal dynamic characteristics of regional tourism differences and spatial structure, constructed a coupled coordination model of tourism efficiency and development level and analyzed their coupling excellence and synergistic consistency. The results were as follows: (1) The spatial differences of comprehensive tourism efficiency from 31 provinces were evident, and the average situation showed high and low distribution characteristics in the east and west, respectively. The interannual changes showed a fluctuating downward trend, with the scale efficiency playing a supporting role for comprehensive efficiency and technical efficiency playing an influencing and restraining role. (2) Less fluctuation existed in the local spatial structure of tourism efficiency and development level; the direction of dependence was more stable, tourism development level was slightly more volatile, and the spatial dependency direction changes were similar. The tourism efficiency of local structure competition posture was stronger than that of collaboration, with the tourism development level collaboration integration being stronger. (3) The local spatial structure of tourism development level was more stable, the relative position of provincial units was more difficult to change, tourism efficiency of local spatial structure was unstable, and provincial units exhibited a greater possibility of change. (4) Tourism efficiency and the scale of the overall coupling degree and coupling coordination gradually improved, with similar spatiotemporal values. The overall coupling degree and coupling coordination degree of tourism efficiency and development level gradually improved, with similar spatiotemporal heterogeneity and volatility of local evolution. The area with a higher value coupling coordination degree spread slower and more widely.
Dual pH- and temperature-responsive poly(dimethylaminoethyl methacrylate)-coated mesoporous silica nanoparticles as a smart drug delivery system
Authors: Ramezanian Sina , Moghaddas Jafarsadegh , Roghani-Mamaqani Hossein , Rezamand Azim
Published: November 2023

A robust drug delivery system was created by grafting poly(dimethylaminoethyl methacrylate) (PDMAEMA) onto silica nanoparticles with two different lengths using an in situ atom transfer radical polymerization, resulting in the formation of a pH- and temperature-sensitive shell. The high molecular weight PDMAEMA demonstrated effective controlled drug release, and prevented drug release in healthy cells. Drug release occurred through polymer shell protonation at pH 5. The critical temperature of 41 °C facilitated rapid solvation of the shell polymers in the blood, preventing tissue accumulation and reducing toxicity compared to systems with lower critical solution temperatures. Field-emission scanning electron microscopy analysis and nitrogen adsorption/desorption analysis showed that the nanoparticles have a fine network, mesoporous structure, and a mean size of around 17 nm that show their excellent capacity for loading drugs. Fourier-transform infrared spectroscopy showed that all the modification steps and polymerization were successfully implemented. Thermogravimetric analysis showed PDMAEMA chains with two different lengths grafted onto the nanoparticles. Transmission electron microscopy analysis also showed grafted polymer chains on the hybrid nanoparticles. The release profile of model cancer drugs (doxorubicin and methotrexate) varied with pH and temperature, with high molecular weight PDMAEMA shells effectively preventing drug release at neutral pH. In vitro analysis using the HeLa cell line showed minimal toxicity in blank samples and significant release profile in acidic environment.
Temperature modulates the osmosensitivity of tilapia prolactin cells
Authors: Malintha G. H. T. , Woo Daniel W. , Celino-Brady Fritzie T. , Seale Andre P.
Published: November 2023

In euryhaline fish, prolactin (Prl) plays an essential role in freshwater (FW) acclimation. In the euryhaline and eurythermal Mozambique tilapia, Oreochromis mossambicus, Prl cells are model osmoreceptors, recently described to be thermosensitive. To investigate the effects of temperature on osmoreception, we incubated Prl cells of tilapia acclimated to either FW or seawater (SW) in different combinations of temperatures (20, 26 and 32 °C) and osmolalities (280, 330 and 420 mOsm/kg) for 6 h. Release of both Prl isoforms, Prl188 and Prl177, increased in hyposmotic media and were further augmented with a rise in temperature. Hyposmotically-induced release of Prl188, but not Prl177, was suppressed at 20 °C. In SW fish, mRNA expression of prl188 increased with rising temperatures at lower osmolalities, while and prl177 decreased at 32 °C and higher osmolalities. In Prl cells of SW-acclimated tilapia incubated in hyperosmotic media, the expressions of Prl receptors, prlr1 and prlr2, and the stretch-activated Ca2+ channel, trpv4,decreased at 32 °C, suggesting the presence of a cellular mechanism to compensate for elevated Prl release. Transcription factors, pou1f1, pou2f1b, creb3l1, cebpb, stat3, stat1a and nfat1c, known to regulate prl188 and prl177, were also downregulated at 32 °C. Our findings provide evidence that osmoreception is modulated by temperature, and that both thermal and osmotic responses vary with acclimation salinity.
Reliability and validity of a widely-available AI tool for assessment of stress based on speech
Authors: Yawer Batul A. , Liss Julie , Berisha Visar
Published: November 2023

Cigna’s online stress management toolkit includes an AI-based tool that purports to evaluate a person’s psychological stress level based on analysis of their speech, the Cigna StressWaves Test (CSWT). In this study, we evaluate the claim that the CSWT is a “clinical grade” tool via an independent validation. The results suggest that the CSWT is not repeatable and has poor convergent validity; the public availability of the CSWT despite insufficient validation data highlights concerns regarding premature deployment of digital health tools for stress and anxiety management.
Automated analysis of feeding behaviors of females of the mosquito Aedes aegypti using a modified flyPAD system
Authors: Henriques-Santos Bianca Monteiro , Xiong Caixing , Pietrantonio Patricia V.
Published: November 2023

Mosquitoes present a global health challenge due to their ability to transmit human and animal pathogens upon biting and blood feeding. The investigation of tastants detected by mosquitoes and their associated feeding behaviors is needed to answer physiological and ecological questions that could lead to novel control methods. A high-throughput system originally developed for research in fruit flies feeding behavior, the flyPAD, was adapted and tested for behaviors associated with the interaction or consumption of liquid diets offered to females of the mosquito Aedes aegypti Liverpool strain. Females were given water, sucrose solution and sheep blood in choice and non-choice assays. The volume ingested was evaluated with fluorescein. The placement of the system on a heated surface allowed blood consumption, and without females puncturing a membrane. The flyPAD system recorded nine feeding behavioral variables, of which the number of sips and number of activity bouts correlated with meal volume ingested for both sucrose solution and blood. The adaptation to mosquitoes of the flyPAD system differentiated feeding behavior variables between two feeding deterrents, capsaicin, and caffeine. The flyPAD has potential to quickly assess diverse tastants in both sucrose and blood and may contribute to characterizing more precisely their mode of action.
A versatile model for lifetime of a component under stress
Authors: Almuhayfith Fatimah E. , Arslan Talha , Bakouch Hassan S. , Alnaghmosh Aminh M.
Published: November 2023

In this study, a versatile model, called $$\alpha$$
α
-monotone inverse Weibull distribution ($$\alpha$$
α
IW), for lifetime of a component under stress is introduced by using the $$\alpha$$
α
-monotone concept. The $$\alpha$$
α
IW distribution is also expressed as a scale-mixture between the inverse Weibull distribution and uniform distribution on (0, 1). The $$\alpha$$
α
IW distribution includes $$\alpha$$
α
-monotone inverse exponential and $$\alpha$$
α
-monotone inverse Rayleigh distributions as submodels and converenges to the inverse Weibull, inverse exponential, and inverse Rayleigh distributions as limiting cases. Also, slash Weibull, slash Rayleigh, and slash exponential distribuitons can be obtained under certain variable transformation and parameter settings. The $$\alpha$$
α
IW distribution is characterized by its hazard rate function and characterizing conditions are provided as well. Maximum likelihood, maximum product of spacing, and least squares methods are used to estimate distribution parameters. A Monte-Carlo simulation study is conducted to compare the efficiencies of the considered estimation methods. In the application part, two practical data sets, Kevlar 49/epoxy and Kevlar 373/epoxy, are modeled via the $$\alpha$$
α
IW distribution. Modeling performance of the $$\alpha$$
α
IW distribution is compared with its rivals by means of some well-known goodness-of-fit statistics and results show that $$\alpha$$
α
IW distribution performs better modeling than them. Results of comparison also indicate that obtaining the $$\alpha$$
α
IW distribution by using the $$\alpha$$
α
-monotone concept is cost effective since the new shape parameter added to the distribution by using the $$\alpha$$
α
-monotone concept significantly increases the modeling capability of the IW distribution. As a result of this study, it is shown that the $$\alpha$$
α
IW distribution can be an alternative to the well-known and recently-introduced distributions for modeling purposes.
Single-cell and bulk RNA sequencing reveals Anoikis related genes to guide prognosis and immunotherapy in osteosarcoma
Authors: Zhong Cheng , Yang Dongliang , Zhong Liping , Xie Weixing , Sun Guodong , Jin Daxiang , Li Yuming
Published: November 2023

Anoikis resistance, a notable factor in osteosarcoma, plays a significant role in tumor invasion and metastasis. This study seeks to identify a distinct gene signature that is specifically associated with the anoikis subcluster in osteosarcoma. Clinical, single-cell, and transcriptional data from TARGET and GEO datasets were used to develop a gene signature for osteosarcoma based on the anoikis subcluster. Univariate Cox and LASSO regression analyses were employed. The signature's predictive value was evaluated using time-dependent ROC and Kaplan–Meier analyses. Functional enrichment analyses and drug sensitivity analyses were conducted. Validation of three modular genes was performed using RT-qPCR and Western blotting. Signature (ZNF583, CGNL1, CXCL13) was developed to predict overall survival in osteosarcoma patients, targeting the anoikis subcluster. The signature demonstrated good performance in external validation. Stratification based on the signature revealed significantly different prognoses. The signature was an independent prognostic factor. The low-risk group showed enhanced immune cell infiltration and improved immune function. Drug sensitivity analysis indicated efficacy of chemotherapy agents. Prognostic nomograms incorporating the signature provided greater predictive accuracy and clinical utility. Signatures related to the anoikis subcluster play a significant role in osteosarcoma progression. Incorporating these findings into clinical decision-making can improve osteosarcoma treatment and patient outcomes.
The effect of visual rivalry in peripheral head-mounted displays on mobility
Authors: Han Shui’er , Kim Sujin , Jung Jae-Hyun
Published: November 2023

Recent head-mounted displays and smart glasses use vision multiplexing, an optical approach where two or more views are superimposed on each other. In vision multiplexing, augmented information is presented over an observer’s natural field of view, providing field expansion and critical information during mobility situations like walking and driving. Yet despite its utility, vision multiplexing may produce visual rivalry, a phenomenon where perception alternates between the augmented information and the background scene for seconds at a time. To investigate, we compared the effect of different peripheral vision multiplexing configurations (unilateral opaque, unilateral see-through and bilateral see-through) on the detection of augmented information, incorporating at the same time real-world characteristics (target eccentricity, depth condition, and gaze movement) for a more realistic assessment. Results showed a persistently lower target detection rate in unilateral configurations than the bilateral configuration, suggesting a larger effect of binocular rivalry on target visibility. Nevertheless, this effect does become attenuated when more naturalistic elements are incorporated, and we discuss recommendations for vision multiplexing design and possible avenues for further research.
CT-based comparison of porcine, ovine, and human pulmonary arterial morphometry
Authors: Goubergrits Leonid , Schafstedde Marie , Cesarovic Nikola , Szengel Angelika , Schmitt Boris , Wiegand Moritz , Romberg Jan , Arndt Andreas , Kuehne Titus , Brüning Jan
Published: November 2023

To facilitate pre-clinical animal and in-silico clinical trials for implantable pulmonary artery pressure sensors, understanding the respective species pulmonary arteries (PA) anatomy is important. Thus, morphological parameters describing PA of pigs and sheep, which are common animal models, were compared with humans. Retrospective computed tomography data of 41 domestic pigs (82.6 ± 18.8 kg), 14 sheep (49.1 ± 6.9 kg), and 49 patients (76.8 ± 18.2 kg) were used for reconstruction of the subject-specific PA anatomy. 3D surface geometries including main, left, and right PA as well as LPA and RPA side branches were manually reconstructed. Then, specific geometric parameters (length, diameters, taper, bifurcation angle, curvature, and cross-section enlargement) affecting device implantation and post-interventional device effect and efficacy were automatically calculated. For both animal models, significant differences to the human anatomy for most geometric parameters were found, even though the respective parameters’ distributions also featured relevant overlap. Out of the two animal models, sheep seem to be better suitable for a preclinical study when considering only PA morphology. Reconstructed geometries are provided as open data for future studies. These findings support planning of preclinical studies and will help to evaluate the results of animal trials.
Computational analysis and experimental verification of donor–acceptor behaviour of berberine, and its co-oligomers and co-polymers with ethylenedıoxythıophene
Authors: Gamini Rajapakse R. M. , Horrocks Benjamin R. , Gunarathna H. M. N. P. , Malikaramage A. U. , Egodawele M. G. S. A. M. E. W. D. D. K. , Herath W. H. M. R. N. K. , Sandakelum Lahiru , Bandara V. M. Y. S. U. , Bowatta W. V. N. S. , Susanthi Jayasinghe J. M. , Seneviratne V. N. , Ranatunga Udayana , Perera L. L. K. , Dassanayake S. M. , Udawatte Chandana P.
Published: November 2023

The donor–acceptor (D-A) type of conjugated polymers has emerged as the paradigm of the third generation of electronically conducting polymers demonstrating improved infrared activity and intrinsic electronic conductivity. Judicious selection of donor (D) and acceptor (A) monomers for copolymerization can further fine-tune these properties. Notably, for such refinement, natural compounds provide many conjugated molecules with various functional groups. Berberine cation (Ber+) found in Coscinium fenestratum has extensive conjugation and contains both an electron deficient isoquinolium A moiety and electron-rich D-type methylenedioxy and methoxy groups. The incorporation of natural products in electronic materials is a novel area of research which opens a wide scope for future electronic and optoelectronic devices. Investigation of their fundamental properties via computer simulations is therefore important. In this study, quantum chemical calculations are performed using density functional theory (DFT) to investigate the electronic and optical properties of oligomers of Ber+ and 3,4-ethylenedioxythiophene (EDOT) and to explore the possibilities for homo-polymerization of Ber+ and its copolymerization with EDOT. It has been revealed that homo-polymerization is not favoured but copolymerization with EDOT is possible. As such, Ber+ was copolymerized with EDOT and the copolymers formed by electro-polymerization are extensively characterised and the D-A behaviour of the copolymers verified. Furthermore, the theoretical predictions have been compared with the experimental data.
The synergistic effect of dry air and surfactants enables water to be a promising green solvent for stable and efficient perovskite solar cells
Authors: Zhang Yanrui , Ren Lixia , Zhai Peng , Xin Jingjing , Wu Jiarong , Zhang Qi , Chen Xin , Zhao Kui , Zhang Lu , (Frank) Liu Shengzhong
Published: November 2023

Through the synergistic effect of dry air and surfactants, high-quality, pinhole free perovskite films prepared from aqueous inks (Pb(NO3)2/H2O) can be easily obtained.