bluuebunny/crossref_metadata_2025 huggingface dataset:
3D Simulations of the Early Martian Hydrological Cycle Mediated by a H2‐CO2Greenhouse
Authors: Guzewich Scott D. , Way Michael J. , Aleinov Igor , Wolf Eric T. , Del Genio Anthony , Wordsworth Robin , Tsigaridis Kostas
Published: July 2021

For decades, the scientific community has been trying to reconcile abundant evidence for fluvial activity on Noachian and early Hesperian Mars with the faint young Sun and reasonable constraints on ancient atmospheric pressure and composition. Recently, the investigation of H2‐CO2collision‐induced absorption has opened up a new avenue to warm Noachian Mars. We use the ROCKE‐3D global climate model to simulate plausible states of the ancient Martian climate with this absorptive warming and reasonable constraints on surface paleopressure. We find that 1.5–2 bar CO2‐dominated atmospheres with ≥3% H2can produce global mean surface temperatures above freezing, while also providing sufficient warming to avoid surface atmospheric CO2condensation at 0°–45° obliquity. Simulations conducted with both modern topography and a paleotopography, before Tharsis formed, highlight the importance of Tharsis as a cold trap for water on the planet. Additionally, we find that low obliquity (modern and 0°) is more conducive to rainfall over valley network locations than high (45°) obliquity.
Nontuberculous mycobacterial infection and environmental molybdenum in persons with cystic fibrosis: a case–control study in Colorado
Authors: Lipner Ettie M. , Crooks James L. , French Joshua , Strong Michael , Nick Jerry A. , Prevots D. Rebecca
Published: July 2021

Rationale

Nontuberculous mycobacteria (NTM) are ubiquitous environmental bacteria that may cause chronic lung disease and are one of the most difficult-to-treat infections among persons with cystic fibrosis (pwCF). Environmental factors likely contribute to increased NTM densities, with higher potential for exposure and infection.

Objective

To identify water-quality constituents that influence odds of NTM infection among pwCF in Colorado.

Methods

We conducted a population-based nested case–control study using patient data from the Colorado CF Center NTM database. We associated data from pwCF and water-quality data extracted from the Water Quality Portal to estimate odds of NTM infection. Using Bayesian generalized linear models with binomial-distributed discrete responses, we modeled three separate outcomes; any NTM infection, infections due to Mycobacterium avium complex species, and infections due to M. abscessus group species.

Results

We observed a consistent association with molybdenum in the source water and M. abscessus group species infection among pwCF in all models. For every 1-unit increase in the log concentration of molybdenum in surface water, the odds of infection for those with M. abscessus group species compared to those who were NTM culture-negative increased by 79%. The odds of M. abscessus group infection varied by county; the counties with the highest probability of infection are located along the major rivers.

Conclusions

We have identified molybdenum in the source water as the most predictive factor of M. abscessus group infection among pwCF in Colorado. This finding will help inform patients at risk for NTM of their relative risks in residing within specific regions.
Genetic and phylogenetic analysis of dissimilatory iodate-reducing bacteria identifies potential niches across the world’s oceans
Authors: Reyes-Umana Victor , Henning Zachary , Lee Kristina , Barnum Tyler P , Coates John D
Published: July 2021

Iodine is oxidized and reduced as part of a biogeochemical cycle that is especially pronounced in the oceans, where the element naturally concentrates. The use of oxidized iodine in the form of iodate (IO3−) as an electron acceptor by microorganisms is poorly understood. Here, we outline genetic, physiological, and ecological models for dissimilatory IO3− reduction to iodide (I−) by a novel estuarine bacterium, Denitromonas sp. IR-12. Our results show that dissimilatory iodate reduction (DIR) by strain IR-12 is molybdenum-dependent and requires an IO3− reductase (idrA) and likely other genes in a mobile cluster with a conserved association across known and predicted DIR microorganisms (DIRM). Based on genetic and physiological data, we propose a model where three molecules of IO3− are likely reduced to three molecules of hypoiodous acid (HIO), which rapidly disproportionate into one molecule of IO3− and two molecules of iodide (I−), in a respiratory pathway that provides an energy yield equivalent to that of nitrate or perchlorate respiration. Consistent with the ecological niche expected of such a metabolism, idrA is enriched in the metagenome sequence databases of marine sites with a specific biogeochemical signature (high concentrations of nitrate and phosphate) and diminished oxygen. Taken together, these data suggest that DIRM help explain the disequilibrium of the IO3−:I− concentration ratio above oxygen-minimum zones and support a widespread iodine redox cycle mediated by microbiology.
Dissimilatory nitrate reduction by a freshwater cable bacterium
Authors: Marzocchi Ugo , Thorup Casper , Dam Ann-Sofie , Schramm Andreas , Risgaard-Petersen Nils
Published: July 2021

Cable bacteria (CB) are filamentous Desulfobulbaceae that split the energy-conserving reaction of sulfide oxidation into two half reactions occurring in distinct cells. CB can use nitrate, but the reduction pathway is unknown, making it difficult to assess their direct impact on the N-cycle. Here we show that the freshwater cable bacterium Ca. Electronema sp. GS performs dissimilatory nitrate reduction to ammonium (DNRA). 15NO3−-amended sediment with Ca. Electronema sp. GS showed higher rates of DNRA and nitrite production than sediment without Ca. Electronema sp. GS. Electron flux from sulfide oxidation, inferred from electric potential (EP) measurements, matched the electron flux needed to drive CB-mediated nitrate reduction to nitrite and ammonium. Ca. Electronema sp. GS expressed a complete nap operon for periplasmic nitrate reduction to nitrite, and a putative octaheme cytochrome c (pOCC), whose involvement in nitrite reduction to ammonium remains to be verified. Phylogenetic analysis suggests that the capacity for DNRA was acquired in multiple events through horizontal gene transfer from different organisms, before CB split into different salinity niches. The architecture of the nitrate reduction system suggests absence of energy conservation through oxidative phosphorylation, indicating that CB primarily conserve energy through the half reaction of sulfide oxidation.
Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes
Authors: Gumeni Sentiljana , Papanagnou Eleni-Dimitra , Manola Maria S. , Trougakos Ioannis P.
Published: July 2021

The balanced functionality of cellular proteostatic modules is central to both proteome stability and mitochondrial physiology; thus, the age-related decline of proteostasis also triggers mitochondrial dysfunction, which marks multiple degenerative disorders. Non-functional mitochondria are removed by mitophagy, including Parkin/Pink1-mediated mitophagy. A common feature of neuronal or muscle degenerative diseases, is the accumulation of damaged mitochondria due to disrupted mitophagy rates. Here, we exploit Drosophila as a model organism to investigate the functional role of Parkin/Pink1 in regulating mitophagy and proteostatic responses, as well as in suppressing degenerative phenotypes at the whole organism level. We found that Parkin or Pink1 knock down in young flies modulated proteostatic components in a tissue-dependent manner, increased cell oxidative load, and suppressed mitophagy in neuronal and muscle tissues, causing mitochondrial aggregation and neuromuscular degeneration. Concomitant to Parkin or Pink1 knock down cncC/Nrf2 overexpression, induced the proteostasis network, suppressed oxidative stress, restored mitochondrial function, and elevated mitophagy rates in flies’ tissues; it also, largely rescued Parkin or Pink1 knock down-mediated neuromuscular degenerative phenotypes. Our in vivo findings highlight the critical role of the Parkin/Pink1 pathway in mitophagy, and support the therapeutic potency of Nrf2 (a druggable pathway) activation in age-related degenerative diseases.
Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity
Authors: Chen Lin , Luo Guangjin , Liu Yameng , Lin Hairuo , Zheng Cankun , Xie Dongxiao , Zhu Yingqi , Chen Lu , Huang Xiaoxia , Hu Donghong , Xie Jiahe , Chen Zhenhuan , Liao Wangjun , Bin Jianping , Wang Qiancheng , Liao Yulin
Published: July 2021

It has been reported that growth differentiation factor 11 (GDF11) protects against myocardial ischemia/reperfusion (IR) injury, but the underlying mechanisms have not been fully clarified. Considering that GDF11 plays a role in the aging/rejuvenation process and that aging is associated with telomere shortening and cardiac dysfunction, we hypothesized that GDF11 might protect against IR injury by activating telomerase. Human plasma GDF11 levels were significantly lower in acute coronary syndrome patients than in chronic coronary syndrome patients. IR mice with myocardial overexpression GDF11 (oe-GDF11) exhibited a significantly smaller myocardial infarct size, less cardiac remodeling and dysfunction, fewer apoptotic cardiomyocytes, higher telomerase activity, longer telomeres, and higher ATP generation than IR mice treated with an adenovirus carrying a negative control plasmid. Furthermore, mitochondrial biogenesis-related proteins and some antiapoptotic proteins were significantly upregulated by oe-GDF11. These cardioprotective effects of oe-GDF11 were significantly antagonized by BIBR1532, a specific telomerase inhibitor. Similar effects of oe-GDF11 on apoptosis and mitochondrial energy biogenesis were observed in cultured neonatal rat cardiomyocytes, whereas GDF11 silencing elicited the opposite effects to oe-GDF11 in mice. We concluded that telomerase activation by GDF11 contributes to the alleviation of myocardial IR injury through enhancing mitochondrial biogenesis and suppressing cardiomyocyte apoptosis.
Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury
Authors: Liu Qinjie , Wu Jie , Zhang Xufei , Li Xuanheng , Wu Xiuwen , Zhao Yun , Ren Jianan
Published: July 2021

The STING pathway and its induction of autophagy initiate a potent immune defense response upon the recognition of pathogenic DNA. However, this protective response is minimal, as STING activation worsens organ damage, and abnormal autophagy is observed during progressive sepsis. Whether and how the STING pathway affects autophagic flux during sepsis-induced acute lung injury (sALI) are currently unknown. Here, we demonstrate that the level of circulating mtDNA and degree of STING activation are increased in sALI patients. Furthermore, STING activation was found to play a pivotal role in mtDNA-mediated lung injury by evoking an inflammatory storm and disturbing autophagy. Mechanistically, STING activation interferes with lysosomal acidification in an interferon (IFN)-dependent manner without affecting autophagosome biogenesis or fusion, aggravating sepsis. Induction of autophagy or STING deficiency alleviated lung injury. These findings provide new insights into the role of STING in the regulatory mechanisms behind extrapulmonary sALI.
Molecular-scale visualization of sarcomere contraction within native cardiomyocytes
Authors: Burbaum Laura , Schneider Jonathan , Scholze Sarah , Böttcher Ralph T. , Baumeister Wolfgang , Schwille Petra , Plitzko Jürgen M. , Jasnin Marion
Published: July 2021

Sarcomeres, the basic contractile units of striated muscle, produce the forces driving muscular contraction through cross-bridge interactions between actin-containing thin filaments and myosin II-based thick filaments. Until now, direct visualization of the molecular architecture underlying sarcomere contractility has remained elusive. Here, we use in situ cryo-electron tomography to unveil sarcomere contraction in frozen-hydrated neonatal rat cardiomyocytes. We show that the hexagonal lattice of the thick filaments is already established at the neonatal stage, with an excess of thin filaments outside the trigonal positions. Structural assessment of actin polarity by subtomogram averaging reveals that thin filaments in the fully activated state form overlapping arrays of opposite polarity in the center of the sarcomere. Our approach provides direct evidence for thin filament sliding during muscle contraction and may serve as a basis for structural understanding of thin filament activation and actomyosin interactions inside unperturbed cellular environments.
Orbital coupling of hetero-diatomic nickel-iron site for bifunctional electrocatalysis of CO2 reduction and oxygen evolution
Authors: Zeng Zhiping , Gan Li Yong , Bin Yang Hong , Su Xiaozhi , Gao Jiajian , Liu Wei , Matsumoto Hiroaki , Gong Jun , Zhang Junming , Cai Weizhen , Zhang Zheye , Yan Yibo , Liu Bin , Chen Peng
Published: July 2021

While inheriting the exceptional merits of single atom catalysts, diatomic site catalysts (DASCs) utilize two adjacent atomic metal species for their complementary functionalities and synergistic actions. Herein, a DASC consisting of nickel-iron hetero-diatomic pairs anchored on nitrogen-doped graphene is synthesized. It exhibits extraordinary electrocatalytic activities and stability for both CO2 reduction reaction (CO2RR) and oxygen evolution reaction (OER). Furthermore, the rechargeable Zn-CO2 battery equipped with such bifunctional catalyst shows high Faradaic efficiency and outstanding rechargeability. The in-depth experimental and theoretical analyses reveal the orbital coupling between the catalytic iron center and the adjacent nickel atom, which leads to alteration in orbital energy level, unique electronic states, higher oxidation state of iron, and weakened binding strength to the reaction intermediates, thus boosted CO2RR and OER performance. This work provides critical insights to rational design, working mechanism, and application of hetero-DASCs.
Liquid flow reversibly creates a macroscopic surface charge gradient
Authors: Ober Patrick , Boon Willem Q. , Dijkstra Marjolein , Backus Ellen H. G. , van Roij René , Bonn Mischa
Published: July 2021

The charging and dissolution of mineral surfaces in contact with flowing liquids are ubiquitous in nature, as most minerals in water spontaneously acquire charge and dissolve. Mineral dissolution has been studied extensively under equilibrium conditions, even though non-equilibrium phenomena are pervasive and substantially affect the mineral-water interface. Here we demonstrate using interface-specific spectroscopy that liquid flow along a calcium fluoride surface creates a reversible spatial charge gradient, with decreasing surface charge downstream of the flow. The surface charge gradient can be quantitatively accounted for by a reaction-diffusion-advection model, which reveals that the charge gradient results from a delicate interplay between diffusion, advection, dissolution, and desorption/adsorption. The underlying mechanism is expected to be valid for a wide variety of systems, including groundwater flows in nature and microfluidic systems.
Direct and selective access to amino-poly(phenylene vinylenes)s with switchable properties by dimerizing polymerization of aminoaryl carbenes
Authors: Sobczak Quentin , Kunche Aravindu , Magis Damien , Carrizo Daiann Sosa , Miqueu Karinne , Sotiropoulos Jean-Marc , Cloutet Eric , Brochon Cyril , Landais Yannick , Taton Daniel , Vignolle Joan
Published: July 2021

Despite the ubiquity of singlet carbenes in chemistry, their utility as true monomeric building blocks for the synthesis of functional organic polymers has been underexplored. In this work, we exploit the capability of purposely designed mono- and bis-acyclic amino(aryl)carbenes to selectively dimerize as a general strategy to access diaminoalkenes and hitherto unknown amino-containing poly(p-phenylene vinylene)s (N-PPV’s). The unique selectivity of the dimerization of singlet amino(aryl)carbenes, relative to putative C-H insertion pathways, is rationalized by DFT calculations. Of particular interest, unlike classical PPV’s, the presence of amino groups in α-position of C=C double bonds in N-PPV’s allows their physico-chemical properties to be manipulated in different ways by a simple protonation reaction. Hence, depending on the nature of the amino group (iPr2N vs. piperidine), either a complete loss of conjugation or a blue-shift of the maximum of absorption is observed, as a result of the protonation at different sites (nitrogen vs. carbon). Overall, this study highlights that singlet bis-amino(aryl)carbenes hold great promise to access functional polymeric materials with switchable properties, through a proper selection of their substitution pattern.
Reduction of corpus callosum activity during whisking leads to interhemispheric decorrelation
Authors: Oran Yael , Katz Yonatan , Sokoletsky Michael , Malina Katayun Cohen-Kashi , Lampl Ilan
Published: July 2021

Interhemispheric correlation between homotopic areas is a major hallmark of cortical physiology and is believed to emerge through the corpus callosum. However, how interhemispheric correlations and corpus callosum activity are affected by behavioral states remains unknown. We performed laminar extracellular and intracellular recordings simultaneously from both barrel cortices in awake mice. We find robust interhemispheric correlations of both spiking and synaptic activities that are reduced during whisking compared to quiet wakefulness. Accordingly, optogenetic inactivation of one hemisphere reveals that interhemispheric coupling occurs only during quiet wakefulness, and chemogenetic inactivation of callosal terminals reduces interhemispheric correlation especially during quiet wakefulness. Moreover, in contrast to the generally elevated firing rate observed during whisking epochs, we find a marked decrease in the activity of imaged callosal fibers. Our results indicate that the reduction in interhemispheric coupling and correlations during active behavior reflects the specific reduction in the activity of callosal neurons.
The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival
Authors: Valpione Sara , Mundra Piyushkumar A. , Galvani Elena , Campana Luca G. , Lorigan Paul , De Rosa Francesco , Gupta Avinash , Weightman John , Mills Sarah , Dhomen Nathalie , Marais Richard
Published: July 2021

Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy.
Reduced efficacy of a Src kinase inhibitor in crowded protein solution
Authors: Kasahara Kento , Re Suyong , Nawrocki Grzegorz , Oshima Hiraku , Mishima-Tsumagari Chiemi , Miyata-Yabuki Yukako , Kukimoto-Niino Mutsuko , Yu Isseki , Shirouzu Mikako , Feig Michael , Sugita Yuji
Published: July 2021

The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, 4-amino-5-(4-methylphenyl)−7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase.
SS18 regulates pluripotent-somatic transition through phase separation
Authors: Kuang Junqi , Zhai Ziwei , Li Pengli , Shi Ruona , Guo Wenjing , Yao Yuxiang , Guo Jing , Zhao Guoqing , He Jiangpin , Xu Shuyang , Wu Chuman , Yu Shengyong , Zhou Chunhua , Wu Linlin , Qin Yue , Cai Baomei , Li Wei , Wu Zichao , Li Xiaoxi , Chu Shilong , Yang Tingting , Wang Bo , Cao Shangtao , Li Dongwei , Zhang Xiaofei , Chen Jiekai , Liu Jing , Pei Duanqing
Published: July 2021

The transition from pluripotent to somatic states marks a critical event in mammalian development, but remains largely unresolved. Here we report the identification of SS18 as a regulator for pluripotent to somatic transition or PST by CRISPR-based whole genome screens. Mechanistically, SS18 forms microscopic condensates in nuclei through a C-terminal intrinsically disordered region (IDR) rich in tyrosine, which, once mutated, no longer form condensates nor rescue SS18−/− defect in PST. Yet, the IDR alone is not sufficient to rescue the defect even though it can form condensates indistinguishable from the wild type protein. We further show that its N-terminal 70aa is required for PST by interacting with the Brg/Brahma-associated factor (BAF) complex, and remains functional even swapped onto unrelated IDRs or even an artificial 24 tyrosine polypeptide. Finally, we show that SS18 mediates BAF assembly through phase separation to regulate PST. These studies suggest that SS18 plays a role in the pluripotent to somatic interface and undergoes liquid-liquid phase separation through a unique tyrosine-based mechanism.
Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma
Authors: Sun Yun-Fan , Wu Liang , Liu Shi-Ping , Jiang Miao-Miao , Hu Bo , Zhou Kai-Qian , Guo Wei , Xu Yang , Zhong Yu , Zhou Xiao-Rui , Zhang Ze-Fan , Liu Geng , Liu Sheng , Shi Ying-Hong , Ji Yuan , Du Min , Li Nan-Nan , Li Gui-Bo , Zhao Zhi-Kun , Huang Xiao-Yun , Xu Li-Qin , Yu Qi-Chao , Peng David H. , Qiu Shuang-Jian , Sun Hui-Chuan , Dean Michael , Wang Xiang-Dong , Chung Wen-Yuan , Dennison Ashley R. , Zhou Jian , Hou Yong , Fan Jia , Yang Xin-Rong
Published: July 2021

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.
Super-elasticity at 4 K of covalently crosslinked polyimide aerogels with negative Poisson’s ratio
Authors: Cheng Yang , Zhang Xiang , Qin Yixiu , Dong Pei , Yao Wei , Matz John , Ajayan Pulickel M. , Shen Jianfeng , Ye Mingxin
Published: July 2021

The deep cryogenic temperatures encountered in aerospace present significant challenges for the performance of elastic materials in spacecraft and related apparatus. Reported elastic carbon or ceramic aerogels overcome the low-temperature brittleness in conventional elastic polymers. However, complicated fabrication process and high costs greatly limited their applications. In this work, super-elasticity at a deep cryogenic temperature of covalently crosslinked polyimide (PI) aerogels is achieved based on scalable and low-cost directional dimethyl sulfoxide crystals assisted freeze gelation and freeze-drying strategy. The covalently crosslinked chemical structure, cellular architecture, negative Poisson’s ratio (−0.2), low volume shrinkage (3.1%), and ultralow density (6.1 mg/cm3) endow the PI aerogels with an elastic compressive strain up to 99% even in liquid helium (4 K), almost zero loss of resilience after dramatic thermal shocks (∆T = 569 K), and fatigue resistance over 5000 times compressive cycles. This work provides a new pathway for constructing polymer-based materials with super-elasticity at deep cryogenic temperature, demonstrating much promise for extensive applications in ongoing and near-future aerospace exploration.
Cellphone enabled point-of-care assessment of breast tumor cytology and molecular HER2 expression from fine-needle aspirates
Authors: Joh Daniel Y. , Heggestad Jacob T. , Zhang Shengwei , Anderson Gray R. , Bhattacharyya Jayanta , Wardell Suzanne E. , Wall Simone A. , Cheng Amy B. , Albarghouthi Faris , Liu Jason , Oshima Sachi , Hucknall Angus M. , Hyslop Terry , Hall Allison H. S. , Wood Kris C. , Shelley Hwang E. , Strickland Kyle C. , Wei Qingshan , Chilkoti Ashutosh
Published: July 2021

Management of breast cancer in limited-resource settings is hindered by a lack of low-cost, logistically sustainable approaches toward molecular and cellular diagnostic pathology services that are needed to guide therapy. To address these limitations, we have developed a multimodal cellphone-based platform—the EpiView-D4—that can evaluate both cellular morphology and molecular expression of clinically relevant biomarkers directly from fine-needle aspiration (FNA) of breast tissue specimens within 1 h. The EpiView-D4 is comprised of two components: (1) an immunodiagnostic chip built upon a “non-fouling” polymer brush-coating (the “D4”) which quantifies expression of protein biomarkers directly from crude cell lysates, and (2) a custom cellphone-based optical microscope (“EpiView”) designed for imaging cytology preparations and D4 assay readout. As a proof-of-concept, we used the EpiView-D4 for assessment of human epidermal growth factor receptor-2 (HER2) expression and validated the performance using cancer cell lines, animal models, and human tissue specimens. We found that FNA cytology specimens (prepared in less than 5 min with rapid staining kits) imaged by the EpiView-D4 were adequate for assessment of lesional cellularity and tumor content. We also found our device could reliably distinguish between HER2 expression levels across multiple different cell lines and animal xenografts. In a pilot study with human tissue (n = 19), we were able to accurately categorize HER2-negative and HER2-positve tumors from FNA specimens. Taken together, the EpiView-D4 offers a promising alternative to invasive—and often unavailable—pathology services and may enable the democratization of effective breast cancer management in limited-resource settings.
The Rayleigh–Lorentz invariant for superconducting resonators and optimal adiabatic qubit-information detection
Authors: Choi Jeong Ryeol
Published: July 2021

Dynamical properties of a resonator can be analyzed using the Rayleigh–Lorentz invariant which is not an exact constant but varies more or less over time depending on variations of parameters. We investigate the time behavior of this invariant for a superconducting nano-resonator in order for better understanding of qubit-information detection with the resonator. Superconducting resonators which uses parametric resonance in a Josephson junction circuit can be utilized in implementing diverse next generation nano-optic and nano-electronic devices such as quantum computing systems. Through the analyses of the temporal evolution of the invariant, we derive a condition for optimal adiabatic qubit-information detection with the resonator. This condition is helpful for controlling the dynamics of the resonators over long periods of time. It is necessary to consider it when designing a nano-resonator used for quantum nondemolition readouts of qubit states, crucial in quantum computation.
The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial
Authors: Pizzuti Laura , Barba Maddalena , Mazzotta Marco , Krasniqi Eriseld , Maugeri-Saccà Marcello , Gamucci Teresa , Berardi Rossana , Livi Lorenzo , Ficorella Corrado , Natoli Clara , Cortesi Enrico , Generali Daniele , La Verde Nicla , Cassano Alessandra , Bria Emilio , Moscetti Luca , Michelotti Andrea , Adamo Vincenzo , Zamagni Claudio , Tonini Giuseppe , Sergi Domenico , Marinelli Daniele , Paoletti Giancarlo , Tomao Silverio , Botticelli Andrea , Marchetti Paolo , Tinari Nicola , Grassadonia Antonino , Valerio Maria Rosaria , Mirabelli Rosanna , Fabbri Maria Agnese , D’Ostilio Nicola , Veltri Enzo , Corsi Domenico , Garrone Ornella , Paris Ida , Sarobba Giuseppina , Meattini Icro , Pistelli Mirco , Giotta Francesco , Lorusso Vito , Garufi Carlo , Russo Antonio , Cazzaniga Marina , Del Medico Pietro , Roselli Mario , Vaccaro Angela , Perracchio Letizia , di Benedetto Anna , Daralioti Theodora , Sperduti Isabella , De Maria Ruggero , Di Leo Angelo , Sanguineti Giuseppe , Ciliberto Gennaro , Vici Patrizia
Published: July 2021

In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2‐positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.
An empirical investigation of deviations from the Beer–Lambert law in optical estimation of lactate
Authors: Mamouei M. , Budidha K. , Baishya N. , Qassem M. , Kyriacou P. A.
Published: July 2021

The linear relationship between optical absorbance and the concentration of analytes—as postulated by the Beer-Lambert law—is one of the fundamental assumptions that much of the optical spectroscopy literature is explicitly or implicitly based upon. The common use of linear regression models such as principal component regression and partial least squares exemplifies how the linearity assumption is upheld in practical applications. However, the literature also establishes that deviations from the Beer-Lambert law can be expected when (a) the light source is far from monochromatic, (b) the concentrations of analytes are very high and (c) the medium is highly scattering. The lack of a quantitative understanding of when such nonlinearities can become predominant, along with the mainstream use of nonlinear machine learning models in different fields, have given rise to the use of methods such as random forests, support vector regression, and neural networks in spectroscopic applications. This raises the question that, given the small number of samples and the high number of variables in many spectroscopic datasets, are nonlinear effects significant enough to justify the additional model complexity? In the present study, we empirically investigate this question in relation to lactate, an important biomarker. Particularly, to analyze the effects of scattering matrices, three datasets were generated by varying the concentration of lactate in phosphate buffer solution, human serum, and sheep blood. Additionally, the fourth dataset pertained to invivo, transcutaneous spectra obtained from healthy volunteers in an exercise study. Linear and nonlinear models were fitted to each dataset and measures of model performance were compared to attest the assumption of linearity. To isolate the effects of high concentrations, the phosphate buffer solution dataset was augmented with six samples with very high concentrations of lactate between (100–600 mmol/L). Subsequently, three partly overlapping datasets were extracted with lactate concentrations varying between 0–11, 0–20 and 0–600 mmol/L. Similarly, the performance of linear and nonlinear models were compared in each dataset. This analysis did not provide any evidence of substantial nonlinearities due high concentrations. However, the results suggest that nonlinearities may be present in scattering media, justifying the use of complex, nonlinear models.
The measurement, evolution, and neural representation of action grammars of human behavior
Authors: Stout Dietrich , Chaminade Thierry , Apel Jan , Shafti Ali , Faisal A. Aldo
Published: July 2021

Human behaviors from toolmaking to language are thought to rely on a uniquely evolved capacity for hierarchical action sequencing. Testing this idea will require objective, generalizable methods for measuring the structural complexity of real-world behavior. Here we present a data-driven approach for extracting action grammars from basic ethograms, exemplified with respect to the evolutionarily relevant behavior of stone toolmaking. We analyzed sequences from the experimental replication of ~ 2.5 Mya Oldowan vs. ~ 0.5 Mya Acheulean tools, finding that, while using the same “alphabet” of elementary actions, Acheulean sequences are quantifiably more complex and Oldowan grammars are a subset of Acheulean grammars. We illustrate the utility of our complexity measures by re-analyzing data from an fMRI study of stone toolmaking to identify brain responses to structural complexity. Beyond specific implications regarding the co-evolution of language and technology, this exercise illustrates the general applicability of our method to investigate naturalistic human behavior and cognition.
Multipartite uncertainty relation with quantum memory
Authors: Haddadi Saeed , Pourkarimi Mohammad Reza , Haseli Soroush
Published: July 2021

We present a new quantum-memory-assisted entropic uncertainty relation for multipartite systems which shows the uncertainty principle of quantum mechanics. Notably, our results recover some well-known entropic uncertainty relations for two arbitrary incompatible observables that demonstrate the uncertainties about the results of two measurements. This uncertainty relation might play a critical role in the foundations of quantum theory.
New evidence for supplementary crop production, foddering and fuel use by Bronze Age transhumant pastoralists in the Tianshan Mountains
Authors: Tian Duo , Festa Marcella , Cong Dexin , Zhao Zhijun , Jia Peter Weiming , Betts Alison
Published: July 2021

The nature of economies and the movement of agricultural crops across Eurasia in the Bronze Age have been the subject of significant research interest in recent years. This study presents and discusses new results of flotation, radiocarbon and carbon stable isotope analyses from the seed assemblage at the Adunqiaolu site (northwestern Xinjiang), in combination with archaeological evidence. Archaeobotanical evidence, including carbonized foxtail millet, broomcorn millet, and naked barley, documents the diversity of local cereal consumption during the mid-second millennium BC. Our results suggest that crops were not grown locally, however, but in the lower Boertala Valley, supporting the argument that Adunqiaolu was a winter camp. These new sets of data constitute an important contribution to the discussion on cereal dispersal across the Tianshan Mountains in the Bronze Age.
OpenHSV: an open platform for laryngeal high-speed videoendoscopy
Authors: Kist Andreas M. , Dürr Stephan , Schützenberger Anne , Döllinger Michael
Published: July 2021

High-speed videoendoscopy is an important tool to study laryngeal dynamics, to quantify vocal fold oscillations, to diagnose voice impairments at laryngeal level and to monitor treatment progress. However, there is a significant lack of an open source, expandable research tool that features latest hardware and data analysis. In this work, we propose an open research platform termed OpenHSV that is based on state-of-the-art, commercially available equipment and features a fully automatic data analysis pipeline. A publicly available, user-friendly graphical user interface implemented in Python is used to interface the hardware. Video and audio data are recorded in synchrony and are subsequently fully automatically analyzed. Video segmentation of the glottal area is performed using efficient deep neural networks to derive glottal area waveform and glottal midline. Established quantitative, clinically relevant video and audio parameters were implemented and computed. In a preliminary clinical study, we recorded video and audio data from 28 healthy subjects. Analyzing these data in terms of image quality and derived quantitative parameters, we show the applicability, performance and usefulness of OpenHSV. Therefore, OpenHSV provides a valid, standardized access to high-speed videoendoscopy data acquisition and analysis for voice scientists, highlighting its use as a valuable research tool in understanding voice physiology. We envision that OpenHSV serves as basis for the next generation of clinical HSV systems.
A pseudohomogeneous nanocarrier based on carbon quantum dots decorated with arginine as an efficient gene delivery vehicle
Authors: Rezaei Aram , Hashemi Ehsan
Published: July 2021

A pseudohomogeneous carrier as an emerging term refers to subnanometric carbon-based vehicle with a high ability to interact with genetic materials to form stable carboplex and successfully transfer them into the cell which will result in inhibiting or expressing of therapeutic genes. Chitosan is a non-toxic polyaminosaccharide used as a precursor in the presence of citric acid to produce carbon quantum dots (CQDs), which decorated with arginine as a surface passivation agent with high amine density in hydrothermal methodology. The Arginine-CQDs are comprehensively characterized by Fourier-transform infrared spectroscopy (FT-IR), Ultraviolet–visible spectroscopy (UV–vis), Atomic force microscopy (AFM), field emission scanning electron microscope (FE-SEM), Energy-dispersive X-ray (EDX) mapping, fluorescence, High-resolution transmission electron microscopy (HR-TEM), zeta potential and X-ray powder diffraction (XRD). In this regard, for the first time, carboplex are formed by electrostatic conjugating of Arginine-CQDs with DNA to protect it from enzymatic degradation. Moreover, the carboplex, like the chitosan precursor, has not shown toxicity against AGS cell line. Interestingly, the Arginine-CQDs have exhibited an excellent ability to overcome cell barriers to deliver into cells compared to chitosan at the same weight ratio. The Arginine-CQDs/pEGFP (W/W) nanocomplex, not only lead to transfection with a relatively higher efficiency than PEI polymer, which is the “golden standard”, but carboplex also demonstrates no significant toxicity. Indeed, the EGFP expression level has reached to 2.4 ± 0.2 via Arginine-CQDs carboplex at W/W 50 weight ratio. To the best of our knowledge, this is the first report includes chitosan-based CQDs functionalized by arginine which is applied to serve as a pseudohomogeneous vehicle for gene transfection.
Early and long term antibody kinetics of asymptomatic and mild disease COVID-19 patients
Authors: Efrati Shai , Catalogna Merav , Abu Hamed Ramzia , Hadanny Amir , Bar-Chaim Adina , Benveniste-Levkovitz Patricia , Strugo Refael , Levtzion-korach Osnat
Published: July 2021

Most patients infected with SARS-CoV-2 are asymptomatic or mildly symptomatic. However, the early and late antibody kinetics, and the association between antibody levels, clinical symptoms, and disease phase in these patients have not yet been fully defined. Confirmed SARS-CoV-2 patients and their household contacts were evaluated over a period four months. The evaluation procedure included symptom monitoring, viral load and serology analysis every ten days. A total of 1334 serum samples were collected from 135 patients and analyzed using three assays for IgG-N, IgG-S and IgM antibodies. Of the study participants, 97% were seropositive during the study, and two distinct clusters were identified. These clusters were significantly different in their inflammatory related symptoms. Peak IgG-S was 40.0 AU/ml for the non-inflammatory cluster and 71.5 AU/ml for the inflammatory cluster (P = 0.006), whereas IgG-N peaks were 4.3 and 5.87 (P = 0.023) respectively. Finally, a decision tree model was designed to predict the disease phase based on the serological titer levels, and had an overall accuracy of 80.7%. The specific profile of seroconversion and decay of serum antibodies can be used to predict the time-course from the acute infection.
A systematic review and meta-analysis of association between brain-derived neurotrophic factor and type 2 diabetes and glycemic profile
Authors: Davarpanah Milad , Shokri-mashhadi Nafiseh , Ziaei Rahele , Saneei Parvane
Published: July 2021

Several epidemiologic studies have evaluated the relation between serum/plasma brain-derived neurotrophic factor (BDNF) levels and glycemic parameters, but the findings were conflicting. We performed a systematic review and meta-analysis to compare circulating BDNF levels in individuals with type 2 diabetes (T2D) or other glycemic disorders with healthy controls and to evaluate correlation between BDNF concentrations with glycemic profile. A systematic search up to July 2020 was conducted in reliable electronic databases (MEDLINE (Pubmed), EMBASE, Scopus) and Google scholar. Sixteen observational studies compared serum/plasma BDNF levels in diabetic patients (or individuals with glycemic disorders) vs. healthy controls or reported correlations between serum BDNF levels and glycemic parameters in adults were included in the review. Overall weighted mean difference (WMD) of circulating BDNF levels in 1306 patients with T2D (or other glycemic disorders) was 1.12 ng/mL lower than 1250 healthy subjects (WMD: − 1.12; 95%CI − 1.37, − 0.88, I2 = 98.7%, P < 0.001). Subgroup analysis revealed that both diabetic patients and subjects with other glycemic disorders had lower serum/plasma BDNF levels than healthy controls (WMD: − 1.74; 95%CI − 2.15, − 1.33 and WMD: − 0.49; 95%CI − 0.82, − 0.16, respectively). No significant correlation was found between BDNF levels and glycemic parameters [fasting blood glucose (FBG) (Fisher’s Z = 0.05; 95%CI − 0.21, 0.11; n = 1400), homeostatic model assessment for insulin resistance (HOMA-IR) (Fisher’s Z = 0.12; 95%CI − 0.20, 0.44; n = 732) and glycosylated hemoglobin (HbA1c) (Fisher’s Z = 0.04; 95%CI − 0.05, 0.12; n = 2222)]. We found that diabetic patients and subjects with glycemic disorders had lower circulating BDNF levels than healthy controls. However, there was no significant correlation between BDNF concentrations and glycemic parameters including FBG, HOMA-IR and HbA1c. Further prospective investigations are required to confirm these findings.
Flutamide treatment reveals a relationship between steroidogenic activity of Leydig cells and ultrastructure of their mitochondria
Authors: Brzoskwinia Malgorzata , Pardyak Laura , Kaminska Alicja , Tworzydlo Wacław , Hejmej Anna , Marek Sylwia , Bilinski Szczepan M. , Bilinska Barbara
Published: July 2021

Our present knowledge on interrelation between morphology/ultrastructure of mitochondria of the Leydig cell and its steroidogenic function is far from satisfactory and needs additional studies. Here, we analyzed the effects of blockade of androgen receptor, triggered by exposure to flutamide, on the expression of steroidogenic proteins (1) and ultrastructure of Leydig cells’ constituents (2). We demonstrated that increase in the expression level of steroidogenic (StAR, CYP11A1, 3β-HSD, and CYP19A1) proteins (and respective mRNAs) in rat testicular tissue as well as elevation of intratesticular sex steroid hormone (testosterone and estradiol) levels observed in treated animals correspond well to morphological alterations of the Leydig cell ultrastructure. Most importantly, up-regulation of steroidogenic proteins’ expression apparently correlates with considerable multiplication of Leydig cell mitochondria and subsequent formation of local mitochondrial networks. Interestingly, we showed also that the above-mentioned processes were associated with elevated transcription of Drp1 and Mfn2 genes, encoding proteins implicated in mitochondrial dynamics. Collectively, our studies emphasize the importance of mitochondrial homeostasis to the steroidogenic function of Leydig cells.
Warfarin maintenance dose prediction for Chinese after heart valve replacement by a feedforward neural network with equal stratified sampling
Authors: Ma Weijie , Li Hongying , Dong Li , Zhou Qin , Fu Bo , Hou Jiang-long , Wang Jing , Qin Wenzhe , Chen Jin
Published: July 2021

Patients requiring low-dose warfarin are more likely to suffer bleeding due to overdose. The goal of this work is to improve the feedforward neural network model's precision in predicting the low maintenance dose for Chinese in the aspect of training data construction. We built the model from a resampled dataset created by equal stratified sampling (maintaining the same sample number in three dose-groups with a total of 3639) and performed internal and external validations. Comparing to the model trained from the raw dataset of 19,060 eligible cases, we improved the low-dose group's ideal prediction percentage from 0.7 to 9.6% and maintained the overall performance (76.4% vs. 75.6%) in external validation. We further built neural network models on single-dose subsets to invest whether the subsets samples were sufficient and whether the selected factors were appropriate. The training set sizes were 1340 and 1478 for the low and high dose subsets; the corresponding ideal prediction percentages were 70.2% and 75.1%. The training set size for the intermediate dose varied and was 1553, 6214, and 12,429; the corresponding ideal prediction percentages were 95.6, 95.1%, and 95.3%. Our conclusion is that equal stratified sampling can be a considerable alternative approach in training data construction to build drug dosing models in the clinic.