bluuebunny/crossref_metadata_2025 huggingface dataset:
Like principal, like agent? Managerial preferences in employee-owned firms
Authors: Alves Guillermo , Blanchard Pablo , Burdin Gabriel , Chávez Mariana , Dean Andrés
Published: November 2021

The relationship between firms’ owners and managers is a quintessential example of costly principal–agent interaction. Optimal design of monetary incentives and supervision mechanisms are the two traditional ways of reducing agency costs in this relationship. In this paper, we show evidence which is consistent with a third mechanism: firms have managers whose economic preferences are aligned with owners' interests. We uncover differences in economic preferences between managers employed in firms controlled by two distinct classes of ‘patrons’: employee-owned firms (worker cooperatives) and conventional investor-owned firms. In a high-stakes lab-in-the-field experiment, we find that co-op managers are less risk-loving and more altruistic than their conventional counterparts. We do not observe differences between the two groups in terms of time preferences, reciprocity, and trust. Our findings are consistent with existing evidence on worker cooperatives, such as their tendency to self-select into less risky industries and their compressed compensation structures.
Supergreen Trees Can Signal Sites of Eruptions
Authors: Besl J.
Published: November 2021

Tree core chemistry can explain what happened before Mount Etna’s 2002 eruption and suggests that trees could play a role in rebuilding past eruptions.
Improving Absolute Hypocenter Accuracy With 3D Pg and Sg Body‐Wave Inversion Procedures and Application to Earthquakes in the Central Alps Region
Authors: Diehl Tobias , Kissling Edi , Herwegh Marco , Schmid Stefan M.
Published: November 2021

Accuracy of hypocenter location, in particular focal depth, is a precondition for high‐resolution seismotectonic analysis of natural and induced seismicity. For instance, linking seismicity with mapped fault segments requires hypocenter accuracy at the sub‐kilometer scale. In this study, we demonstrate that inaccurate velocity models and improper phase selection can bias absolute hypocenter locations and location uncertainties, resulting in errors larger than the targeted accuracy. To avoid such bias in densely instrumented seismic networks, we propose a coupled hypocenter‐velocity inversion procedure restricted to direct, first‐arriving, mainly upper‐crustal Pg and Sg phases. On the basis of synthetic tests and selected ground‐truth events we demonstrate that a sub‐kilometer hypocenter accuracy can be achieved by regional‐scale, three‐dimensional Pg and Sg velocity models combined with dynamic phase selection and a non‐linear location algorithm. The tomographic inversion uses about 60,000 Pg and 30,000 Sg quality‐checked phases of local earthquakes in the Central Alps region. The derived models image the VP and VS structure of the Central Alps upper crust at unprecedented resolution, including small‐scale anomalies such as those caused by Subalpine Molasse units below the Alpine front. The relocation procedure is applied to more than 18,000 earthquakes and the relocated hypocenters reveal previously unrecognized seismogenic structures, for instance in the Swiss Molasse basin south of Bern. The ML 4.6 Urnerboden earthquake of 2017 is used as an example to demonstrate how the derived 3D velocity structure and relocated hypocenters can be jointly interpreted to constrain the lithology hosting upper‐crustal seismicity in the Central Alps.
Ephemeral Magma Reservoirs During the Incremental Growth of the Neoproterozoic Jiuling Composite Batholith in South China
Authors: Wang Di , Wang Xiao‐Lei , Bindeman Ilya N. , Du De‐Hong , Li Jun‐Yong , Jiang Chang‐Hong
Published: November 2021

Large‐volume magma bodies in the crust are crucial to magmatic differentiation and intracrustal mass redistribution. Their magmatic residence timescales during solidification in the upper crust reflect the intensity of magmatic activity and control the formation of economic deposits. Here we explore the use of zircon crystal size distributions (CSDs) and oxygen isotopic diffusion modeling to constrain the magmatic timescales of the four main intrusions of the Neoproterozoic Jiuling composite batholith in eastern Jiangnan Orogen, South China. We present laser‐ablation–inductively coupled plasma–mass spectrometry zircon U–Pb ages and co‐registered secondary ion mass spectrometry zircon O isotopes for the four main intrusions. The dating results show that the intrusions were emplaced at 826–810 Ma, with a few inherited zircon domains in the range of 3,800–3,835 Ma. The magmatic zircon grains/rims commonly have wide δ18O variations from 5.9‰ to 13.1‰, and magmatic centers have similar δ18O ranges (3.9‰–12.2‰) to those of inherited zircon domains (3.8‰–11.4‰). The application of zircon CSD measurements reveals short zircon crystallization timescales and thus possible magmatic residence times in the order of 103–104 yr, consistent with the maximum residence times (18–47 kyr, as an upper limit) constrained by zircon oxygen isotopic diffusion modeling. This study of such ephemeral reservoirs provides unique insights into the state of magmas and the processes that occur within magma reservoirs.
Caribbean Plate Boundaries Control on the Tectonic Duality in the Back‐Arc of the Lesser Antilles Subduction Zone During the Eocene
Authors: Cerpa N. G. , Hassani R. , Arcay D. , Lallemand S. , Garrocq C. , Philippon M. , Cornée J.‐J. , Münch P. , Garel F. , Marcaillou B. , Mercier de Lépinay B. , Lebrun J.‐F.
Published: November 2021

The Eocene tectonic evolution of the easternmost Caribbean Plate (CP) boundary, that is the Lesser Antilles subduction zone (LASZ), is debated. Recents works shed light on a peculiar period of tectonic duality in the arc/back‐arc regions. A compressional‐to‐transpressional regime occurred in the north, while rifting and seafloor spreading occurred in Grenada basin to the south. The mechanism for this strong spatial variation and its evolution through time has yet to be established. Here, using 3‐D subduction mechanical models, we evaluate whether the change in the trench‐curvature radius at the northeast corner of the CP could have modulated the duality. We assume asymmetrical CP boundaries at the north (from east to west: oblique subduction to strike‐slip) and at the south (subduction‐transform edge propagator‐like behavior). Regardless of the imposed trench curvature, the southern half of our modeled CP undergoes a NW‐to‐W‐oriented extension due to the tendency of the southernmost part of the South‐America oceanic slab to rollback. In contrast, the tectonic regime in the northeast corner of the CP depends on the trench‐curvature radius. A low radius promotes transtension‐to‐transpression, with a NE‐oriented compressive component of the principal stress. A high radius largely reduces the compressive component and promotes an extensional regime similar to that in the south. We thus propose that an initially low‐curvature radius of the NE‐LASZ triggered the tectonic N‐S duality in the Eocene and led to an ephemeral period of transpression/compression at the north. However, an additional mechanism might have been required to locally enhance compression.
Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis
Authors: Wu Limin , Chung Joon Yong , Cao Tian , Jin Gina , Edmiston William J. , Hickman Suzanne , Levy Emily S. , Whalen Jordyn A. , Abrams Eliza Sophie LaRovere , Degterev Alexei , Lo Eng H. , Tozzi Lorenzo , Kaplan David L. , El Khoury Joseph , Whalen Michael J.
Published: November 2021

Traumatic brain injury (TBI) is a leading cause of death and disability with no specific effective therapy, in part because disease driving mechanisms remain to be elucidated. Receptor interacting protein kinases (RIPKs) are serine/threonine kinases that assemble multi-molecular complexes that induce apoptosis, necroptosis, inflammasome and nuclear factor kappa B activation. Prior studies using pharmacological inhibitors implicated necroptosis in the pathogenesis of TBI and stroke, but these studies cannot be used to conclusively demonstrate a role for necroptosis because of the possibility of off target effects. Using a model of cerebral contusion and RIPK3 and mixed lineage kinase like knockout (MLKL−/−) mice, we found evidence for activation of RIPK3 and MLKL and assembly of a RIPK1-RIPK3-MLKL necrosome complex in pericontusional brain tissue. Phosphorylated forms of RIPK3 and MLKL were detected in endothelium, CD11b + immune cells, and neurons, and RIPK3 was upregulated and activated in three-dimensional human endothelial cell cultures subjected to CCI. RIPK3−/− and MLKL−/− mice had reduced blood-brain barrier damage at 24 h (p < 0.05), but no differences in neuronal death (6 h, p = ns in CA1, CA3 and DG), brain edema (24 h, p = ns), or lesion size (4 weeks, p = ns) after CCI. RIPK3−/−, but not MLKL−/− mice, were protected against postinjury motor and cognitive deficits at 1–4 weeks (RIPK3−/− vs WT: p < 0.05 for group in wire grip, Morris water maze hidden platform trials, p < 0.05 for novel object recognition test, p < 0.01 for rotarod test). RIPK3−/− mice had reduced infiltrating leukocytes (p < 0.05 vs WT in CD11b + cells, microglia and macrophages), HMGB1 release and interleukin-1 beta activation at 24–48 h (p < 0.01) after CCI. Our data indicate that RIPK3 contributes to functional outcome after cerebral contusion by mechanisms involving inflammation but independent of necroptosis.
A GeV-TeV particle component and the barrier of cosmic-ray sea in the Central Molecular Zone
Authors: Huang Xiaoyuan , Yuan Qiang , Fan Yi-Zhong
Published: November 2021

Cosmic rays are important probe of a number of fundamental physical problems such as the acceleration of high and very high energy particles in extreme astrophysical environments. The Galactic center is widely anticipated to be an important cosmic-ray source and the observations of some Imaging Atmospheric Cherenkov Telescopes did successfully reveal a component of TeV-PeV cosmic rays in the vicinity of the Galactic center. Here we report the identification of GeV-TeV cosmic rays in the central molecular zone with the γ-ray observations of the Fermi Large Area Telescope, whose spectrum and spatial gradient are consistent with that measured by the Imaging Atmospheric Cherenkov Telescopes but the corresponding cosmic-ray energy density is substantially lower than the so-called cosmic-ray sea component, suggesting the presence of a high energy particle accelerator at the Galactic center and the existence of a barrier that can effectively suppress the penetration of the particles from the cosmic-ray sea to the central molecular zone.
Extended antibody-framework-to-antigen distance observed exclusively with broad HIV-1-neutralizing antibodies recognizing glycan-dense surfaces
Authors: Lee Myungjin , Changela Anita , Gorman Jason , Rawi Reda , Bylund Tatsiana , Chao Cara W. , Lin Bob C. , Louder Mark K. , Olia Adam S. , Zhang Baoshan , Doria-Rose Nicole A. , Zolla-Pazner Susan , Shapiro Lawrence , Chuang Gwo-Yu , Kwong Peter D.
Published: November 2021

Antibody-Framework-to-Antigen Distance (AFAD) – the distance between the body of an antibody and a protein antigen – is an important parameter governing antibody recognition. Here, we quantify AFAD for ~2,000 non-redundant antibody-protein-antigen complexes in the Protein Data Bank. AFADs showed a gaussian distribution with mean of 16.3 Å and standard deviation (σ) of 2.4 Å. Notably, antibody-antigen complexes with extended AFADs (>3σ) were exclusively human immunodeficiency virus-type 1 (HIV-1)-neutralizing antibodies. High correlation (R2 = 0.8110) was observed between AFADs and glycan coverage, as assessed by molecular dynamics simulations of the HIV-1-envelope trimer. Especially long AFADs were observed for antibodies targeting the glycosylated trimer apex, and we tested the impact of introducing an apex-glycan hole (N160K); the cryo-EM structure of the glycan hole-targeting HIV-1-neutralizing antibody 2909 in complex with an N160K-envelope trimer revealed a substantially shorter AFAD. Overall, extended AFADs exclusively recognized densely glycosylated surfaces, with the introduction of a glycan hole enabling closer recognition.
Mouse strain-specific polymorphic provirus functions as cis-regulatory element leading to epigenomic and transcriptomic variations
Authors: Zhou Xuemeng , Sam Tsz Wing , Lee Ah Young , Leung Danny
Published: November 2021

Polymorphic integrations of endogenous retroviruses (ERVs) have been previously detected in mouse and human genomes. While most are inert, a subset can influence the activity of the host genes. However, the molecular mechanism underlying how such elements affect the epigenome and transcriptome and their roles in driving intra-specific variation remain unclear. Here, by utilizing wildtype murine embryonic stem cells (mESCs) derived from distinct genetic backgrounds, we discover a polymorphic MMERGLN (GLN) element capable of regulating H3K27ac enrichment and transcription of neighboring loci. We demonstrate that this polymorphic element can enhance the neighboringKlhdc4gene expression incis, which alters the activity of downstream stress response genes. These results suggest that the polymorphic ERV-derivedcis-regulatory element contributes to differential phenotypes from stimuli between mouse strains. Moreover, we identify thousands of potential polymorphic ERVs in mESCs, a subset of which show an association between proviral activity and nearby chromatin states and transcription. Overall, our findings elucidate the mechanism of how polymorphic ERVs can shape the epigenome and transcriptional networks that give rise to phenotypic divergence between individuals.
The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma
Authors: Pan Min , Wright William C. , Chapple Richard H. , Zubair Asif , Sandhu Manbir , Batchelder Jake E. , Huddle Brandt C. , Low Jonathan , Blankenship Kaley B. , Wang Yingzhe , Gordon Brittney , Archer Payton , Brady Samuel W. , Natarajan Sivaraman , Posgai Matthew J. , Schuetz John , Miller Darcie , Kalathur Ravi , Chen Siquan , Connelly Jon Patrick , Babu M. Madan , Dyer Michael A. , Pruett-Miller Shondra M. , Freeman Burgess B. , Chen Taosheng , Godley Lucy A. , Blanchard Scott C. , Stewart Elizabeth , Easton John , Geeleher Paul
Published: November 2021

Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors in improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity—often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.
Gateway-driven weakening of ocean gyres leads to Southern Ocean cooling
Authors: Sauermilch Isabel , Whittaker Joanne M. , Klocker Andreas , Munday David R. , Hochmuth Katharina , Bijl Peter K. , LaCasce Joseph H.
Published: November 2021

Declining atmospheric CO2 concentrations are considered the primary driver for the Cenozoic Greenhouse-Icehouse transition, ~34 million years ago. A role for tectonically opening Southern Ocean gateways, initiating the onset of a thermally isolating Antarctic Circumpolar Current, has been disputed as ocean models have not reproduced expected heat transport to the Antarctic coast. Here we use high-resolution ocean simulations with detailed paleobathymetry to demonstrate that tectonics did play a fundamental role in reorganising Southern Ocean circulation patterns and heat transport, consistent with available proxy data. When at least one gateway (Tasmanian or Drake) is shallow (300 m), gyres transport warm waters towards Antarctica. When the second gateway subsides below 300 m, these gyres weaken and cause a dramatic cooling (average of 2–4 °C, up to 5 °C) of Antarctic surface waters whilst the ACC remains weak. Our results demonstrate that tectonic changes are crucial for Southern Ocean climate change and should be carefully considered in constraining long-term climate sensitivity to CO2.
A site of vulnerability at V3 crown defined by HIV-1 bNAb M4008_N1
Authors: Chan Kun-Wei , Luo Christina C. , Lu Hong , Wu Xueling , Kong Xiang-Peng
Published: November 2021

Identification of vulnerable sites defined by broadly neutralizing antibodies (bNAbs) on HIV-1 envelope (Env) is crucial for vaccine design, and we present here a vulnerable site defined by bNAb M4008_N1, which neutralizes about 40% of a tier-2 virus panel. A 3.2 Å resolution cryo-EM structure of M4008_N1 in complex with BG505 DS-SOSIP reveals a large, shallow protein epitope surface centered at the V3 crown of gp120 and surrounded by key glycans. M4008_N1 interacts with gp120 primarily through its hammerhead CDR H3 to form a β-sheet interaction with the V3 crown hairpin. This makes M4008_N1 compatible with the closed conformation of the prefusion Env trimer, and thus distinct from other known V3 crown mAbs. This mode of bNAb approaching the immunogenic V3 crown in the native Env trimer suggests a strategy for immunogen design targeting this site of vulnerability.
Laughlin anyon complexes with Bose properties
Authors: Kulik L. V. , Zhuravlev A. S. , Musina L. I. , Belozerov E. I. , Van’kov A. B. , Volkov O. V. , Zagitova A. A. , Kukushkin I. V. , Umansky V. Y.
Published: November 2021

Two-dimensional electron systems in a quantizing magnetic field are regarded as of exceptional interest, considering the possible role of anyons—quasiparticles with non-boson and non-fermion statistics—in applied physics. To this day, essentially none but the fractional states of the quantum Hall effect (FQHE) have been experimentally realized as a system with anyonic statistics. In determining the thermodynamic properties of anyon matter, it is crucial to gain insight into the physics of its neutral excitations. We form a macroscopic quasi-equilibrium ensemble of neutral excitations - spin one anyon complexes in the Laughlin state ν = 1/3, experimentally, where ν is the electron filling factor. The ensemble is found to have such a long lifetime that it can be considered the new state of anyon matter. The properties of this state are investigated by optical techniques to reveal its Bose properties.
Integrated polarization-sensitive amplification system for digital information transmission
Authors: Ran Wenhao , Ren Zhihui , Wang Pan , Yan Yongxu , Zhao Kai , Li Linlin , Li Zhexin , Wang Lili , Yang Juehan , Wei Zhongming , Lou Zheng , Shen Guozhen
Published: November 2021

Polarized light can provide significant information about objects, and can be used as information carrier in communication systems through artificial modulation. However, traditional polarized light detection systems integrate polarizers and various functional circuits in addition to detectors, and are supplemented by complex encoding and decoding algorithms. Although the in-plane anisotropy of low-dimensional materials can be utilized to manufacture polarization-sensitive photodetectors without polarizers, the low anisotropic photocurrent ratio makes it impossible to realize digital output of polarized information. In this study, we propose an integrated polarization-sensitive amplification system by introducing a nanowire polarized photodetector and organic semiconductor transistors, which can boost the polarization sensitivity from 1.24 to 375. Especially, integrated systems are universal in that the systems can increase the anisotropic photocurrent ratio of any low-dimensional material corresponding to the polarized light. Consequently, a simple digital polarized light communication system can be realized based on this integrated system, which achieves certain information disguising and confidentiality effects.
Usefulness of MRI targeted prostate biopsy for detecting clinically significant prostate cancer in men with low prostate-specific antigen levels
Authors: Bang Seokhwan , Yu Jiwoong , Chung Jae Hoon , Song Wan , Kang Minyong , Sung Hyun Hwan , Jeon Hwang Gyun , Jeong Byong Chang , Seo Seong Il , Lee Hyun Moo , Jeon Seong Soo
Published: November 2021

We aimed to evaluate the detection rates of prostate cancer (PCa) and clinically significant PCa (csPCa) using magnetic resonance imaging-targeted biopsy (MRI-TBx) in men with low prostate-specific antigen (PSA) levels (2.5–4.0 ng/mL). Clinicopathologic data of 5502 men with PSA levels of 2.5–10.0 ng/mL who underwent transrectal ultrasound-guided biopsy (TRUS-Bx) or MRI-TBx were reviewed. Participants were divided into four groups: LP-T [low PSA (2.5–4.0 ng/mL) and TRUS-Bx, n = 2018], LP-M (low PSA and MRI-TBx, n = 186), HP-T [high PSA (4.0–10.0 ng/mL) and TRUS-Bx, n = 2953], and HP-M (high PSA and MRI-TBx, n = 345). The detection rates of PCa and csPCa between groups were compared, and association of biopsy modality with detection of PCa and csPCa in men with low PSA levels were analyzed. The detection rates of PCa (20.0% vs. 38.2%; P < 0.001) and csPCa (11.5% vs. 32.3%; P < 0.001) were higher in the LP-M group than in the LP-T group. Conversely, there were no significant differences in the detection rates of PCa (38.2% vs. 43.2%; P = 0.263) and csPCa (32.3% vs. 39.4%; P = 0.103) between the LP-M and HP-M groups. Multivariate analyses revealed that using MRI-TBx could predict the detection of csPCa (odds ratio 2.872; 95% confidence interval 1.996‒4.132; P < 0.001) in men with low PSA levels. In summary, performing MRI-TBx in men with low PSA levels significantly improved the detection rates of PCa and csPCa as much as that in men with high PSA levels.
An enhanced version of Harris Hawks Optimization by dimension learning-based hunting for Breast Cancer Detection
Authors: Kaur Navneet , Kaur Lakhwinder , Cheema Sikander Singh
Published: November 2021

Swarm intelligence techniques have a vast range of real world applications.Some applications are in the domain of medical data mining where, main attention is on structure models for the classification and expectation of numerous diseases. These biomedical applications have grabbed the interest of numerous researchers because these are most serious and prevalent causes of death among the human whole world out of which breast cancer is the most serious issue. Mammography is the initial screening assessment of breast cancer. In this study, an enhanced version of Harris Hawks Optimization (HHO) approach has been developed for biomedical databases, known as DLHO. This approach has been introduced by integrating the merits of dimension learning-based hunting (DLH) search strategy with HHO. The main objective of this study is to alleviate the lack of crowd diversity, premature convergence of the HHO and the imbalance amid the exploration and exploitation. DLH search strategy utilizes a dissimilar method to paradigm a neighborhood for each search member in which the neighboring information can be shared amid search agents. This strategy helps in maintaining the diversity and the balance amid global and local search. To evaluate the DLHO lot of experiments have been taken such as (i) the performance of optimizers have analysed by using 29-CEC -2017 test suites, (ii) to demonstrate the effectiveness of the DLHO it has been tested on different biomedical databases out of which we have used two different databases for Breast i.e. MIAS and second database has been taken from the University of California at Irvine (UCI) Machine Learning Repository.Also to test the robustness of the proposed method its been tested on two other databases of such as Balloon and Heart taken from the UCI Machine Learning Repository. All the results are in the favour of the proposed technique.
Prevalence of non-communicable diseases among healthy male decontamination workers after the Fukushima nuclear disaster in Japan: an observational study
Authors: Sawano Toyoaki , Murakami Michio , Ozaki Akihiko , Nishikawa Yoshitaka , Fukuda Aoi , Oikawa Tomoyoshi , Tsubokura Masaharu
Published: November 2021

The health status of healthy decontamination workers employed after the Fukushima nuclear disaster remains unclear. This study aimed to evaluate the prevalence of non-communicable diseases among such workers. In this observational study, questionnaires on lifestyle and social factors were administered as part of a health promotion program for decontamination workers in 2016 in Minamisoma City, Fukushima. The questionnaires and health check-up results were compared with those of the 2016 National Health and Nutrition Examination Survey (NHANES) in Japan. Overall, 123 male decontamination workers were enrolled; 93 (75.6%) were drinkers, and 84 (68.3%) were current smokers. The age-adjusted prevalence (95% confidence interval) of hypertension, dyslipidemia, diabetes mellitus, and obesity were 27.2% (20.1–34.4%), 30.4% (22.6–38.2%), 11.3% (5.5–17.1%), and 49.0% (39.0–58.9%), respectively. The age-adjusted prevalence in the NHANES were 32.8% (31.1–34.5%), 16.1% (14.5–17.6%), 7.0% (6.2–7.7%), and 31.2% (29.9–32.5%), respectively. The prevalence of obesity, dyslipidemia, binge drinking, and smoking were higher in healthy male decontamination workers than in the general population. Decontamination workers in disaster-struck areas may have higher risks of developing non-communicable diseases, possibly due to their original health status. Continuous monitoring of their health status and proper interventions are warranted.
Novel tensorial Thixo-Visco-Plastic framework for rheological characterization of human blood
Authors: Pincot André , Armstrong Matthew
Published: November 2021

Characterizing human blood, a complex material with a spectrum of thixo-elasto-visco-plastic properties, through the development of more effective and efficient models has achieved special interest of late. This effort details the development a new approach, the tensorial-enhanced-Thixo-Visco-Plastic model (t-e-TVP), which integrates elements from the proven Bingham and generalized Maxwell systems to create a more robust framework and subsequently cast into a tensorial format. Here, the elastic and viscoelastic stress contributions from the microstructure are superimposed upon the viscoelastic backbone solution for stress offered by the modified TVP frame. The utility of this novel model is tested against the contemporary tensorial-ethixo-mHAWB (t-ethixo-mHAWB) framework, a similar model with a greater number of parameters, using rheological data of human blood collected on an ARESG2 strain-controlled rheometer. The blood samples are parametrically and statistically analyzed, entailing the comparison of the t-e-TVP and t-ethixo-mHAWB models with their capacity to accurately predict small and large amplitude oscillatory shear as well as unidirectional large amplitude oscillatory shear flow in blood.
Application of digital infrared thermography for carpal tunnel syndrome evaluation
Authors: Park Dougho , Kim Byung Hee , Lee Sang-Eok , Kim Dong Young , Eom Yoon Sik , Cho Jae Man , Yang Joong Won , Kim Mansu , Kwon Heum Dai , Lee Jang Woo
Published: November 2021

We investigated the thermographic findings of carpal tunnel syndrome (CTS). We enrolled 304 hands with electrodiagnostically identified CTS and 88 control hands. CTS hands were assigned to duration groups (D1, < 3 months; D2, 3‒6 months; D3, 6‒12 months; D4, ≥ 12 months) and severity groups (S1, very mild; S2, mild; S3, moderate; S4, severe). The temperature difference between the median and ulnar nerve territories (ΔM-U territories) decreased as CTS duration and severity increased. Significant differences in ΔM-U territories between the D1 and D3, D1 and D4, D2 and D4, and S1 and S4 groups (P = 0.003, 0.001, 0.001, and < 0.001, respectively) were observed. Thermal anisometry increased as CTS duration and severity increased. Significant differences in thermal anisometry between the D1 and D4 as well as the D2 and D4 groups (P = 0.005 and 0.04, respectively) were noted. Thermal anisometry was higher in the S4 group than in the S1, S2, and S3 groups (P = 0.009, < 0.001, and 0.003, respectively). As CTS progresses, skin temperature tends to decrease and thermal variation tends to increase in the median nerve-innervated area. Thermographic findings reflect the physiological changes of the entrapped median nerve.
Three dimensional and microphysiological bone marrow models detect in vivo positive compounds
Authors: David Rhiannon , Gee Sarah , Khan Kainat , Wilson Amy , Doherty Ann
Published: November 2021

Micronucleus (MN) assessment is a valuable tool in safety assessment. However, several compounds are positive in the in vivo bone marrow (BM) MN assay but negative in vitro, reflecting that BM complexity is not recapitulated in vitro. Importantly, these compounds are not genotoxic; rather, drug-driven pharmacological-effects on the BM increase MN, however, without mechanistic understanding, in vivo positives stop drug-progression. Thus, physiologically-relevant BM models are required to bridge the gap between in vitro and in vivo. The current study aimed to investigate the utility of two human 3D BM models (fluidic and static) for MN assessment. MN induction following treatment with etoposide and Poly-ADP Ribose Polymerase inhibitor (PARPi) and prednisolone (negative in vitro, positive in vivo) was determined in 2D L5178Y and human BM cells, and the 3D BM models. Etoposide (0–0.070 µM) and PARPi (0–150 µM) induced MN in both 3D BM models indicating their utility for genotoxicity testing. Interestingly, PARPi treatment induced a MN trend in 3D more comparable to in vivo. Importantly, prednisolone (0–1.7 mM) induced MN in both 3D BM models, suggesting recapitulation of the in vivo microenvironment. These models could provide a valuable tool to follow up, and eventually predict, suspected pharmacological mechanisms, thereby reducing animal studies.
Association between MR-proADM concentration and treatment intensity of antihypertensive agents in chronic kidney disease patients with insufficient blood pressure control
Authors: Iwao Motoshi , Tanaka Ryota , Suzuki Yosuke , Nakata Takeshi , Aoki Kohei , Fukuda Akihiro , Fukunaga Naoya , Tatsuta Ryosuke , Ohno Keiko , Shibata Hirotaka , Itoh Hiroki
Published: November 2021

Response to antihypertensive drugs in patients with chronic kidney disease (CKD) has great interindividual variability. Adrenomedullin (ADM) is produced abundantly in hypertension, but clearance is very rapid. Mid-regional proADM (MR-proADM) produced from an ADM precursor is considered a surrogate biomarker for quantification of ADM. We investigated the association of MR-proADM with antihypertensive resistance in CKD patients with poor blood pressure (BP) control. This cross-sectional study analyzed 33 CKD patients with poor BP control defined as failure to achieve target BP despite at least two classes of antihypertensive drugs. Treatment intensity score was calculated to facilitate comparability of antihypertensive regimens across subjects taking different drugs. Plasma MR-proADM concentration was measured using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Plasma MR-proADM concentration correlated with estimated glomerular filtration rate (eGFR) (r =  − 0.777, p < 0.001). Treatment intensity score correlated positively with plasma MR-proADM concentration (r = 0.355, p = 0.043), and the correlation was further enhanced after correction by weight (r = 0.538, p = 0.001). Single and multiple regression analysis identified MR-proADM concentration (p = 0.005) as independently associated with weight-corrected treatment intensity score. MR-proADM may be useful as a biomarker to determine the therapeutic intensity of antihypertensive drugs in CKD patients with poor BP control.
Dissecting fine-flavor cocoa bean fermentation through metabolomics analysis to break down the current metabolic paradigm
Authors: Herrera-Rocha Fabio , Cala Mónica P. , Aguirre Mejía Jenny Lorena , Rodríguez-López Claudia M. , Chica María José , Olarte Héctor Hugo , Fernández-Niño Miguel , Gonzalez Barrios Andrés Fernando
Published: November 2021

Cocoa fermentation plays a crucial role in producing flavor and bioactive compounds of high demand for food and nutraceutical industries. Such fermentations are frequently described as a succession of three main groups of microorganisms (i.e., yeast, lactic acid, and acetic acid bacteria), each producing a relevant metabolite (i.e., ethanol, lactic acid, and acetic acid). Nevertheless, this view of fermentation overlooks two critical observations: the role of minor groups of microorganisms to produce valuable compounds and the influence of environmental factors (other than oxygen availability) on their biosynthesis. Dissecting the metabolome during spontaneous cocoa fermentation is a current challenge for the rational design of controlled fermentations. This study evaluates variations in the metabolic fingerprint during spontaneous fermentation of fine flavor cocoa through a multiplatform metabolomics approach. Our data suggested the presence of two phases of differential metabolic activity that correlate with the observed variations on temperature over fermentations: an exothermic and an isothermic phase. We observed a continuous increase in temperature from day 0 to day 4 of fermentation and a significant variation in flavonoids and peptides between phases. While the second phase, from day four on, was characterized for lower metabolic activity, concomitant with small upward and downward fluctuations in temperature. Our work is the first to reveal two phases of metabolic activity concomitant with two temperature phases during spontaneous cocoa fermentation. Here, we proposed a new paradigm of cocoa fermentation that considers the changes in the global metabolic activity over fermentation, thus changing the current paradigm based only on three main groups of microorganism and their primary metabolic products.
Association between choriocapillaris flow deficit and choroidal neovascularization activity in eyes with myopic choroidal neovascularization
Authors: Uematsu Sato , Sakaguchi Hirokazu , Sayanagi Kaori , Ikuno Yasushi , Yokoyama Ayako , Asai Tomoko , Fukushima Yoko , Hara Chikako , Sakimoto Susumu , Nishida Kohji
Published: November 2021

Although choriocapillaris flow deficit (CFD) around choroidal neovascularization (CNV) is less associated with CNV activity in myopic eyes, no reports are investigating its size as an indicator of CNV activity. We investigated the relationship between CFD and high myopia-related CNV. In this retrospective, observational study, patients underwent optical coherence tomography angiography (OCTA) with split-spectrum amplitude-decorrelation angiography for diagnosing pathological myopic CNV (mCNV); CFD features around CNV margins were evaluated. Of the 33 eyes (30 patients), 11 (33.3%) had active mCNV, and 22 (66.7%) had inactive CNV. Six eyes (18.2%) were treatment-naïve, while the remainder previously underwent anti-vascular endothelial growth factor therapy. On OCTA, blood flow signals were detected in CNV in the outer retinal layer in 28 (84.8%) eyes, including all active cases (11 cases) and 17 (77.3%) of 22 inactive cases. CNV flow signal size correlated significantly with activity (P < 0.001). CFD around CNV was observed in 24 eyes (72.7%), including all active cases (11 cases) and 13 (59.1%) of 22 inactive cases. CFD size correlated significantly with CNV activity (P < 0.001). The size of both the CFD area around CNV and CNV flow signal area are useful indicators of CNV activity in eyes with mCNV, which may help determine treatment timing.
The predictive value of serum level of cystatin C for COVID-19 severity
Authors: Lin Luanfeng , Chen Xiaoling , Chen Junnian , Pan Xiaobin , Xia Pincang , Lin Hailong , Du Houwei
Published: November 2021

To investigate the potential prognostic value of Serum cystatin C (sCys C) in patients with COVID-19 and determine the association of sCys C with severe COVID-19 illness. We performed a retrospective review of medical records of 162 (61.7 ± 13.5 years) patients with COVID-19. We assessed the predictive accuracy of sCys C for COVID-19 severity by the receiver operating characteristic (ROC) curve analysis. The participants were divided into two groups based on the sCys C cut-off value. We evaluated the association between high sCys C level and the development of severe COVID-19 disease, using a COX proportional hazards regression model. The area under the ROC curve was 0.708 (95% CI 0.594–0.822), the cut-off value was 1.245 (mg/L), and the sensitivity and specificity was 79.1% and 60.7%, respectively. A multivariable Cox analysis showed that a higher level of sCys C (adjusted HR 2.78 95% CI 1.25–6.18, p = 0.012) was significantly associated with an increased risk of developing a severe COVID-19 illness. Patients with a higher sCys C level have an increased risk of severe COVID-19 disease. Our findings suggest that early assessing sCys C could help to identify potential severe COVID-19 patients.
Prevalence of oropharyngeal dysphagia in geriatric patients and real-life associations with diseases and drugs
Authors: Wolf Ursula , Eckert Sandra , Walter Grit , Wienke Andreas , Bartel Sylva , Plontke Stefan K. , Naumann Christina
Published: November 2021

Risk factors for oropharyngeal dysphagia (OD) in elderly patients are mainly central nervous system (CNS) and structural organic diseases or presbyphagia. We analysed the OD prevalence and association of OD with multimorbidity and polypharmacy using real-life data to complete this spectrum, with a focus on further and iatrogenic risk. This was a cross-sectional retrospective study based on a random sample of 200 patients admitted to a geriatric hospital. Data analysis included diagnoses, the detailed list of drugs, and an intense clinical investigation of swallowing according to Stanschus to screen for OD in each patient. The mean patient age was 84 ± 6.5 years. The prevalence of OD was 29.0%, without an effect of age, but a higher rate was found in men and in nursing home residents and an elevated risk of pneumonia. OD risk was slight in diabetes mellitus and COPD, and pronounced in CNS diseases. A relevant OD association was found, even after adjusting for CNS diseases, with antipsychotics, benzodiazepines, anti-Parkinson drugs, antidepressants, and antiepileptics. Further risk of OD was found with beta-blockers, alpha-blockers, opioids, antiemetics, antivertiginosa or antihistamines, metoclopramide, domperidone, anticholinergics, loop diuretics, urologics, and ophthalmics. From real-life data in patients with and without CNS diseases, we identified drug groups associated with a risk of aggravating/inducing OD. Restrictive indications for these drugs may be a preventative contribution, requiring implementation in dysphagia guidelines and an integrative dysphagia risk scale that considers all associated and cumulative medication risks in addition to diseases.
Phosphorylation-dependent BRD4 dimerization and implications for therapeutic inhibition of BET family proteins
Authors: Malvezzi Francesca , Stubbs Christopher J. , Jowitt Thomas A. , Dale Ian L. , Guo Xieyang , DeGnore Jon P. , Degliesposti Gianluca , Skehel J. Mark , Bannister Andrew J. , McAlister Mark S.
Published: November 2021

Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and oncology drug target that regulates gene transcription through binding to acetylated chromatin via bromodomains. Phosphorylation by casein kinase II (CK2) regulates BRD4 function, is necessary for active transcription and is involved in resistance to BRD4 drug inhibition in triple-negative breast cancer. Here, we provide the first biophysical analysis of BRD4 phospho-regulation. Using integrative structural biology, we show that phosphorylation by CK2 modulates the dimerization of human BRD4. We identify two conserved regions, a coiled-coil motif and the Basic-residue enriched Interaction Domain (BID), essential for the BRD4 structural rearrangement, which we term the phosphorylation-dependent dimerization domain (PDD). Finally, we demonstrate that bivalent inhibitors induce a conformational change within BRD4 dimers in vitro and in cancer cells. Our results enable the proposal of a model for BRD4 activation critical for the characterization of its protein-protein interaction network and for the development of more specific therapeutics.
Machine learning for laser-induced electron diffraction imaging of molecular structures
Authors: Liu Xinyao , Amini Kasra , Sanchez Aurelien , Belsa Blanca , Steinle Tobias , Biegert Jens
Published: November 2021

Ultrafast diffraction imaging is a powerful tool to retrieve the geometric structure of gas-phase molecules with combined picometre spatial and attosecond temporal resolution. However, structural retrieval becomes progressively difficult with increasing structural complexity, given that a global extremum must be found in a multi-dimensional solution space. Worse, pre-calculating many thousands of molecular configurations for all orientations becomes simply intractable. As a remedy, here, we propose a machine learning algorithm with a convolutional neural network which can be trained with a limited set of molecular configurations. We demonstrate structural retrieval of a complex and large molecule, Fenchone (C10H16O), from laser-induced electron diffraction (LIED) data without fitting algorithms or ab initio calculations. Retrieval of such a large molecular structure is not possible with other variants of LIED or ultrafast electron diffraction. Combining electron diffraction with machine learning presents new opportunities to image complex and larger molecules in static and time-resolved studies.
Tuning scalar spin chirality in ultrathin films of the kagome-lattice ferromagnet Fe3Sn
Authors: Fujiwara Kohei , Kato Yasuyuki , Seki Takeshi , Nomura Kentaro , Takanashi Koki , Motome Yukitoshi , Tsukazaki Atsushi
Published: November 2021

Non-coplanar spin textures with finite scalar spin chirality can be artificially induced at surfaces and interfaces through the interfacial Dzyaloshinskii-Moriya interaction. However, stabilizing a proper magnetic skyrmion crystal via this route remains elusive. Here, using an epitaxial bilayer of platinum and geometrically frustrated kagome-lattice ferromagnet Fe3Sn, we show the possible formation of a two-dimensional skyrmion crystal under well-regulated Fe3Sn thickness conditions. Magnetization measurements reveal that the magnetic anisotropy is systematically varied from an inherent in-plane type to a perpendicular type with the thickness reduction. Below approximately 0.5 nm, we clearly detect a topological Hall effect that provides evidence for finite scalar spin chirality. Our topological Hall effect analysis, combined with theoretical simulations, not only establishes its interfacial Dzyaloshinskii-Moriya interaction origin, but also indicates the emergence of a stable skyrmion crystal phase, demonstrating the potential of kagome-lattice ferromagnets in spin chirality engineering using thin-film nanostructures.
Paleo-diatom composition from Santa Barbara Basin deep-sea sediments: a comparison of 18S-V9 and diat-rbcL metabarcoding vs shotgun metagenomics
Authors: Armbrecht Linda , Eisenhofer Raphael , Utge José , Sibert Elizabeth C , Rocha Fabio , Ward Ryan , Pierella Karlusich Juan José , Tirichine Leila , Norris Richard , Summers Mindi , Bowler Chris
Published: November 2021

Sedimentary ancient DNA (sedaDNA) analyses are increasingly used to reconstruct marine ecosystems. The majority of marine sedaDNA studies use a metabarcoding approach (extraction and analysis of specific DNA fragments of a defined length), targeting short taxonomic marker genes. Promising examples are 18S-V9 rRNA (~121–130 base pairs, bp) and diat-rbcL (76 bp), targeting eukaryotes and diatoms, respectively. However, it remains unknown how 18S-V9 and diat-rbcL derived compositional profiles compare to metagenomic shotgun data, the preferred method for ancient DNA analyses as amplification biases are minimised. We extracted DNA from five Santa Barbara Basin sediment samples (up to ~11 000 years old) and applied both a metabarcoding (18S-V9 rRNA, diat-rbcL) and a metagenomic shotgun approach to (i) compare eukaryote, especially diatom, composition, and (ii) assess sequence length and database related biases. Eukaryote composition differed considerably between shotgun and metabarcoding data, which was related to differences in read lengths (~112 and ~161 bp, respectively), and overamplification of short reads in metabarcoding data. Diatom composition was influenced by reference bias that was exacerbated in metabarcoding data and characterised by increased representation of Chaetoceros, Thalassiosira and Pseudo-nitzschia. Our results are relevant to sedaDNA studies aiming to accurately characterise paleo-ecosystems from either metabarcoding or metagenomic data.
Signal-on electrochemical DNA (E-DNA) sensor for accurate quantification of nicking-assisted rolling circle amplification (N-RCA) products with attomolar sensitivity
Authors: Li Mengmeng , Li Dandan , Huang Guidan , Zhou Linying , Wen Qilin , Zhu Wenyuan , Pan Hongcheng
Published: November 2021

A signal-on E-DNA sensor was developed for accurate quantification of N-RCA products with high specificity and sensitivity.
Size controlled silver nanoparticles on β-cyclodextrin/graphitic carbon nitride: an excellent nanohybrid material for SERS and catalytic applications
Authors: Santhoshkumar S. , Murugan E.
Published: November 2021

Synthesis and characterization of high dispersion of silver nanoparticles (AgNPs) on β-cyclodextrin (β-CD)/graphitic carbon nitride (g-CN) nanohybrids (AgNPs/β-CD/g-CN-NH) for enhanced SERS and Catalysis applications.
Tertiary arsine ligands for the Stille coupling reaction
Authors: Chishiro Akane , Konishi Masafumi , Inaba Ryoto , Yumura Takashi , Imoto Hiroaki , Naka Kensuke
Published: November 2021

Tertiary arsenic ligands were utilized for the Stille coupling reaction to elucidate the relationship between ligand structure and catalytic activity. Tri(p-anisyl)arsine showed the highest yield, and the mechanism was analysed by DFT calculations.
Unexpected high selectivity for acetate formation from CO2 reduction with copper based 2D hybrid catalysts at ultralow potentials
Authors: Cai Rongming , Sun Mingzi , Ren Jiazheng , Ju Min , Long Xia , Huang Bolong , Yang Shihe
Published: November 2021

A two-dimensional (2D) copper hybrid catalyst (Cu/CuxOF) composed of metallic Cu well dispersed on 2D F-doped CuxO nanoplates (CuxOF) is reported, which shows high catalytic activity toward the CO2RR for acetate generation.