bluuebunny/crossref_metadata_2025 huggingface dataset:
On finite groups with exactly one vanishing conjugacy class size
Authors: Ahanjideh Neda
Published: February 2022

Let $G$ be a finite group. An element $g \in G$ is called a vanishing element in $G$ if there exists an irreducible character $\chi$ of $G$ such that $\chi (g)=0$. The size of a conjugacy class of $G$ containing a vanishing element is called a vanishing conjugacy class size of $G$. In this paper, we give an affirmative answer to the problem raised by Bianchi, Camina, Lewis and Pacifici about the solvability of finite groups with exactly one vanishing conjugacy class size.
Actively Keeping Secrets From Creditors: Evidence From the Uniform Trade Secrets Act
Authors: Guernsey Scott , John Kose , Litov Lubomir P.
Published: February 2022

We find that an increase in a firm’s incentives to use trade secrets to protect its intellectual property results in a more actively managed capital structure. Exploiting U.S. states’ adoption of the Uniform Trade Secrets Act as a positive “shock” in the protection afforded to trade secrets, we find that firms covered by the Act reduce debt levels while increasing investments in intangibles. Additional tests suggest that firms fund these financing and investment activities by issuing more equity. Consistent with an increase in overall intangibility magnifying contracting problems with creditors, we find that covered firms experience higher costs of debt.
Machine learning political orders
Authors: Amoore Louise
Published: February 2022

A significant set of epistemic and political transformations are taking place as states and societies begin to understand themselves and their problems through the paradigm of deep neural network algorithms. A machine learning political order does not merely change the political technologies of governance, but is itself a reordering of politics, of what the political can be. When algorithmic systems reduce the pluridimensionality of politics to the output of a model, they simultaneously foreclose the potential for other political claims to be made and alternative political projects to be built. More than this foreclosure, a machine learning political order actively profits and learns from the fracturing of communities and the destabilising of democratic rights. The transformation from rules-based algorithms to deep learning models has paralleled the undoing of rules-based social and international orders – from the use of machine learning in the campaigns of the UK EU referendum, to the trialling of algorithmic immigration and welfare systems, and the use of deep learning in the COVID-19 pandemic – with political problems becoming reconfigured as machine learning problems. Machine learning political orders decouple their attributes, features and clusters from underlying social values, no longer tethered to notions of good governance or a good society, but searching instead for the optimal function of abstract representations of data.
Distinguishing endpoint sets from Erdős space
Authors: LIPHAM DAVID S.
Published: February 2022

We prove that the set of all endpoints of the Julia set of
$f(z)=\exp\!(z)-1$
which escape to infinity under iteration of f is not homeomorphic to the rational Hilbert space
$\mathfrak E$
. As a corollary, we show that the set of all points
$z\in \mathbb C$
whose orbits either escape to
$\infty$
or attract to 0 is path-connected. We extend these results to many other functions in the exponential family.
Automation, productivity, and innovation in information technology
Authors: Pillai Unni
Published: February 2022

The rate of innovation in Information Technology (IT) has slowed down over time. The slowdown is evident both in the data on quality-adjusted prices of computers, and performance of microprocessors used in computers. The model in this paper shows that an IT–labor elasticity of substitution that is greater than 1 can explain the slowdown. With an elasticity of substitution greater than 1, however, slowing innovation can result in sustained labor productivity and output growth. Sustained growth is possible because an IT–labor elasticity of substitution greater than 1 results in a continuously increasing share of IT in production costs, which counteracts the effect of slowing innovation on labor productivity and output growth. In this environment of slowing innovation, increasing IT share and sustained growth, employment can increase or decrease, depending on the values of the IT–labor elasticity of substitution and the price elasticity of demand for IT-enabled consumption goods.
A Novel Monochromator with Offset Cylindrical Lenses and Its Application to a Low-Voltage Scanning Electron Microscope
Authors: Ogawa Takashi , Yamazawa Yu , Kawai Satoshi , Mouri Atsushi , Katane Junichi , Park In-Yong , Takai Yoshizo , Agemura Toshihide
Published: February 2022

Low-voltage scanning electron microscopes (LV-SEMs) are widely used in nanoscience. However, image resolution for SEMs is restricted by chromatic aberration due to energy spread of the electron beam at low acceleration voltage. This study introduces a new monochromator (MC) with offset cylindrical lenses (CLs) as one solution for LV-SEMs. The MC optics, with highly excited CLs in offset layouts, has advantageous high performance and simple experimental setup, making it suitable for field emission LV-SEMs. In a preliminary evaluation, our MC reduced the energy spread from 770 to 67 meV. The MC was integrated into a commercial SEM equipped with an out-lens (a conventional objective lens without immersion magnetic or retarding electric fields) and an Everhart–Thornley detector. Comparing SEM images under two conditions with the MC turned on or off, the spatial resolution was improved by 58% at 0.5 and 1 keV. The filtering effect of the MC decreased the probe current with a ratio (i.e., transmittance) of 5.7%, which was consistent with estimations based on measured energy spreads. To the best of our knowledge, this is the first report on an effective MC with higher-energy resolution than 100 meV and the results offer encouraging prospects for LV-SEM technology.
Constructions of Unemployed Individuals in German Parliamentary Debates on Active Labour Market Policy Reforms: A Comparative Analysis of 2003 and 2016
Authors: Ariaans Mareike , Reibling Nadine
Published: February 2022

Active labour market policy (ALMP) reforms have fundamentally changed welfare states over the last decades. Their objectives are quite diverse: workfare reforms have increased conditionality and sanctioning of benefits, while enabling reforms have extended education and training opportunities for the unemployed. Little is known about the political discourse on ALMP reforms. We investigate how the individual unemployed person is portrayed in ALMP reforms via a comparative coding analysis of parliamentary debates on labour market reforms that took place in Germany in 2003 (workfare) and in 2016 (enabling). Our results indicate that compared to enabling reforms the individual unemployed is less important in the framing of workfare reforms but more often blamed. Party characteristics matter: parties on the left more often point to the deservingness of the unemployed. However, when the social democratic party in government introduced a workfare reform they used blaming of unemployed persons as a framing strategy.
INDIVISIBILITY OF HEEGNER CYCLES OVER SHIMURA CURVES AND SELMER GROUPS
Authors: Wang Haining
Published: February 2022

In this article, we show that the Abel–Jacobi images of the Heegner cycles over the Shimura curves constructed by Nekovar, Besser and the theta elements contructed by Chida–Hsieh form a bipartite Euler system in the sense of Howard. As an application of this, we deduce a converse to Gross–Zagier–Kolyvagin type theorem for higher weight modular forms generalising works of Wei Zhang and Skinner for modular forms of weight 2. That is, we show that if the rank of certain residual Selmer group is 1, then the Abel–Jacobi image of the Heegner cycle is nonzero in this residual Selmer group.
Existential uncertainty in the patient cancer experience: Delimiting the concept
Authors: Dwan Conor , Willig Carla
Published: February 2022

Objective

To delimit the concept of existential uncertainty in the patient cancer experience from other, related aspects of uncertainty in the context of an existing framework of health-related uncertainty.

Methods

In-depth interviews were carried out with six people living with cancer and analyzed using theory-driven, concept-focused thematic analysis.

Results

Our analysis suggests that existential uncertainty is concerned with meaning rather than information; with the person rather than the disease; and with the fundamental nature of our human being-in-the-world rather than the more practical aspects of our relationships with others. Patient expressions of existential uncertainty may involve a nonscientific discourse of metaphor, analogy, and imagination.

Significance of results

It is important for professionals working in supportive oncology to have a conceptual understanding of uncertainty in order to choose how best to respond to patients’ needs, as different interventions may be more or less appropriate to different aspects of patient uncertainty.
The 29 July 2021 MW 8.2 Chignik, Alaska Peninsula Earthquake Rupture Inferred From Seismic and Geodetic Observations: Re‐Rupture of the Western 2/3 of the 1938 Rupture Zone
Authors: Liu Chengli , Lay Thorne , Xiong Xiong
Published: February 2022

On 29 July 2021, an MW 8.2 thrust‐faulting earthquake ruptured offshore of the Alaska Peninsula within the rupture zone of the 1938 MW 8.2 earthquake. The spatiotemporal distribution of megathrust slip is resolved by jointly inverting regional and teleseismic broadband waveforms along with co‐seismic static and high‐rate GNSS displacements. The primarily unilateral rupture expanded northeastward, away from the rupture zone of the 22 July 2020 MW 7.8 Shumagin earthquake. Large slip extends along approximately 175 km, spanning about two third of the estimated 1938 aftershock zone, with well‐bounded depth from 20 to 40 km, and up to 8.6 m slip near the hypocenter. The rupture terminated in the eastern portion of the 1938 aftershock zone in a region of very large geodetic slip deficit where peak slip appears to have occurred in the 1938 rupture. The 2021 and 1938 events do not have similar slip distributions and do not indicate persistent asperities.
Sensitivity of Melting, Freezing and Marine Ice Beneath Larsen C Ice Shelf to Changes in Ocean Forcing
Authors: Harrison Lianne C. , Holland Paul R. , Heywood Karen J. , Nicholls Keith W. , Brisbourne Alex M.
Published: February 2022

Observations of surface lowering on Larsen C Ice Shelf (LCIS), Antarctica, have prompted concern about its stability. In this study, an ocean model is used to investigate the extent to which changes in ocean forcing may have influenced ice loss and the distribution of stabilizing marine ice beneath LCIS. The model uses a new bathymetry, containing a southern seabed trough discovered using seismic observations. The modeled extent of marine ice, thought to stabilize LCIS, is in good agreement with observations. Experiments applying idealized ocean warming yield an increase in melting over the southern trough. This is inconsistent with lowering observed in northern LCIS, suggesting oceanic forcing is not responsible for that signal. The marine ice extent and thickness reduces significantly under ocean warming, implying a high sensitivity of LCIS stability to changes in ocean forcing. This result could have wide implications for other cold‐water ice shelves around Antarctica.
Simultaneous Observations of a Sporadic E Layer by Digisonde and SuperDARN HF Radars at Zhongshan, Antarctica
Authors: Chen Xiangcai , Liu Jianjun , Kosch Michael J. , Hu Zejun , Wang Zhiwei , Zhang Beichen , Yang Huigen , Hu Hongqiao
Published: February 2022

Sporadic E (Es) layers could be composed of metallic ions and formed, modified, or transported by the action of convective electric fields in the high latitude ionosphere. In this paper, by utilizing simultaneous observations from Digisonde and Super Dual Auroral Radar Network (SuperDARN) HF radars at Zhongshan Station (ZHS, 69.4°S, 76.4°E), Antarctica, a thin Es layer, which initially formed in the lower F region and descended into the lower E region, with wavelike structures, was recorded by Digisonde on 14 November 2019. The Es layer‐related concurrent ionospheric irregularities were also detected by the SuperDARN ZHS HF radar. By using a global‐scale 2‐D convection map, combined with images from the Special Sensor Ultraviolet Spectrographic Imager instruments onboard Defense Meteorological Satellite Program (DMSP) spacecraft, it is proposed that the flow shears associated with the duskside convective circulation are responsible for the evolution of the Es layer. Moreover, using the HF radar elevation angle data to measure the scatter height, it is strongly suggested that the Es layer was elongated with convection circulation. The electrodynamic processes responsible for the formation and evolution of the Es layer are discussed.
Exploration and Evaluation of Deep-Sea Mining Sites
Authors: Sidder Aaron
Published: February 2022

Two studies chart new territory for the fledgling deep-sea mining industry through advances in the identification and analysis of seafloor hydrothermal mounds.
C1GALT1 expression predicts a favorable prognosis and suppresses malignant phenotypes via TrkA signaling in neuroblastoma
Authors: Lin Neng-Yu , Chen Syue-Ting , Chang Hsiu-Ling , Lu Meng-Yao , Yang Yung-Li , Chou Shu-Wei , Lin Dong-Tsamn , Lin Kai-Hsin , Jou Shiann-Tarng , Hsu Wen-Ming , Huang Min-Chuan , Chang Hsiu-Hao
Published: February 2022

Neuroblastoma (NB) is a childhood tumor derived from the sympathoadrenal lineage of the neural crest progenitor cells. Core 1 β1,3-galactosyltransferase (C1GALT1) controls the crucial step of GalNAc-type O-glycosylation, and its altered expression affects cancer behaviors. However, the role of C1GALT1 in NB tumors remains unclear. Our data showed that C1GALT1 expression was significantly associated with differentiated tumor histology, correlated with TrkA expression, and predicted good prognosis independently in NB. Downregulation of C1GALT1 promotes malignant behaviors of NB cells in vitro and in vivo. Mechanistic investigation showed that knockdown of C1GALT1 in NB cells increased TrkA pulled down through Vicia villosa agglutinin beads, indicating the modulation of O-glycans on TrkA by C1GALT1, and silencing C1GALT1 suppressed the TrkA expression on the NB cell surface. Overexpression of C1GALT1 increased the protein levels of TrkA and promoted the differentiation of NB cells, whereas knockdown of TrkA inhibited C1GALT1-induced neuronal differentiation. Moreover, the inhibitory effects of migration and invasion in C1GALT1-overexpressing NB cells were blocked by TrkA downregulation. C1GALT1 knockdown enhanced AKT phosphorylation but attenuated ERK phosphorylation, and these properties were consistent in C1GALT1-overexpressing NB cells with TrkA knockdown. Taken together, our data provided the first evidence for the existence of GalNAc-type O-glycans on TrkA and altered O-glycan structures by C1GALT1 can regulate TrkA signaling in NB cells. This study sheds light on the novel prognostic role of C1GALT1 in NB and provides new information of C1GALT1 and TrkA on the pathogenesis of NB.
Broad ultra-potent neutralization of SARS-CoV-2 variants by monoclonal antibodies specific to the tip of RBD
Authors: Ma Hang , Guo Yingying , Tang Haoneng , Tseng Chien-Te K. , Wang Lei , Zong Huifang , Wang Zhenyu , He Yang , Chang Yunsong , Wang Shusheng , Huang Haiqiu , Ke Yong , Yuan Yunsheng , Wu Mingyuan , Zhang Yuanyuan , Drelich Aleksandra , Kempaiah Kempaiah Rayavara , Peng Bi-Hung , Wang Ailin , Yang Kaiyong , Yin Haiyang , Liu Junjun , Yue Yali , Xu Wenbo , Zhu Shuangli , Ji Tianjiao , Zhang Xiaoju , Wang Ziqi , Li Gang , Liu Guangchun , Song Jingjing , Mu Lingling , Xiang ZongShang , Song Zhangyi , Chen Hua , Bian Yanlin , Zhang Baohong , Chen Hui , Zhang Jiawei , Liao Yunji , Zhang Li , Yang Li , Chen Yi , Gilly John , Xiao Xiaodong , Han Lei , Jiang Hua , Xie Yueqing , Zhou Qiang , Zhu Jianwei
Published: February 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with angiotensin converting enzyme 2 (ACE2) interface, which enables 2G1 to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar half maximal inhibitory concentration in vitro. In SARS-CoV-2, Beta or Delta variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 is potentially capable of dealing with emerging SARS-CoV-2 variants in the future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.
Binding events through the mutual synchronization of spintronic nano-neurons
Authors: Romera Miguel , Talatchian Philippe , Tsunegi Sumito , Yakushiji Kay , Fukushima Akio , Kubota Hitoshi , Yuasa Shinji , Cros Vincent , Bortolotti Paolo , Ernoult Maxence , Querlioz Damien , Grollier Julie
Published: February 2022

The brain naturally binds events from different sources in unique concepts. It is hypothesized that this process occurs through the transient mutual synchronization of neurons located in different regions of the brain when the stimulus is presented. This mechanism of ‘binding through synchronization’ can be directly implemented in neural networks composed of coupled oscillators. To do so, the oscillators must be able to mutually synchronize for the range of inputs corresponding to a single class, and otherwise remain desynchronized. Here we show that the outstanding ability of spintronic nano-oscillators to mutually synchronize and the possibility to precisely control the occurrence of mutual synchronization by tuning the oscillator frequencies over wide ranges allows pattern recognition. We demonstrate experimentally on a simple task that three spintronic nano-oscillators can bind consecutive events and thus recognize and distinguish temporal sequences. This work is a step forward in the construction of neural networks that exploit the non-linear dynamic properties of their components to perform brain-inspired computations.
Using language in social media posts to study the network dynamics of depression longitudinally
Authors: Kelley Sean W. , Gillan Claire M.
Published: February 2022

Network theory of mental illness posits that causal interactions between symptoms give rise to mental health disorders. Increasing evidence suggests that depression network connectivity may be a risk factor for transitioning and sustaining a depressive state. Here we analysed social media (Twitter) data from 946 participants who retrospectively self-reported the dates of any depressive episodes in the past 12 months and current depressive symptom severity. We construct personalised, within-subject, networks based on depression-related linguistic features. We show an association existed between current depression severity and 8 out of 9 text features examined. Individuals with greater depression severity had higher overall network connectivity between depression-relevant linguistic features than those with lesser severity. We observed within-subject changes in overall network connectivity associated with the dates of a self-reported depressive episode. The connectivity within personalized networks of depression-associated linguistic features may change dynamically with changes in current depression symptoms.
Data-driven modeling and prediction of non-linearizable dynamics via spectral submanifolds
Authors: Cenedese Mattia , Axås Joar , Bäuerlein Bastian , Avila Kerstin , Haller George
Published: February 2022

We develop a methodology to construct low-dimensional predictive models from data sets representing essentially nonlinear (or non-linearizable) dynamical systems with a hyperbolic linear part that are subject to external forcing with finitely many frequencies. Our data-driven, sparse, nonlinear models are obtained as extended normal forms of the reduced dynamics on low-dimensional, attracting spectral submanifolds (SSMs) of the dynamical system. We illustrate the power of data-driven SSM reduction on high-dimensional numerical data sets and experimental measurements involving beam oscillations, vortex shedding and sloshing in a water tank. We find that SSM reduction trained on unforced data also predicts nonlinear response accurately under additional external forcing.
HSL1 and BAM1/2 impact epidermal cell development by sensing distinct signaling peptides
Authors: Roman Andra-Octavia , Jimenez-Sandoval Pedro , Augustin Sebastian , Broyart Caroline , Hothorn Ludwig A. , Santiago Julia
Published: February 2022

The membrane receptor kinases HAESA and HSL2 recognize a family of IDA/IDL signaling peptides to control cell separation processes in different plant organs. The homologous HSL1 has been reported to regulate epidermal cell patterning by interacting with a different class of signaling peptides from the CLE family. Here we demonstrate that HSL1 binds IDA/IDL peptides with high, and CLE peptides with lower affinity, respectively. Ligand sensing capability and receptor activation of HSL1 require a SERK co-receptor kinase. Crystal structures with IDA/IDLs or with CLE9 reveal that HSL1-SERK1 complex recognizes the entire IDA/IDL signaling peptide, while only parts of CLE9 are bound to the receptor. In contrast, the receptor kinase BAM1 interacts with the entire CLE9 peptide with high affinity and specificity. Furthermore, the receptor tandem BAM1/BAM2 regulates epidermal cell division homeostasis. Consequently, HSL1-IDLs and BAM1/BAM2-CLEs independently regulate cell patterning in the leaf epidermal tissue.
Care-seeking and delay of care during COPD exacerbations
Authors: Locke Emily R. , Young Jessica P. , Battaglia Catherine , Simpson Tracy L. , Trivedi Ranak , Simons Carol , Fortney John C. , Hebert Paul , Swenson Erik R. , Edelman Jeffrey , Fan Vincent S.
Published: February 2022

Patients who receive earlier treatment for acute exacerbations of chronic obstructive pulmonary disease (COPD) have a better prognosis, including earlier symptom resolution and reduced risk of future emergency-department visits (ED) or hospitalizations. However, many patients delay seeking care or do not report worsening symptoms to their healthcare provider. In this study, we aimed to understand how patients perceived their breathing symptoms and identify factors that led to seeking or delaying care for an acute exacerbation of COPD. We conducted semistructured interviews with 60 individuals following a recent COPD exacerbation. Participants were identified from a larger study of outpatients with COPD by purposive sampling by exacerbation type: 15 untreated, 15 treated with prednisone and/or antibiotics in the outpatient setting, 16 treated in an urgent care or ED setting, and 14 hospitalized. Data were analyzed using inductive content analysis. Participants were primarily male (97%) with a mean age of 69.1 ± 6.9 years, mean FEV1 1.42 (±0.63), and mean mMRC dyspnea of 2.7 (±1.1). We identified 4 primary themes: (i) access and attitudinal barriers contribute to reluctance to seek care, (ii) waiting is a typical response to new exacerbations, (iii) transitioning from waiting to care-seeking: the tipping point, and (iv) learning from and avoiding worse outcomes. Interventions to encourage earlier care-seeking for COPD exacerbations should consider individuals’ existing self-management approaches, address attitudinal barriers to seeking care, and consider health-system changes to increase access to non-emergent outpatient treatment for exacerbations.

Clinical Trial Registration NCT02725294
The Digital Brain Tumour Atlas, an open histopathology resource
Authors: Roetzer-Pejrimovsky Thomas , Moser Anna-Christina , Atli Baran , Vogel Clemens Christian , Mercea Petra A. , Prihoda Romana , Gelpi Ellen , Haberler Christine , Höftberger Romana , Hainfellner Johannes A. , Baumann Bernhard , Langs Georg , Woehrer Adelheid
Published: February 2022

Currently, approximately 150 different brain tumour types are defined by the WHO. Recent endeavours to exploit machine learning and deep learning methods for supporting more precise diagnostics based on the histological tumour appearance have been hampered by the relative paucity of accessible digital histopathological datasets. While freely available datasets are relatively common in many medical specialties such as radiology and genomic medicine, there is still an unmet need regarding histopathological data. Thus, we digitized a significant portion of a large dedicated brain tumour bank based at the Division of Neuropathology and Neurochemistry of the Medical University of Vienna, covering brain tumour cases from 1995–2019. A total of 3,115 slides of 126 brain tumour types (including 47 control tissue slides) have been scanned. Additionally, complementary clinical annotations have been collected for each case. In the present manuscript, we thoroughly discuss this unique dataset and make it publicly available for potential use cases in machine learning and digital image analysis, teaching and as a reference for external validation.
E2F1-induced lncRNA, EMSLR regulates lncRNA LncPRESS1
Authors: Priyanka Priyanka , Sharma Madhur , Das Sanjeev , Saxena Sandeep
Published: February 2022

E2F1 induces hundreds of protein-coding genes influencing diverse signaling pathways but much less is known about its non-coding RNA targets. For identifying E2F1-dependent oncogenic long non-coding RNAs (lncRNAs), we carried out genome-wide transcriptome analysis and discovered an lncRNA, EMSLR, which is induced both in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). EMSLR depletion blocks the cells in G1 phase and inhibits the clonogenic ability indicating that it is essential for the tumor-related phenotypes. We discovered that EMSLR represses the promoter activity of another lncRNA, LncPRESS1, which is located 6.9 kb upstream of EMSLR and they display an inverse expression pattern in lung cancer cell lines. Depletion of C-MYC results in downregulation of EMSLR and simultaneous upregulation of EMSLR target LncPRESS1, exemplifying how C-MYC and E2F1 signal transduction pathways control the network of lncRNA genes to modulate cell proliferation and differentiation.
Biomechanical duality of fracture healing captured using virtual mechanical testing and validated in ovine bones
Authors: Inglis Brendan , Schwarzenberg Peter , Klein Karina , von Rechenberg Brigitte , Darwiche Salim , Dailey Hannah L.
Published: February 2022

Bone fractures commonly repair by forming a bridging structure called callus, which begins as soft tissue and gradually ossifies to restore rigidity to the bone. Virtual mechanical testing is a promising technique for image-based assessment of structural bone healing in both preclinical and clinical settings, but its accuracy depends on the validity of the material model used to assign tissue mechanical properties. The goal of this study was to develop a constitutive model for callus that captures the heterogeneity and biomechanical duality of the callus, which contains both soft tissue and woven bone. To achieve this, a large-scale optimization analysis was performed on 2363 variations of 3D finite element models derived from computed tomography (CT) scans of 33 osteotomized sheep under normal and delayed healing conditions. A piecewise material model was identified that produced high absolute agreement between virtual and physical tests by differentiating between soft and hard callus based on radiodensity. The results showed that the structural integrity of a healing long bone is conferred by an internal architecture of mineralized hard callus that is supported by interstitial soft tissue. These findings suggest that with appropriate material modeling, virtual mechanical testing is a reliable surrogate for physical biomechanical testing.
A prospective cohort study about the effect of repeated living high and working higher on cerebral autoregulation in unacclimatized lowlanders
Authors: Graf Laura C. , Hartmann Sara E. , Lichtblau Mona , Muralt Lara , Bader Patrick R. , Lopez Ivan , Rawling Jean M. , Ulrich Silvia , Bloch Konrad E. , Poulin Marc J. , Furian Michael
Published: February 2022

Cerebral autoregulation (CA) is impaired during acute high-altitude (HA) exposure, however, effects of temporarily living high and working higher on CA require further investigation. In 18 healthy lowlanders (11 women), we hypothesized that the cerebral autoregulation index (ARI) assessed by the percentage change in middle cerebral artery peak blood velocity (Δ%MCAv)/percentage change in mean arterial blood pressure (Δ%MAP) induced by a sit-to-stand maneuver, is (i) reduced on Day1 at 5050 m compared to 520 m, (ii) is improved after 6 days at 5050 m, and (iii) is less impaired during re-exposure to 5050 m after 7 days at 520 m compared to Cycle1. Participants spent 4-8 h/day at 5050 m and slept at 2900 m similar to real-life working shifts. High/low ARI indicate impaired/intact CA, respectively. With the sit-to-stand at 520 m, mean (95% CI) in ΔMAP and ΔMCAv were − 26% (− 41 to − 10) and − 13% (− 19 to − 7), P < 0.001 both comparisons; mean ± SD in ARI was 0.58 ± 2.44Δ%/Δ%, respectively. On Day1 at 5050 m, ARI worsened compared to 520 m (3.29 ± 2.42Δ%/Δ%), P = 0.006 but improved with acclimatization (1.44 ± 2.43Δ%/Δ%, P = 0.039). ARI was less affected during re-exposure to 5050 m (1.22 ± 2.52Δ%/Δ%, P = 0.027 altitude-induced change between sojourns). This study showed that CA (i) is impaired during acute HA exposure, (ii) improves with living high, working higher and (iii) is ameliorated during re-exposure to HA.
Development of behavioral patterns in young C57BL/6J mice: a home cage-based study
Authors: Reiber Maria , Koska Ines , Pace Claudia , Schönhoff Katharina , von Schumann Lara , Palme Rupert , Potschka Heidrun
Published: February 2022

Evidence exists that behavioral patterns only stabilize once mice reach adulthood. Detailed information about the course of behavioral patterns is of particular relevance for neuroscientific research and for the assessment of cumulative severity in genetically modified mice. The analysis considered five age groups focusing on behavioral assessments in the animals’ familiar home cage environment during the adolescence phase. We confirmed age- and sex-specific differences for several of the behavioral parameters and fecal corticosterone metabolites. Interestingly, an age-dependent decline in saccharin preference was detected in female mice. Regardless of sex, relevant levels of burrowing activity were only observed during later developmental phases. The development of nest complexity following the offer of new material was affected by age in female mice. In female and male mice, an age-dependency was evident for wheel running reaching a peak at P 50. A progressive increase with age was also observed for Open field activity. The data sets provide guidance for behavioral studies and for development of composite measure schemes for evidence-based severity assessment in young mice. Except for the burrowing test, the different behavioral tests can be applied in different age groups during post-weaning development. However, age- and sex-specific characteristics need to be considered.
Neuronal modulation in the mouse superior colliculus during covert visual selective attention
Authors: Wang Lupeng , Herman James P. , Krauzlis Richard J.
Published: February 2022

Covert visual attention is accomplished by a cascade of mechanisms distributed across multiple brain regions. Visual cortex is associated with enhanced representations of relevant stimulus features, whereas the contributions of subcortical circuits are less well understood but have been associated with selection of relevant spatial locations and suppression of distracting stimuli. As a step toward understanding these subcortical circuits, here we identified how neuronal activity in the intermediate layers of the superior colliculus (SC) of head-fixed mice is modulated during covert visual attention. We found that spatial cues modulated both firing rate and spike-count correlations. Crucially, the cue-related modulation in firing rate was due to enhancement of activity at the cued spatial location rather than suppression at the uncued location, indicating that SC neurons in our task were modulated by an excitatory or disinhibitory circuit mechanism focused on the relevant location, rather than broad inhibition of irrelevant locations. This modulation improved the neuronal discriminability of visual-change-evoked activity, but only when assessed for neuronal activity between the contralateral and ipsilateral SC. Together, our findings indicate that neurons in the mouse SC can contribute to covert visual selective attention by biasing processing in favor of locations expected to contain task-relevant information.
Mitochondrial DNA diversity of the Sardinian local cattle stock
Authors: Petretto Elena , Dettori Maria Luisa , Pazzola Michele , Manca Fabio , Amills Marcel , Vacca Giuseppe Massimo
Published: February 2022

The aim of this research was to characterize the genetic diversity of the Sarda (Sa, n = 131), Sardo Bruna (SB, n = 44) and Sardo Modicana (SM, n = 26) cattle breeds, reared in the island of Sardinia (Italy). A portion of the mitochondrial DNA hypervariable region was sequenced, in order to identify a potential signature of African introgression. The FST coefficients among populations ranged between 0.056 for Sa vs SB and 0.167 for SB vs SM. AMOVA analysis indicated there was a significant differentiation of the three breeds, although most of diversity was gathered at the within-breed level. The Median Joining Network of the Sardinian sequences showed a potential founder effect signature. A MJ network including Sardinian cattle plus African, Italian, Iberian and Asian sequences, revealed the presence of haplogroup T3, already detected in Sa cattle, and the presence of Hg T1 and Hg T1′2′3, in Sa and SB. The presence of a private haplotype belonging to haplogroup T1, which is characteristic of African taurine breeds, may be due to the introgression of Sardinian breeds with African cattle, either directly (most probable source: North African cattle) or indirectly (through a Mediterranean intermediary already introgressed with African blood).
Evaluation of machine learning algorithms for trabeculectomy outcome prediction in patients with glaucoma
Authors: Banna Hasan Ul , Zanabli Ahmed , McMillan Brian , Lehmann Maria , Gupta Sumeet , Gerbo Michael , Palko Joel
Published: February 2022

The purpose of this study was to evaluate the performance of machine learning algorithms to predict trabeculectomy surgical outcomes. Preoperative systemic, demographic and ocular data from consecutive trabeculectomy surgeries from a single academic institution between January 2014 and December 2018 were incorporated into models using random forest, support vector machine, artificial neural networks and multivariable logistic regression. Mean area under the receiver operating characteristic curve (AUC) and accuracy were used to evaluate the discrimination of each model to predict complete success of trabeculectomy surgery at 1 year. The top performing model was optimized using recursive feature selection and hyperparameter tuning. Calibration and net benefit of the final models were assessed. Among the 230 trabeculectomy surgeries performed on 184 patients, 104 (45.2%) were classified as complete success. Random forest was found to be the top performing model with an accuracy of 0.68 and AUC of 0.74 using 5-fold cross-validation to evaluate the final optimized model. These results provide evidence that machine learning models offer value in predicting trabeculectomy outcomes in patients with refractory glaucoma.
The effect of unexpected rewards on decision making in cuttlefish
Authors: Chung Tzu-Ting , Darmaillacq Anne-Sophie , Dickel Ludovic , Chiao Chuan-Chin
Published: February 2022

Despite numerous studies demonstrating the cognitive ability of cephalopods, there is currently no study showing an emotion-like behavior in this group of animals. To examine whether cuttlefish have different internal states, we developed a behavioral paradigm to assess if prior surprised events are able to alter the choice made by cuttlefish. By presenting unexpected food rewards to cuttlefish before the test, we investigated whether the reaction time of choosing between two shrimps, an intuitive response toward the prey without previous learning, at three different levels of discriminative tests (easy, difficult, and ambiguous), are different compared to the one without an unexpected reward. This behavioral paradigm serves to demonstrate whether cuttlefish are aware of ambiguous situations, and their choice outcome and reaction time are dependent of their internal states. The results show that the response latency was significantly shortened in the difficult and ambiguous tests when choosing from two shrimps that are either moderately different in size or similar sizes, respectively, when cuttlefish have received unexpected rewards before the test. These results were compared with tests during which the cuttlefish did not receive any reward in advance. Furthermore, this shortening of latency did not result in a difference in choice outcome during the difficult and ambiguous tests. Interestingly, even when cuttlefish have obtained the expected food rewards or simply made tentacular strike without prey capture each time before test, these prior experiences were sufficient to shorten the response latency in the difficult and ambiguous tests. However, different from the result of unexpected rewards, food consumption alone or prey capture failure did affect the choice outcome during the simple and difficult tests. Taken together, our findings suggest that pre-test treatments of unexpected and expected rewards or simply unsuccessful visual attack seem to induce cuttlefish to adopt different foraging behaviors. This context dependent decision making suggests that cuttlefish’s foraging strategies are influenced by the previously surprised event and their internal states. It also shows a speed-accuracy tradeoff in difficult and ambiguous situations when foraging for prey. This observation may lead to a future investigation of the presence of emotional state in cephalopods.
Dual use of e-cigarettes with conventional tobacco is associated with increased sleep latency in cross-sectional Study
Authors: Advani Ira , Gunge Deepti , Boddu Shreyes , Mehta Sagar , Park Kenneth , Perera Samantha , Pham Josephine , Nilaad Sedtavut , Olay Jarod , Ma Lauren , Masso-Silva Jorge , Sun Xiaoying , Jain Sonia , Malhotra Atul , Crotty Alexander Laura E.
Published: February 2022

The health effects of e-cigarettes remain relatively unknown, including their impact on sleep quality. We previously showed in a pilot study that females who smoke both conventional tobacco and vape e-cigarettes (dual users) had decreased sleep quality (measurement of how well an individual is sleeping) and increased sleep latency (amount of time to fall asleep), suggesting an influence by gender. Cough is also known to adversely impact sleep quality and may be caused by inhalant use. As a result, we undertook this study to assess the impact of e-cigarette, conventional tobacco, and dual use on sleep quality, sleep latency, cough, and drug use. Participants (n = 1198) were recruited through online surveys posted to social media sites with a monetary incentive. Participants were grouped by inhalant use, with 8% e-cigarette users, 12% conventional tobacco users, 30% dual users, and 51% non-smokers/non-vapers. Dual use of e-cigarettes and conventional tobacco was associated with increased sleep latency relative to non-smokers/non-vapers by multivariable linear regression (mean difference of 4.08; 95% CI: 1.12 to 7.05, raw p = 0.007, adjusted p = 0.042); however, dual usage was not significantly associated with sleep quality relative to non-smokers/non-vapers (mean difference 0.22, 95%CI: (−0.36, 0.80), raw p = 0.452, adjust p = 0.542). Dual use was also associated with a higher reporting of cough (p = 0.038), as well as increased marijuana (p < 0.001) and cocaine (p < 0.001) usage. This study demonstrates that  dual use is associated with longer sleep latency, and suggests that the shared component of nicotine may be a driver. Because sleep broadly impacts multiple aspects of human health, defining the associations of e-cigarettes and vaping devices on sleep is critical to furthering our understanding of their influence on the body.
Muscle protein synthesis and muscle/metabolic responses to resistance exercise training in South Asian and White European men
Authors: Alkhayl Faris F. Aba , Ismail Ahmad D. , Celis-Morales Carlos , Wilson John , Radjenovic Aleksandra , Johnston Lynsey , Welsh Paul , Sattar Naveed , Gill Jason M. R. , Preston Tom , Gray Stuart R.
Published: February 2022

The aims of the current study, therefore, were to compare (1) free-living MPS and (2) muscle and metabolic adaptations to resistance exercise in South Asian and white European adults. Eighteen South Asian and 16 White European men were enrolled in the study. Free-living muscle protein synthesis was measured at baseline. Muscle strength, body composition, resting metabolic rate, VO2maxand metabolic responses (insulin sensitivity) to a mixed meal were measured at baseline and following 12 weeks of resistance exercise training. Free-living muscle protein synthesis was not different between South Asians (1.48 ± 0.09%/day) and White Europeans (1.59 ± 0.15%/day) (p = 0.522). In response to resistance exercise training there were no differences, between South Asians and White Europeans, muscle mass, lower body strength or insulin sensitivity. However, there were differences between the ethnicities in response to resistance exercise training in body fat, resting carbohydrate and fat metabolism, blood pressure, VO2maxand upper body strength with responses less favourable in South Asians. In this exploratory study there were no differences in muscle protein synthesis or anabolic and metabolic responses to resistance exercise, yet there were less favourable responses in several outcomes. These findings require further investigation.
A gene signature consisting of ubiquitin ligases and deubiquitinating enzymes of SKP2 is associated with clinical outcome in breast cancer
Authors: Fong Lon W. R. , Lee Jangsoon , Lin Hui-Kuan , Ueno Naoto T. , Zhang Shuxing
Published: February 2022

The ubiquitination of SKP2, an oncoprotein, is controlled by its E3 ligases, including APC/CFZR1 and deubiquitinases such as USP10. We identified a two-gene signature for the ubiquitination of SKP2, consisting of the copy number of FZR1 compared to the copy number of USP10. The signature reflects the level of SKP2 activity, stratifying BC patients into two groups with significantly different protein levels of SKP2 ubiquitination substrate p27 (t-test p < 0.01) and recapitulating the expression patterns of SKP2 between tumor and normal tissue (Spearman’s ρ = 0.39.) The signature is also highly associated with clinical outcome in luminal BC but not other subtypes, characterizing patients into two groups with significantly different overall survival times (log-rank p = 0.006). In addition, it is dramatically associated with tumor grade (Chi-squared p = 6.7 × 10−3), stage (Chi-squared p = 1.6 × 10−11), and the number of positive lymph nodes (negative binomial regression coefficient p = 2.0 × 10−3). Our study provides a rationale for targeting the SKP2 ubiquitination pathway in luminal BC and for further investigation of the use of ubiquitinase/deubiquitinase genes as prognosis and treatment biomarkers.
A small molecule high throughput screening platform to profile conformational properties of nascent, ribosome-bound proteins
Authors: Shishido Hideki , Yoon Jae Seok , Skach William R.
Published: February 2022

Genetic mutations cause a wide spectrum of human disease by disrupting protein folding, both during and after synthesis. Transient de-novo folding intermediates therefore represent potential drug targets for pharmacological correction of protein folding disorders. Here we develop a FRET-based high-throughput screening (HTS) assay in 1,536-well format capable of identifying small molecules that interact with nascent polypeptides and correct genetic, cotranslational folding defects. Ribosome nascent chain complexes (RNCs) containing donor and acceptor fluorophores were isolated from cell free translation reactions, immobilized on Nickel-NTA/IDA beads, and imaged by high-content microscopy. Quantitative FRET measurements obtained from as little as 0.4 attomole of protein/bead enabled rapid assessment of conformational changes with a high degree of reproducibility. Using this assay, we performed a pilot screen of ~ 50,000 small molecules to identify compounds that interact with RNCs containing the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) harboring a disease-causing mutation (A455E). Screen results yielded 133 primary hits and 1 validated hit that normalized FRET values of the mutant nascent peptide. This system provides a scalable, tractable, structure-based discovery platform for screening small molecules that bind to or impact the folding of protein substrates that are not amenable to traditional biochemical analyses.
The cell adhesion protein dystroglycan affects the structural remodeling of dendritic spines
Authors: Figiel Izabela , Bączyńska Ewa , Wójtowicz Tomasz , Magnowska Marta , Buszka Anna , Bijata Monika , Włodarczyk Jakub
Published: February 2022

Dystroglycan (DG) is a cell membrane protein that binds to the extracellular matrix in various mammalian tissues. The function of DG has been well defined in embryonic development as well as in the proper migration of differentiated neuroblasts in the central nervous system (CNS). Although DG is known to be a target for matrix metalloproteinase-9 (MMP-9), cleaved in response to enhanced synaptic activity, the role of DG in the structural remodeling of dendritic spines is still unknown. Here, we report for the first time that the deletion of DG in rat hippocampal cell cultures causes pronounced changes in the density and morphology of dendritic spines. Furthermore, we noted a decrease in laminin, one of the major extracellular partners of DG. We have also observed that the lack of DG evokes alterations in the morphological complexity of astrocytes accompanied by a decrease in the level of aquaporin 4 (AQP4), a protein located within astrocyte endfeet surrounding neuronal dendrites and synapses. Regardless of all of these changes, we did not observe any effect of DG silencing on either excitatory or inhibitory synaptic transmission. Likewise, the knockdown of DG had no effect on Psd-95 protein expression. Our results indicate that DG is involved in dendritic spine remodeling that is not functionally reflected. This may suggest the existence of unknown mechanisms that maintain proper synaptic signaling despite impaired structure of dendritic spines. Presumably, astrocytes are involved in these processes.