bluuebunny/crossref_metadata_2025 huggingface dataset:
Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level
Authors: Zhu Rong , Canena Daniel , Sikora Mateusz , Klausberger Miriam , Seferovic Hannah , Mehdipour Ahmad Reza , Hain Lisa , Laurent Elisabeth , Monteil Vanessa , Wirnsberger Gerald , Wieneke Ralph , Tampé Robert , Kienzl Nikolaus F. , Mach Lukas , Mirazimi Ali , Oh Yoo Jin , Penninger Josef M. , Hummer Gerhard , Hinterdorfer Peter
Published: December 2022

Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We report that the Spike trimer acts as a highly dynamic molecular caliper, thereby forming up to three tight bonds through its RBDs with ACE2 expressed on the cell surface. The Spike of both Delta and Omicron (B.1.1.529) Variant enhance and markedly prolong viral attachment to the host cell receptor ACE2, as opposed to the early Wuhan-1 isolate. Delta Spike shows rapid binding of all three Spike RBDs to three different ACE2 molecules with considerably increased bond lifetime when compared to the reference strain, thereby significantly amplifying avidity. Intriguingly, Omicron (B.1.1.529) Spike displays less multivalent bindings to ACE2 molecules, yet with a ten time longer bond lifetime than Delta. Delta and Omicron (B.1.1.529) Spike variants enhance and prolong viral attachment to the host, which likely not only increases the rate of viral uptake, but also enhances the resistance of the variants against host-cell detachment by shear forces such as airflow, mucus or blood flow. We uncover distinct binding mechanisms and strategies at single-molecule resolution, employed by circulating SARS-CoV-2 variants to enhance infectivity and viral transmission.
Phase I study of LZM005 in patients with HER2-positive metastatic breast cancer
Authors: Xue Cong , Li Haifeng , Yao Herui , Lin Ying , An Xin , Chen Meiting , Huang Riqing , Li Lu , Hu Anqi , Ni Mengqian , Zhang Lulu , Yang Wei , Xu Zhonghui , Li Su , Shi Yanxia
Published: December 2022

The prognosis of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) remained unsatisfactory currently, more anti-HER2 agents are needed. Here we report a phase I study that evaluated the safety, activity, and biomarkers of LZM005, a HER2 antibody, used as a monotherapy or in combination with trastuzumab plus docetaxel in patients with HER2-positive MBC. From October 2017 to December 2019, 34 patients received LZM005 (14 monotherapy, 20 combination therapy). No DLT was observed. The common adverse events (AEs) in phase Ia included diarrhea (21.4%), infusion reaction (21.4%), and hypertriglyceridemia (21.4%), while those in phase Ib were leukopenia (85.0%), neutropenia (75.0%), anemia (60.0%), diarrhea (60.0%), and rash/pruritus (50.0%). All AEs were manageable. In phase Ia, partial response (PR) was achieved in one case (1/14, overall response rate [ORR]: 7.1%); the disease control rate was 42.90% (6/14). In phase Ib, 11 patients (55.0%) achieved PR, and eight (40.0%) had stable disease. The ORR was 100% (6/6) in trastuzumab-naive and 35.7% (5/14) in trastuzumab-pretreated patients. Biomarker analysis showed that chromatin remodeling genesKMT2BandBRWD1were associated with better progression-free survival. LZM005 is well tolerated and shows potent activity in patients with HER2-positive MBC.
Machine learning guided discovery of ternary compounds involving La and immiscible Co and Pb elements
Authors: Wang Renhai , Xia Weiyi , Slade Tyler J. , Fan Xinyu , Dong Huafeng , Ho Kai-Ming , Canfield Paul C. , Wang Cai-Zhuang
Published: December 2022

Ternary compounds with an immiscible pair of elements are relatively unexplored but promising for novel quantum materials discovery. Exploring what third element and its ratio that can be added to make stable ternary compounds out of an immiscible pair of elements remains a great challenge. In this work, we combine a machine learning (ML) method with ab initio calculations to efficiently search for the energetically favorable ternary La-Co-Pb compounds containing immiscible elements Co and Pb. Three previously reported structures are correctly captured by our approach. Moreover, we predict a ground state La3CoPb compound and 57 low-energy La-Co-Pb ternary compounds. Attempts to synthesize La3CoPb via multiple techniques produce mixed or multi-phases samples with, at best, ambiguous signals of the predicted lowest-energy La3CoPb and the second lowest-energy La18Co28Pb3 phases. The calculated results of Gibbs free energy are consistent with experiments, and will provide very useful guidance for further experimental synthesis.
Graph neural network modeling of grain-scale anisotropic elastic behavior using simulated and measured microscale data
Authors: Pagan Darren C. , Pash Calvin R. , Benson Austin R. , Kasemer Matthew P.
Published: December 2022

Here we assess the applicability of graph neural networks (GNNs) for predicting the grain-scale elastic response of polycrystalline metallic alloys. Using GNN surrogate models, grain-averaged stresses during uniaxial elastic tension in low solvus high-refractory (LSHR) Ni Superalloy and Ti 7 wt%Al (Ti-7Al) are predicted as example face-centered cubic and hexagonal closed packed alloys, respectively. A transfer learning approach is taken in which GNN surrogate models are trained using crystal elasticity finite element method (CEFEM) simulations and then the trained surrogate models are used to predict the mechanical response of microstructures measured using high-energy X-ray diffraction microscopy (HEDM). The performance of using various microstructural and micromechanical descriptors for input nodal features to the GNNs is explored through comparisons to traditional mean-field theory predictions, reserved full-field CEFEM data, and measured far-field HEDM data. The effects of elastic anisotropy on GNN model performance and outlooks for the extension of the framework are discussed.
Clinical recommendations for dry powder inhaler use in the management of COPD in primary care
Authors: Leving Marika T. , Bosnic-Anticevich Sinthia , van Cooten Joyce , de Sousa Jaime Correia , Cvetkovski Biljana , Dekhuijzen Richard , Dijk Lars , Pardo Marina Garcia , Gardev Asparuh , Gawlik Radosław , van der Ham Iris , Janse Ymke , Lavorini Federico , Maricoto Tiago , Meijer Jiska , Metz Boyd , Price David , Roman-Rodriguez Miguel , Schuttel Kirsten , Stoker Nilouq , Tsiligianni Ioanna , Usmani Omar , Emerson-Stadler Rachel , Kocks Janwillem W. H.
Published: December 2022

Over 1400 patients using dry powder inhalers (DPIs) to deliver COPD maintenance therapies were recruited across Europe and Australia. Their peak inspiratory flow (PIF) was measured, inhaler technique was observed, and adherence to treatment assessed. From relating the findings with patient health status, and thereby identifying critical errors, key clinical recommendations for primary care clinicians were determined, namely – measure PIF before prescribing a DPI to ensure inhalation manoeuvre ability is well-matched with the device. Some patients could benefit from inhalation training whereas others should have their DPI changed for one better suited to their inspiratory ability or alternatively be prescribed an active device (such as a soft mist inhaler or pressurized metered dose inhaler). Observing the inhalation technique was valuable however this misses suboptimal PIF (approaching one fourth of patients with a satisfactory observed manoeuvre had a suboptimal PIF for their DPI). Assess adherence as deliberate non-adherence can point to a mismatch between a patient and their inhaler (deliberate non-adherence was significantly associated with PIFs below the minimum for the DPI). In-person observation of inhalation technique was found to be inferior to video rating based on device-specific checklists. Where video assessments are not possible, observation training for healthcare professionals would therefore be valuable particularly to improve the ability to identify the critical errors associated with health status namely ‘teeth and lips sealed around mouthpiece’, ‘breathe in’ and ‘breathing out calmly after inhalation’. However, it is recommended that observation alone should not replace PIF measurement in the DPI selection process.

Trial registration:https://clinicaltrials.gov/ct2/show/NCT04532853.
A 3D geomodel of the deep aquifers in the Orléans area of the southern Paris Basin (France)
Authors: Mas Perrine , Calcagno Philippe , Caritg-Monnot Séverine , Beccaletto Laurent , Capar Laure , Hamm Virginie
Published: December 2022

An increasing number of cities are interested in deep geothermal energy in order to increase the share of renewable energies in their district heating networks. To reduce the risks related to deep geothermal energy operations, reliable digital models are needed: they make it possible to predict the depth of aquifers away from borehole locations, and their thermal and hydrological evolution by supporting detailed water and heat flow simulations. This paper presents a 3D geomodel developed for this purpose in the southern Paris Basin of France in the Orléans area. The 3D geomodel integrates various data such as reprocessed and interpreted seismic lines, well data, and a pre-existing larger-scale and lower-resolution 3D geological model. The resulting 3D geomodel gives a new and reliable representation of the main aquifers underlying the study area. Within the framework of the project, hydrological and thermal simulations were then performed based on this 3D geomodel. Other environmental investigations (e.g. CO2 storage) and teaching/communication activities could also benefit from the dataset.
The autism risk factor CHD8 is a chromatin activator in human neurons and functionally dependent on the ERK-MAPK pathway effector ELK1
Authors: Haddad Derafshi Bahareh , Danko Tamas , Chanda Soham , Batista Pedro J. , Litzenburger Ulrike , Lee Qian Yi , Ng Yi Han , Sebin Anu , Chang Howard Y. , Südhof Thomas C. , Wernig Marius
Published: December 2022

The chromodomain helicase DNA-binding protein CHD8 is the most frequently mutated gene in autism spectrum disorder. Despite its prominent disease involvement, little is known about its molecular function in the human brain. CHD8 is a chromatin regulator which binds to the promoters of actively transcribed genes through genomic targeting mechanisms which have yet to be fully defined. By generating a conditional loss-of-function and an endogenously tagged allele in human pluripotent stem cells, we investigated the molecular function and the interaction of CHD8 with chromatin in human neurons. Chromatin accessibility analysis and transcriptional profiling revealed that CHD8 functions as a transcriptional activator at its target genes in human neurons. Furthermore, we found that CHD8 chromatin targeting is cell context-dependent. In human neurons, CHD8 preferentially binds at ETS motif-enriched promoters. This enrichment is particularly prominent on the promoters of genes whose expression significantly changes upon the loss of CHD8. Indeed, among the ETS transcription factors, we identified ELK1 as being most highly correlated with CHD8 expression in primary human fetal and adult cortical neurons and most highly expressed in our stem cell-derived neurons. Remarkably, ELK1 was necessary to recruit CHD8 specifically to ETS motif-containing sites. These findings imply that ELK1 and CHD8 functionally cooperate to regulate gene expression and chromatin states at MAPK/ERK target genes in human neurons. Our results suggest that the MAPK/ERK/ELK1 axis potentially contributes to the pathogenesis caused by CHD8 mutations in human neurodevelopmental disorders.
A machine-learned spin-lattice potential for dynamic simulations of defective magnetic iron
Authors: Chapman Jacob B. J. , Ma Pui-Wai
Published: December 2022

A machine-learned spin-lattice interatomic potential (MSLP) for magnetic iron is developed and applied to mesoscopic scale defects. It is achieved by augmenting a spin-lattice Hamiltonian with a neural network term trained to descriptors representing a mix of local atomic configuration and magnetic environments. It reproduces the cohesive energy of BCC and FCC phases with various magnetic states. It predicts the formation energy and complex magnetic structure of point defects in quantitative agreement with density functional theory (DFT) including the reversal and quenching of magnetic moments near the core of defects. The Curie temperature is calculated through spin-lattice dynamics showing good computational stability at high temperature. The potential is applied to study magnetic fluctuations near sizable dislocation loops. The MSLP transcends current treatments using DFT and molecular dynamics, and surpasses other spin-lattice potentials that only treat near-perfect crystal cases.
The preparation of polyvinyl imidazole-functionalized magnetic biochar decorated by silver nanoparticles as an efficient catalyst for the synthesis of spiro-2-Amino-4H-pyran compounds
Authors: Mohammadi Leila , Heravi Majid M. , Saljooqi Asma , Mohammadi Pourya
Published: December 2022

The silver nanoparticle was synthesized by developing poly (1-vinylimidazole) on the surface of magnetized biochar (the stem and roots of Spear Thistle) (biochar/Fe3O4/PVIm/Ag). This nanocomposite was characterized by Fourier-transformed infrared spectroscopy (FTIR), powder X-ray diffraction (XRD), vibrating sample magnetometer (VSM), scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM–EDS), and transmission electron microscopy (TEM). The SEM and TEM images of the nanocatalyst, biochar/Fe3O4/PVIm/Ag-NPs, confirmed the observation of microscopic sheets of biochar. The catalytic activity of these Ag NPs was tested via multicomponent reaction plus reusing to successful formation of 2-amino-4H-pyran and functionalized spirochromen derivatives. The prepared nanocatalyst was easily separated by an external magnet and reused in repeating coupling reaction cycles four times without remarkable activity loss. The catalyst showed great efficiency and reusability, thus making it an ideal candidate for catalytic purposes in several organic transformations.
Consciousness alteration in focal epilepsy is related to loss of signal complexity and information processing
Authors: El Youssef Nada , Jegou Aude , Makhalova Julia , Naccache Lionel , Bénar Christian , Bartolomei Fabrice
Published: December 2022

Alteration of awareness is a main feature of focal epileptic seizures. In this work, we studied how the information contained in EEG signals was modified during temporal lobe seizures with altered awareness by using permutation entropy (PE) as a measure of the complexity of the signal. PE estimation was performed in thirty-six seizures of sixteen patients with temporal lobe epilepsy who underwent SEEG recordings. We tested whether altered awareness (based on the Consciousness Seizure Score) was correlated with a loss of signal complexity. We estimated global changes in PE as well as regional changes to gain insight into the mechanisms associated with awareness impairment. Our results reveal a positive correlation between the decrease of entropy and the consciousness score as well as the existence of a threshold on entropy that could discriminate seizures with no alteration of awareness from seizures with profound alteration of awareness. The loss of signal complexity was diffuse, extending bilaterally and to the associative cortices, in patients with profound alteration of awareness and limited to the temporal mesial structures in patients with no alteration of awareness. Thus PE is a promising tool to discriminate between the different subgroups of awareness alteration in TLE.
Sperm morphology and performance in relation to postmating prezygotic isolation in two recently diverged passerine species
Authors: Poignet Manon , Baránková Lucie , Reif Jiří , Stopka Pavel , Stopková Romana , Frolikova Michaela , Cramer Emily R. A. , Johnsen Arild , Kverek Pavel , Osiejuk Tomasz S. , Komrskova Katerina , Albrecht Tomáš , Reifová Radka
Published: December 2022

Divergence in sperm phenotype and female reproductive environment may be a common source of postmating prezygotic (PMPZ) isolation between species. However, compared to other reproductive barriers it has received much less attention. In this study, we examined sperm morphology and velocity in two hybridizing passerine species, the common nightingale (Luscinia megarhynchos) and thrush nightingale (L. luscinia). In addition, we for the first time characterized a passerine female reproductive tract fluid proteome. We demonstrate that spermatozoa of the common nightingale have significantly longer and wider midpiece (proximal part of the flagellum containing mitochondria) and longer tail compared to spermatozoa of thrush nightingale. On the other hand, they have significantly shorter and narrower acrosome. Importantly, these differences did not have any effect on sperm velocity. Furthermore, the fluid from the reproductive tract of common nightingale females did not differentially affect velocity of conspecific and heterospecific sperm. Our results indicate that the observed changes in the flagellum and acrosome size are unlikely to contribute to PMPZ isolation through differential sperm velocity of conspecific and heterospecific sperm in the female reproductive tract. However, they could affect other postcopulatory processes, which might be involved in PMPZ isolation, such as sperm storage, longevity or sperm-egg interaction.
The relationship between parenting engagement and academic performance
Authors: Derrick Gemma E. , Chen Pei-Ying , van Leeuwen Thed , Larivière Vincent , Sugimoto Cassidy R.
Published: December 2022

Gender differences in research productivity have been well documented. One frequent explanation of these differences is disproportionate child-related responsibilities for women. However, changing social dynamics around parenting has led to fathers taking an increasingly active role in parenting. This demands a more nuanced approach to understanding the relationship between parenting and productivity for both men and women. To gain insight into associations between parent roles, partner type, research productivity, and research impact, we conducted a global survey that targeted 1.5 million active scientists; we received viable responses from 10,445 parents (< 1% response rate), thus providing a basis for exploratory analyses that shed light on associations between parenting models and research outcomes, across men and women. Results suggest that the gendered effect observed in production may be related by differential engagement in parenting: men who serve in lead roles suffer similar penalties for parenting engagement, but women are more likely to serve in lead roles and to be more engaged across time and tasks, therefore suffering a higher penalty. Taking a period of parental leave is associated with higher levels of productivity; however, the productivity advantage dissipates after six months for the US-sample, and at 12-months for the non-US sample. These results suggest that parental engagement is a more powerful variable to explain gender differences in academic productivity than the mere existence of children, and that policies should factor these labor differentials into account.
A switch from horizontal compression to vertical extension in the Vrancea slab explained by the volume reduction of serpentine dehydration
Authors: Craiu Andreea , Ferrand Thomas P. , Manea Elena F. , Vrijmoed Johannes C. , Mărmureanu Alexandru
Published: December 2022

The Vrancea slab, Romania, is a subducted remnant of the Tethyan lithosphere characterized by a significant intermediate-depth seismicity (60–170 km). A recent study showed a correlation between this seismicity and major dehydration reactions, involving serpentine minerals up to 130 km depth, and high-pressure hydrated talc deeper. Here we investigate the potential link between the triggering mechanisms and the retrieved focal mechanisms of 940 earthquakes, which allows interpreting the depth distribution of the stress field. We observe a switch from horizontal compression to vertical extension between 100 and 130 km depth, where the Clapeyron slope of serpentine dehydration is negative. The negative volume change within dehydrating serpentinized faults, expected mostly sub-horizontal in the verticalized slab, could well explain the vertical extension recorded by the intermediate-depth seismicity. This apparent slab pull is accompanied with a rotation of the main compressive stress, which could favour slab detachments in active subduction zones.
Surrogate “Level-Based” Lagrangian Relaxation for mixed-integer linear programming
Authors: Bragin Mikhail A. , Tucker Emily L.
Published: December 2022

Mixed-Integer Linear Programming (MILP) plays an important role across a range of scientific disciplines and within areas of strategic importance to society. The MILP problems, however, suffer from combinatorial complexity. Because of integer decision variables, as the problem size increases, the number of possible solutions increases super-linearly thereby leading to a drastic increase in the computational effort. To efficiently solve MILP problems, a “price-based” decomposition and coordination approach is developed to exploit 1. the super-linear reduction of complexity upon the decomposition and 2. the geometric convergence potential inherent to Polyak’s stepsizing formula for the fastest coordination possible to obtain near-optimal solutions in a computationally efficient manner. Unlike all previous methods to set stepsizes heuristically by adjusting hyperparameters, the key novel way to obtain stepsizes is purely decision-based: a novel “auxiliary” constraint satisfaction problem is solved, from which the appropriate stepsizes are inferred. Testing results for large-scale Generalized Assignment Problems demonstrate that for the majority of instances, certifiably optimal solutions are obtained. For stochastic job-shop scheduling as well as for pharmaceutical scheduling, computational results demonstrate the two orders of magnitude speedup as compared to Branch-and-Cut. The new method has a major impact on the efficient resolution of complex Mixed-Integer Programming problems arising within a variety of scientific fields.
Effect of external magnetic field and doping on electronic and thermodynamic properties of planer and buckled silicene monolayer
Authors: Abdi Mona , Norian Erfan , Astinchap Bander
Published: December 2022

In this research, the electronic and thermodynamic properties of the planer and buckled silicene monolayer under an external magnetic field and doping using the tight-binding (TB) model and the Green function approach are investigated. Also, the dependence of the electronic heat capacity and magnetic susceptibility with temperature, external magnetic field, electron, and hole doping for the planer and buckled silicene monolayer is calculated. Our numerical calculation exhibits that the planer and buckled silicene monolayer have a zero band gap. We find that the electronic heat capacity increases (decreases) by applying an external magnetic field, and electron and hole doping at lower (higher) temperatures due to the increase in the thermal energy (scattering and collision) of the charge carriers. Finally, we observe that the planer and buckled silicene monolayer is antiferromagnetic, which is changed to the ferromagnetic phase when an external magnetic field and doping are applied, which makes the silicene monolayer suitable for spintronic applications.
The membrane domain of respiratory complex I accumulates during muscle aging in Drosophila melanogaster
Authors: Hossain Kaniz Fatima Binte , Murari Anjaneyulu , Mishra Bibhuti , Owusu-Ansah Edward
Published: December 2022

The boot-shaped respiratory complex I (CI) consists of a mitochondrial matrix and membrane domain organized into N-, Q- and P-modules. The N-module is the most distal part of the matrix domain, whereas the Q-module is situated between the N-module and the membrane domain. The proton-pumping P-module is situated in the membrane domain. We explored the effect of aging on the disintegration of CI and its constituent subcomplexes and modules in Drosophila flight muscles. We find that the fully-assembled complex remains largely intact in aged flies. And while the effect of aging on the stability of many Q- and N-module subunits in subcomplexes was stochastic, NDUFS3 was consistently down-regulated in subcomplexes with age. This was associated with an accumulation of many P-module subunits in subcomplexes. The potential significance of these studies is that genetic manipulations aimed at boosting, perhaps, a few CI subunits may suffice to restore the whole CI biosynthesis pathway during muscle aging.
Deterministic controlled enhancement of local quantum coherence
Authors: Horová Nikola , Stárek Robert , Mičuda Michal , Kolář Michal , Fiurášek Jaromír , Filip Radim
Published: December 2022

We investigate assisted enhancement of quantum coherence in a bipartite setting with control and target systems, which converts the coherence of the control qubit into the enhanced coherence of the target qubit. We assume that only incoherent operations and measurements can be applied locally and classical information can be exchanged. In addition, the two subsystems are also coupled by a fixed Hamiltonian whose interaction strength can be controlled. This coupling does not generate any local coherence from incoherent input states. We show that in this setting a measurement and feed-forward based protocol can deterministically enhance the coherence of the target system while fully preserving its purity. The protocol can be iterated and several copies of the control state can be consumed to drive the target system arbitrarily close to a maximally coherent state. We experimentally demonstrate this protocol with a photonic setup and observe the enhancement of coherence for up to five iterations of the protocol.
The impact of nitroglycerine and volume on gastric tube microperfusion assessed by indocyanine green fluorescence imaging
Authors: von Kroge Philipp H. , Russ Detlef , Rieß Henrik C. , Debus Eike S. , Pinnschmidt Hans. O. , Izbicki Jakob R. , Mann Oliver , Wipper Sabine H. , Duprée Anna
Published: December 2022

The influence of hypervolemia and intraoperative administration of nitroglycerine on gastric tube microperfusion remains unclear The present study aimed to investigate the impact of different hemodynamic settings on gastric tube microperfusion quantified by fluorescence imaging with Indocyanine green (ICG-FI) as a promising tool for perfusion evaluation. Three groups with seven pigs each were formed using noradrenaline, nitroglycerin, and hypervolemia for hemodynamic management, respectively. ICG-FI, hemodynamic parameters, and transit-time flow measurement (TTFM) in the right gastroepiploic artery were continuously assessed. Fluorescent microspheres (FM) were administered, and the partial pressure of tissue oxygen was quantified. The administration of nitroglycerine and hypervolemia were both associated with significantly impaired microperfusion compared to the noradrenaline group quantified by ICG-FI. Even the most minor differences in microperfusion could be sufficiently predicted which, however, could not be represented by the mean arterial pressure measurement. Histopathological findings supported these results with a higher degree of epithelial damage in areas with impaired perfusion. The values measured by ICG-FI significantly correlated with the FM measurement. Using tissue oxygenation and TTFM for perfusion measurement, changes in microperfusion could not be comprehended. Our results support current clinical practice with restrictive volume and catecholamine administration in major surgery. Hypervolemia and continuous administration of nitroglycerine should be avoided.
Association between ranitidine use with potential NDMA impurities and risk of cancer in Korea
Authors: Joung Kyung-In , Hwang Jung Eun , Oh In-Sun , Cho Sung-il , Shin Ju-Young
Published: December 2022

N-Nitrosodimethylamine (NDMA) detected above the acceptable level in ranitidine products has been a great global concern. To examine the risk of cancer among people treated with ranitidine, we conducted a cohort study using the National Health Insurance Service-National Sample Cohort data (2002–2015) of South Korea. Patients were aged 40 or above as of January 2004 and began receiving ranitidine or other histamine-2 receptor antagonist (H2RA), active comparator, without a history of H2RAs prescription during the prior 2-years. The lag time was designated up to 6 years. The outcomes were an overall incident cancer risk and the risk of major single cancers during the follow-up. The association between ranitidine use and cancer risk was examined by Cox regression model. After exclusion and propensity score matching, 25,360 patients were available for analysis. The use of ranitidine was not associated with the overall cancer risk and major individual cancers [overall cancer: incidence rate per 1000 person-years, 2.9 vs 3.0 among the ranitidine users and other H2RAs users, respectively; adjusted hazard ratio (HR) and 95% confidence interval (95% CI) for all cancers, 0.98 (0.81–1.20)]. The higher cumulative exposure to ranitidine did not increase the cancer risk. Given the insufficient follow-up period, these findings should be interpreted carefully.
Voltage stability assessment of grid connected PV systems with FACTS devices
Authors: Abdullah Melat K. , Hassan Lokman H. , Moghavvemi M.
Published: December 2022

Three static techniques (i.e. Power flow, Continuation Power Flow (CPF) and the Q–V curve) are used to assess the voltage stability of the power grid with a Solar Photovoltaic Generator (SPVG) and FACTS devices under nominal and heavy loading conditions. A static model is proposed for the power system that includes conventional power generation units and SPVGs with FACTS devices. Two models of SPVG were used (i.e., PV-model and PQ-model) to elucidate the effect of the SPVGs on the stability of the voltage under various operating conditions. The best location for FACTS devices was obtained under nominal and heavy load conditions using static techniques. A comparison between series and shunt FACTS devices under nominal and heavy loading conditions was carried out using the three static techniques. The interaction between SPVGs and FACTS devices was detailed in this paper. The proposed approach was tested on the New England 39-bus standard test system, and the results confirmed the effectiveness of the proposed approach under various operating conditions.
Measurement of temporal and spatial parameters of ice hockey skating using a wearable system
Authors: Khandan Aminreza , Fathian Ramin , Carey Jason P. , Rouhani Hossein
Published: December 2022

Ice hockey is a dynamic and competitive sport that requires a high level of neuromuscular and cardiovascular function. An objective assessment of skating helps coaches monitor athletes' performance during training sessions and matches. This study aimed to estimate the temporal and spatial parameters of skating by proposing an optimized configuration of wearable inertial measurement units (IMUs) and validating the system compared to in-lab reference systems. Ten participants were recruited to skate on a 14 m synthetic ice surface built in a motion-capture lab. Eight original event detection methods and three more adopted from gait analysis studies were implemented to detect blades-off and skate-strikes. These temporal events were detected with high accuracy and precision using skate-mounted IMUs. Also, four novel stride length estimation methods were developed to correct the estimated skaters' position using IMUs' readouts. The stride time, contact time, stride length, and stride velocity were obtained with relative errors of 3 ± 3%, 4 ± 3%, 2 ± 6%, and 2 ± 8%, respectively. This study showed that the wearable IMUs placed on skates and pelvis enables the estimation of temporal and spatial parameters of skating with high accuracy and precision, which could help coaches monitor skaters' performance in training.
Prevalence of colonization with multidrug-resistant bacteria in communities and hospitals in Kenya
Authors: Ita Teresa , Luvsansharav Ulzii-Orshikh , Smith Rachel M. , Mugoh Robert , Ayodo Charchil , Oduor Beatrice , Jepleting Moureen , Oguta Walter , Ouma Caroline , Juma Jane , Bigogo Godfrey , Kariuki Samuel , Ramay Brooke M. , Caudell Mark , Onyango Clayton , Ndegwa Linus , Verani Jennifer R. , Bollinger Susan , Sharma Aditya , Palmer Guy H. , Call Douglas R. , Omulo Sylvia
Published: December 2022

We estimated the prevalence of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE), carbapenem-resistant Enterobacterales (CRE), and methicillin-resistant Staphylococcus aureus (MRSA) in communities and hospitals in Kenya to identify human colonization with multidrug-resistant bacteria. Nasal and fecal specimen were collected from inpatients and community residents in Nairobi (urban) and Siaya (rural) counties. Swabs were plated on chromogenic agar to presumptively identify ESCrE, CRE and MRSA isolates. Confirmatory identification and antibiotic susceptibility testing were done using the VITEK®2 instrument. A total of 1999 community residents and 1023 inpatients were enrolled between January 2019 and March 2020. ESCrE colonization was higher in urban than rural communities (52 vs. 45%; P = 0.013) and in urban than rural hospitals (70 vs. 63%; P = 0.032). Overall, ESCrE colonization was ~ 18% higher in hospitals than in corresponding communities. CRE colonization was higher in hospital than community settings (rural: 7 vs. 1%; urban: 17 vs. 1%; with non-overlapping 95% confidence intervals), while MRSA was rarely detected (≤ 3% overall). Human colonization with ESCrE and CRE was common, particularly in hospitals and urban settings. MRSA colonization was uncommon. Evaluation of risk factors and genetic mechanisms of resistance can guide prevention and control efforts tailored to different environments.
Genomic analysis of hypoxia inducible factor alpha in ray-finned fishes reveals missing Ohnologs and evidence of widespread positive selection
Authors: Townley Ian K. , Babin Courtney H. , Murphy Taylor E. , Summa Christopher M. , Rees Bernard B.
Published: December 2022

As aquatic hypoxia worsens on a global scale, fishes will become increasingly challenged by low oxygen, and understanding the molecular basis of their response to hypoxia may help to better define the capacity of fishes to cope with this challenge. The hypoxia inducible factor (HIF) plays a critical role in the molecular response to hypoxia by activating the transcription of genes that serve to improve oxygen delivery to the tissues or enhance the capacity of tissues to function at low oxygen. The current study examines the molecular evolution of genes encoding the oxygen-dependent HIFα subunit (HIFA) in the ray-finned fishes (Actinopterygii). Genomic analyses demonstrate that several lineages retain four paralogs ofHIFApredicted from two rounds of genome duplication at the base of vertebrate evolution, broaden the known distribution of teleost-specificHIFAparalogs, and provide evidence for salmonid-specificHIFAduplicates. Evolution of theHIFAgene family is characterized by widespread episodic positive selection at amino acid sites that potentially mediate protein stability, protein–protein interactions, and transcriptional regulation.HIFAtranscript abundance depends upon paralog, tissue, and fish lineage. A phylogenetically-informed gene nomenclature is proposed along with avenues for future research on this critical family of transcription factors.
In vivo micro-computed tomography imaging in liver tumor study of mice using Fenestra VC and Fenestra HDVC
Authors: Tan Ming Jia , Fernandes Nazarine , Williams Karla Chinnery , Ford Nancy Lee
Published: December 2022

Contrast agents are used to enhance the visibility of rodent organs during in vivo micro-computed tomography imaging. Specifically, this non-invasive technique can study liver tumor growth and progression in small animals. Fenestra VC and the novel Fenestra HDVC were compared for enhancement in the liver of healthy and tumor-bearing mice, and the images were compared for their ability to define the tumor border, volume and quantity of tumors. Fenestra VC and Fenestra HDVC were injected into healthy eight-week-old female mice (C57BL/6) via the tail vein then imaged at seven different time points. The experimental results showed that 0.005 mL/g of Fenestra HDVC resulted in the same enhancement for all eight organs as 0.01 mL/g of Fenestra VC across all time points. For the tumor study, B16F10 tumors were surgically introduced into ten eight-week-old female mice (C57BL/6) then imaged in vivo over a 3 day period. Ex vivo micro-CT images of the excised livers were also obtained. The tumor volume and quantity were measured in each image, and the tumour progression observed over 3 days. We showed Fenestra HDVC is effective for in vivo imaging in rodents because the optimal enhancement level in organs is maintained at a reduced injection volume.
Relationship between institutional intensive care volume prior to the COVID-19 pandemic and in-hospital death in ventilated patients with severe COVID-19
Authors: Amagasa Shunsuke , Kashiura Masahiro , Yasuda Hideto , Hayakawa Mineji , Yamakawa Kazuma , Endo Akira , Ogura Takayuki , Hirayama Atsushi , Yasunaga Hideo , Tagami Takashi
Published: December 2022

We aimed to evaluate the association between ICU patient volume before the COVID-19 pandemic and the outcomes of ventilated COVID-19 patients. We analyzed ventilated patients with COVID-19 aged > 17 years and enrolled in the J-RECOVER study, a retrospective multicenter observational study conducted in Japan between January and September 2020. Based on the number of patients admitted to the ICU between January and December 2019, the top third institutions were defined as high-volume centers, the middle third ones as middle-volume centers, and the bottom third ones as low-volume centers. The primary outcome measure was in-hospital mortality. Multivariate logistic regression analysis for in-hospital mortality and ICU patient volume was performed after adjusting for multiple propensity scores. Among 461 patients, 158, 158, and 145 patients were admitted to low-volume (20 institutions), middle-volume (14 institutions), and high-volume (13 institutions) centers, respectively. Admission to middle- and high-volume centers was not significantly associated with in-hospital death compared with admission to low-volume centers (adjusted odds ratio, 1.11 [95% confidence interval (CI): 0.55–2.25] and adjusted odds ratio, 0.81 [95% CI: 0.31–1.94], respectively). In conclusion, institutional intensive care patient volume prior to the COVID-19 pandemic was not significantly associated with in-hospital death in ventilated COVID-19 patients.
Introduction of benzyloxy pharmacophore into aryl/heteroaryl chalcone motifs as a new class of monoamine oxidase B inhibitors
Authors: Sudevan Sachithra Thazhathuveedu , Oh Jong Min , Abdelgawad Mohamed A. , Abourehab Mohammed A. S. , Rangarajan T. M. , Kumar Sunil , Ahmad Iqrar , Patel Harun , Kim Hoon , Mathew Bijo
Published: December 2022

The inhibitory action of fifteen benzyloxy ortho/para-substituted chalcones (B1-B15) was evaluated against human monoamine oxidases (hMAOs). All the molecules inhibited hMAO-B isoform more potently than hMAO-A. Furthermore, the majority of the molecules showed strong inhibitory actions against hMAO-B at 10 μM level with residual activities of less than 50%. Compound B10 has an IC50 value of 0.067 μM, making it the most potent inhibitor of hMAO-B, trailed by compound B15 (IC50 = 0.12 μM). The thiophene substituent (B10) in the A-ring exhibited the strongest hMAO-B inhibition structurally, however, increased residue synthesis did not result in a rise in hMAO-B inhibition. In contrast, the benzyl group at the para position of the B-ring displayed more hMAO-B inhibition than the other positions. Compounds B10 and B15 had relatively high selectivity index (SI) values for hMAO-B (504.791 and 287.600, respectively). Ki values of B10 and B15 were 0.030 ± 0.001 and 0.033 ± 0.001 μM, respectively. The reversibility study showed that B10 and B15 were reversible inhibitors of hMAO-B. PAMPA assay manifested that the benzyloxy chalcones (B10 and B15) had a significant permeability and CNS bioavailability with Pe value higher than 4.0 × 10–6 cm/s. Both compounds were stabilized in protein–ligand complexes by the π-π stacking, which enabled them to bind to the hMAO-B enzyme's active site incredibly effectively. The hMAO-B was stabilized by B10- and B15-hMAO-B complexes, with binding energies of − 74.57 and − 87.72 kcal/mol, respectively. Using a genetic algorithm and multiple linear regression, the QSAR model was created. Based on the best 2D and 3D descriptor-based QSAR model, the following statistics were displayed: R2 = 0.9125, Q2loo = 0.8347. These findings imply that B10 and B15 are effective, selective, and reversible hMAO-B inhibitors.
Multimodal and multidomain lesion network mapping enhances prediction of sensorimotor behavior in stroke patients
Authors: Jimenez-Marin Antonio , De Bruyn Nele , Gooijers Jolien , Llera Alberto , Meyer Sarah , Alaerts Kaat , Verheyden Geert , Swinnen Stephan P. , Cortes Jesus M.
Published: December 2022

Beyond the characteristics of a brain lesion, such as its etiology, size or location, lesion network mapping (LNM) has shown that similar symptoms after a lesion reflects similar dis-connectivity patterns, thereby linking symptoms to brain networks. Here, we extend LNM by using a multimodal strategy, combining functional and structural networks from 1000 healthy participants in the Human Connectome Project. We apply multimodal LNM to a cohort of 54 stroke patients with the aim of predicting sensorimotor behavior, as assessed through a combination of motor and sensory tests. Results are two-fold. First, multimodal LNM reveals that the functional modality contributes more than the structural one in the prediction of sensorimotor behavior. Second, when looking at each modality individually, the performance of the structural networks strongly depended on whether sensorimotor performance was corrected for lesion size, thereby eliminating the effect that larger lesions generally produce more severe sensorimotor impairment. In contrast, functional networks provided similar performance regardless of whether or not the effect of lesion size was removed. Overall, these results support the extension of LNM to its multimodal form, highlighting the synergistic and additive nature of different types of network modalities, and their corresponding influence on behavioral performance after brain injury.
Artificial temperature-compensated biological clock using temperature-sensitive Belousov–Zhabotinsky gels
Authors: Yamada Yuhei , Ito Hiroshi , Maeda Shingo
Published: December 2022

The circadian rhythm is a fundamental physiological function for a wide range of organisms. The molecular machinery for generating rhythms has been elucidated over the last few decades. Nevertheless, the mechanism for temperature compensation of the oscillation period, which is a prominent property of the circadian rhythm, is still controversial. In this study, we propose a new mechanism through a chemically synthetic approach (i.e., we realized temperature compensation by the Belousov–Zhabotinsky (BZ) gels). The BZ gels are prepared by embedding a metal catalyst of the BZ reaction into the gel polymer. We made the body of BZ gels using a temperature-sensitive polymer gel, which enabled temperature compensation of the oscillation by using temperature dependence of volume. Moreover, we constructed a simple mathematical model for the BZ oscillation in temperature-sensitive gels. The model can reproduce temperature compensation of BZ gels, even though all reactions are temperature sensitive according to the Arrhenius rule. Our finding hints that a soft body coupling may be underlying temperature-compensated biological functions, including circadian rhythms.
Mechanical and gas adsorption properties of graphene and graphynes under biaxial strain
Authors: de Oliveira Raphael B. , Borges Daiane Damasceno , Machado Leonardo D.
Published: December 2022

The exceptional properties of two-dimensional (2D) solids have motivated extensive research, which revealed the possibility of controlling many characteristics of these materials through strain. For instance, previous investigations demonstrated that compressive deformation could be used to direct the chemisorption of atomic hydrogen and oxygen. Still, to our knowledge, there is no work detailing how strain affects the adsorption isotherms of 2D materials and the adsorption properties of materials such as the graphynes, which are monolayers composed of sp and sp$$^2$$

2

carbon atoms. In the present work, we analyze how biaxial tensile deformation changes the adsorption properties of four 2D materials (graphene, $$\alpha $$
α
-graphyne, $$\beta $$
β
-graphyne, and $$\gamma $$
γ
-graphyne). To achieve this, we perform Monte Carlo Grand Canonical calculations to obtain the adsorption isotherms of H$$_2$$

2

, CO$$_2$$

2

, and CH$$_4$$

4

on the monolayers with and without strain. And, to apply the deformation, we carry out Molecular Dynamics simulations. We find a substantial reduction in the amount of gas adsorbed on the monolayers for nearly all gas–solid combinations. This is particularly true for graphene, where 14.5% strain reduces the quantity of H$$_2$$

2

/CO$$_2$$

2

/CH$$_4$$

4

by 44.7/64.1/41.7% at P $$=$$
=
1 atm. To understand the results, we calculate adsorption enthalpies and analyze the gas distribution above the monolayers. We also characterize the mechanical properties of the considered solids under biaxial deformation. Finally, a comparison of pore sizes with the kinetic diameters of various gases suggests applications for the graphynes, with and without strain, in gas separation.
The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells
Authors: Criscione Steven W. , Martin Matthew J. , Oien Derek B. , Gorthi Aparna , Miragaia Ricardo J. , Zhang Jingwen , Chen Huawei , Karl Daniel L. , Mendler Kerrin , Markovets Aleksandra , Gagrica Sladjana , Delpuech Oona , Dry Jonathan R. , Grondine Michael , Hattersley Maureen M. , Urosevic Jelena , Floc’h Nicolas , Drew Lisa , Yao Yi , Smith Paul D.
Published: December 2022

Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. While patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic vulnerabilities. We identified several vulnerabilities in osimertinib DTPs that were common across models, including sensitivity to MEK, AURKB, BRD4, and TEAD inhibition. We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.