bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-L1 immunohistochemistry assay optimization to provide more comprehensive pathological information in classic Hodgkin lymphoma
Authors: Shi Yunfei , Mi Lan , Lai Yumei , Zhao Min , Jia Ling , Du Tingting , Song Yuqin , Li Xianghong
Published: February 2023

Overexpression of PD-L1 can be a predictive marker for anti-PD-1 therapeutic efficacy in classic Hodgkin lymphoma (CHL); however, harmonization of different IHC assays remains to be accomplished, and interpretations of PD-L1 immunostaining results remain controversial in CHL. In this study, we sought to optimize the PD-L1 immunohistochemistry (IHC) assay in CHL. All tests were performed on a tumour tissue microarray established from 54 CHL cases. Three IHC antibodies (405.9A11, SP142, 22C3) for detecting PD-L1 expression were compared semi quantitatively with the RNAscope assay (No. 310035, ACD), and the difference in the expression in background immune cells (ICs) between assays and the associations of expression levels with densities of TILs/TAMs were also analysed. 405.9A11 demonstrated best specificity in HRS cells and best sensitivity in ICs. Positive expression of PD-L1 was more frequent in ICs (85.2%) than in HRS cells (48.1%). Different subgroups of background ICs, including tumour-associated macrophages (TAMs), were assessed and scored for CD4, CD8, FOXP3, and CD163 expression. PD-L1 expression on ICs was the factor most associated with the density of TAMs. 405.9A11 provided the most convincing PD-L1 expression results. Pathologists should report PD-L1 expression in a combined manner, including both the status of HRS cells and the percentage of PD-L1-positive ICs.
Optimal surgical approaches for esophageal epiphrenic diverticulum: literature review and our experience
Authors: Sato Yuta , Tanaka Yoshihiro , Ohno Shinya , Endo Masahide , Okumura Naoki , Takahashi Takao , Matsuhashi Nobuhisa
Published: February 2023

Esophageal epiphrenic diverticulum is a rare condition usually secondary to a primary esophageal motility disorder. Although epiphrenic diverticulum may be treated by thoracoscopic and laparoscopic management, the optimal surgical approach have not been established. We successfully treated a left epiphrenic diverticulum along with achalasia and paraesophageal hernia by a planned combination of thoracoscopic and laparoscopic procedures aided by preoperative simulation using three-dimensional imaging. We reviewed a series of 17 reports on esophageal epiphrenic diverticulum that required either planned or unplanned unexpected transthoracic surgery. The main reasons for requiring a transthoracic approach were adhesions, site and size of the diverticulum, and length of the diverticulum neck. Unplanned procedure changes were required in 12 of the 114 cases for a conversion rate of 10.5%. Diverticulectomy, myotomy, and fundoplication were the most common surgical treatments administered at 42.6%. Based on literature review and our experience, we have developed a flowchart to identify the characteristics of epiphrenic diverticulum cases that require a transthoracic approach. This flowchart can help to determine therapeutic strategies and the optimal surgical approach to esophageal epiphrenic diverticulum treatment and may reduce unplanned changes in the surgery.
Opportunities to tackle antibiotic resistance development in the aquatic environment through the Water Framework Directive
Authors: Ågerstrand Marlene , Josefsson Henrik , Wernersson Ann-Sofie , Larsson D. G. Joakim
Published: February 2023

Antibiotics are critical components of modern health care. Protecting their efficacy through managing the rise in antibiotic resistance is therefore a global concern. It is not known to what extent environmental pollution from antibiotics contributes to the development of resistance, but encountered concentrations are frequently above concentrations predicted to select for resistance. Hence, measures are needed to manage risks. Here, we analyse if the indirect health risks from antibiotics in the aquatic environment can be considered in the context of the EU Water Framework Directive and the setting of environmental quality standards (EQS). By scrutinising current legislation, we conclude that it is possible to take the indirect health risks from antimicrobial resistance into account when deriving EQS for substances with antibiotic activity. We base this on the following conclusions: (1) human health concerns can be the main driver when setting an EQS, (2) an EQS can be based on data not specified in the guidance document, and (3) there are no restrictions against establishing EQS using data on antimicrobial resistance properties. In addition, since antimicrobial resistance travel across borders, we see strong reasons to prioritise setting these EQS on the EU level over the national level. Even though there is no agreed-upon method for how to develop EQS protective against resistance selection, there are several suggestions available in the literature and a couple of examples of regulatory initiatives. Also, addressing antimicrobial resistance through the Water Framework Directive can act as a driving force for other applicable legislation where such risks are not considered. We end by providing a set of recommendations for the European Commission and the Members States' future work on addressing aquatic pollution and antimicrobial resistance.
Quantum density peak clustering
Authors: Magano Duarte , Buffoni Lorenzo , Omar Yasser
Published: February 2023

Clustering algorithms are of fundamental importance when dealing with large unstructured datasets and discovering new patterns and correlations therein, with applications ranging from scientific research to medical imaging and marketing analysis. In this work, we introduce a quantum version of the density peak clustering algorithm, built upon a quantum routine for minimum finding. We prove a quantum speedup for a decision version of density peak clustering depending on the structure of the dataset. Specifically, the speedup is dependent on the heights of the trees of the induced graph of nearest-highers, i.e. the graph of connections to the nearest elements with higher density. We discuss this condition, showing that our algorithm is particularly suitable for high-dimensional datasets. Finally, we benchmark our proposal with a toy problem on a real quantum device.
Axial compressive behavior of GFRP-timber-reinforced concrete composite columns
Authors: Zhang Fubin , Luo Hu , Xiao Jianzhuang , Singh Amardeep , Xu Jing , Fang Hai
Published: February 2023

This paper investigated the compressive behavior of a novel glass fiber reinforced polymer (GFRP)-timber-reinforced concrete composite column (GTRC column), which consisted of reinforced concrete with an outer GFRP laminate and a paulownia timber core. The axial compression tests were performed on 13 specimens to validate the effects of various timber core diameters, slenderness ratios, and GFRP laminate layers/angles on the mechanical behaviors. Test results indicated that with the increase in the timber core diameter, the ductility and energy dissipation ability of the composite column increased by 52.6% and 21.6%, respectively, whereas the ultimate load-bearing capacity and initial stiffness showed a slight decrease. In addition, the GFRP laminate considerably improved the ultimate load-bearing capacity, stiffness, ductility and energy dissipation capability by 212.1%, 26.6%, 64.3% and 3820%, accordingly. Moreover, considering the influence of timber core diameter, an ultimate load-bearing capacity adjustment coefficient was proposed. Finally, a formula was established based on the force equilibrium and superposition for predicting the axial bearing capacity of the GTRC columns.
Care in Management: A Review and Justification of an Organizational Value
Authors: Arnold Denis G. , Ross Roxanne L.
Published: February 2023

Care has increasingly been promoted as an element of successful management practice. However, an ethic of care is a normative theory that was initially developed in reference to intimate relationships, and it is unclear if it is an appropriate normative standard in business. The purpose of this review is to bridge the social scientific study of care with philosophical understandings of care and to provide a theoretical justification for care as a managerial value. We review the three different forms of care advanced by the ethics literature: caring relations, organizational care, and care as a virtue. We compare these forms of care to the management litertature. In doing so, we integrate what has previously been a scattered, yet growing, body of research on care. Our review of the literature reveals that care has increasingly been studied in management in relation to an ethic of care. Yet, many of the properties of care have also played a role in other established research domains (e.g., leadership). We discuss and critique the management and ethics literatures on care, paying attention to areas of agreement or disagreeement between the two. We go on to provide a normative justification of care as a value in business. Finally, we close by suggesting directions for future research.
INCOMPATIBILITY OF GENERIC HUGENESS PRINCIPLES
Authors: ESKEW MONROE
Published: February 2023

We show that the weakest versions of Foreman’s minimal generic hugeness axioms cannot hold simultaneously on adjacent cardinals. Moreover, conventional forcing techniques cannot produce a model of one of these axioms.
Shoreline modelling on timescales of days to decades
Authors: Hunt Emily , Davidson Mark , Steele Edward C. C. , Amies Jessica D. , Scott Timothy , Russell Paul
Published: February 2023

Climate change is resulting in global changes to sea level and wave climates, which in many locations significantly increase the probability of erosion, flooding and damage to coastal infrastructure and ecosystems. Therefore, there is a pressing societal need to be able to forecast the morphological evolution of our coastlines over a broad range of timescales, spanning days-to-decades, facilitating more focused, appropriate and cost-effective management interventions and data-informed planning to support the development of coastal environments. A wide range of modelling approaches have been used with varying degrees of success to assess both the detailed morphological evolution and/or simplified indicators of coastal erosion/accretion. This paper presents an overview of these modelling approaches, covering the full range of the complexity spectrum and summarising the advantages and disadvantages of each method. A focus is given to reduced-complexity modelling approaches, including models based on equilibrium concepts, which have emerged as a particularly promising methodology for the prediction of coastal change over multi-decadal timescales. The advantages of stable, computationally-efficient, reduced-complexity models must be balanced against the requirement for good generality and skill in diverse and complex coastal settings. Significant obstacles are also identified, limiting the generic application of models at regional and global scales. Challenges include the accurate long-term prediction of model forcing time-series in a changing climate, and accounting for processes that can largely be ignored in the shorter term but increase in importance in the long term. Further complications include coastal complexities, such as the accurate assessment of the impacts of headland bypassing. Additional complexities include complex structures and geology, mixed grain size, limited sediment supply, sources and sinks. It is concluded that with present computational resources, data availability limitations and process knowledge gaps, reduced-complexity modelling approaches currently offer the most promising solution to modelling shoreline evolution on daily-to-decadal timescales.
COVID-19 vaccination and venous thromboembolism risk in older veterans
Authors: Elkin Peter L. , Brown Steven H. , Resendez Skyler , McCray Wilmon , Resnick Melissa , Hall Kendria , Franklin Gillian , Connors Jean M. , Cushman Mary
Published: February 2023

Introduction

It is important for SARS-CoV-2 vaccine providers, vaccine recipients, and those not yet vaccinated to be well informed about vaccine side effects. We sought to estimate the risk of post-vaccination venous thromboembolism (VTE) to meet this need.

Methods

We conducted a retrospective cohort study to quantify excess VTE risk associated with SARS-CoV-2 vaccination in US veterans age 45 and older using data from the Department of Veterans Affairs (VA) National Surveillance Tool. The vaccinated cohort received at least one dose of a SARS-CoV-2 vaccine at least 60 days prior to 3/06/22 (N = 855,686). The control group was those not vaccinated (N = 321,676). All patients were COVID-19 tested at least once before vaccination with a negative test. The main outcome was VTE documented by ICD10-CM codes.

Results

Vaccinated persons had a VTE rate of 1.3755 (CI: 1.3752–1.3758) per thousand, which was 0.1 percent over the baseline rate of 1.3741 (CI: 1.3738–1.3744) per thousand in the unvaccinated patients, or 1.4 excess cases per 1,000,000. All vaccine types showed a minimal increased rate of VTE (rate of VTE per 1000 was 1.3761 (CI: 1.3754–1.3768) for Janssen; 1.3757 (CI: 1.3754–1.3761) for Pfizer, and for Moderna, the rate was 1.3757 (CI: 1.3748–1.3877)). The tiny differences in rates comparing either Janssen or Pfizer vaccine to Moderna were statistically significant (p < 0.001). Adjusting for age, sex, BMI, 2-year Elixhauser score, and race, the vaccinated group had a minimally higher relative risk of VTE as compared to controls (1.0009927 CI: 1.007673–1.0012181; p < 0.001).

Conclusion

The results provide reassurance that there is only a trivial increased risk of VTE with the current US SARS-CoV-2 vaccines used in veterans older than age 45. This risk is significantly less than VTE risk among hospitalized COVID-19 patients. The risk-benefit ratio favors vaccination, given the VTE rate, mortality, and morbidity associated with COVID-19 infection.
Interfacial-dominated torque response in liquid–liquid Taylor–Couette flows
Authors: Hori Naoki , Ng Chong Shen , Lohse Detlef , Verzicco Roberto
Published: February 2023

Immiscible and incompressible liquid–liquid flows are considered in a Taylor–Couette geometry and analysed by direct numerical simulations coupled with the volume-of-fluid method and a continuum surface force model. The system Reynolds number

$Re \equiv r_i \omega _i d / \nu$

is fixed to

$960$

, where the single-phase flow is in the steady Taylor vortex regime, whereas the secondary-phase volume fraction

$\varphi$

and the system Weber number

$We \equiv \rho r_i^2 \omega _i^2 d / \sigma$

are varied to study the interactions between the interface and the Taylor vortices. We show that different Weber numbers lead to two distinctive flow regimes, namely an advection-dominated regime and an interface-dominated regime. When

$We$

is high, the interface is easily deformed because of its low surface tension. The flow patterns are then similar to the single-phase flow, and the system is dominated mainly by advection (advection-dominated regime). However, when

$We$

is low, the surface tension is so large that stable interfacial structures with sizes comparable to the cylinder gap can exist. The background velocity field is modulated largely by these persistent structures, thus the overall flow dynamics is governed by the interface (interface-dominated regime). The effect of the interface on the global system response is assessed by evaluating the Nusselt number

$Nu_{\omega }$

based on the non-dimensional angular velocity transport. It shows non-monotonic trends as functions of the volume fraction

$\varphi$

for both low and high

$We$

. We explain how these dependencies are closely linked to the velocity and interfacial structures.
Impairment or difference? The case of Theory of Mind abilities and pragmatic competence in the Autism Spectrum
Authors: Marocchini Eleonora
Published: February 2023

Psycholinguistic research on pragmatics in the neurotypical population has increasingly framed pragmatic competence and related cognitive skills in terms of individual differences, co-constructed discourse, and meaning negotiation. However, research on pragmatics in the Autism Spectrum has risen from a wide and biased view of autistic communication as fundamentally compromised and autistic pragmatic abilities as impaired. Mostly due to the impactful theory of a deficit in Theory of Mind, early research on autistic communication presumed a unitary pragmatic impairment, only to find that several pragmatic abilities seem to be “preserved.” However, the interpretation of these findings usually takes an ableist turn, as most studies subsequently suggest that surface-level performance should not be interpreted as competence, but rather as a result of “compensatory” strategies. The raising number of contributions from autistic academics and participatory research enriched the field with new perspectives focusing on differences rather than impairments and drawing hypotheses on communication difficulties between neurotypes rather than within a specific neurotype. However, such contributions are hardly ever cited in the most prominent works. In conclusion, the field would benefit from a higher level of citation of autistic-led research and from an epistemological perspective shift within the mostly neurotypical academic community.
‘Aspire, persevere and indulge not’: new wealth and gentry society in Wales, c. 1760–1840
Authors: Rees Lowri Ann
Published: February 2023

This article examines the various ways new wealth infiltrated the Welsh gentry during the late eighteenth and early nineteenth centuries, considering the behaviours and actions of new men, together with the processes they followed to assimilate into the world of the old families. This study emphasises a level of openness of landed society to new arrivals able to comport themselves according to the expectations of the existing social elite. It demonstrates that acquiring land and property, which served as a visible display of their wealth, was only one strategy deployed by new wealth to secure gentry status. Other approaches included building country houses, consuming fashionable goods, undertaking public duties, political representation, drawing on culture and living heritage by projecting an image of ancient lineage (Welsh gentry understanding of Welshness was heavily reliant on lineage) through name-changing, adopting coats of arms and family mottos.
Challenging a dogma: left ventriculotomy can be used safely in children
Authors: Alpat Safak , Sabuncu Timucin , Aydin Ahmet , Peker Recep Oktay , Guvener Murat , Dogan Riza , Yilmaz Mustafa
Published: February 2023

Objective:

We aimed to discuss our unit’s experience performing left ventriculotomies on children.

Methods:

Between 2000 and 2022, we identified paediatric patients who required left ventriculotomy. Relevant information was gathered retrospectively.

Results:

There were eight patients who underwent surgical procedure including left ventriculotomy. The range of weight and age was between 4.5 and 50 kg and 5 months to 17 years, respectively. Left ventriculotomy was primarily performed for the excision of cardiac masses in all but one who had pseudoaneurysm repair. There were no deaths that occurred early or late. Pre-operative and post-operative ejection fractions and fractional shortening values were comparable. There was no arrhythmia detected post-operatively.

Conclusions:

We conclude that an apical left ventriculotomy does not compromise the function of the left ventricle, even in young infants. In selected patients, it may be used safely for surgical access to the left ventricle.
Describing our experience with the effects of multisystem inflammatory syndrome in children with COVID-19 on the cardiovascular system
Authors: Shehab Norane , English Robert F.
Published: February 2023

Cardiac involvement with multisystem inflammatory syndrome in children can include coronary artery abnormalities, ventricular dysfunction, conduction abnormalities, arrhythmias, pericarditis, and myocarditis. We report the cardiac findings in 34 patients with multisystem inflammatory syndrome in children admitted to a single institution. We looked at patient age, sex, brain natriuretic peptide levels, troponin levels, ejection fraction, presence of pericardial effusion, valvular changes, need for inotropic agents, and electrocardiogram findings. Our data showed that elevated brain natriuretic peptide did not predict troponin elevation and vice versa. Additionally, troponin rise was not a reliable marker for decreased left ventricular ejection fraction. All changes tracked were proven to be transient and resolved after initiating steroids, Intravenous immune globulin (IVIG), and occasionally anakinra.
Exploring the Solar Wind‐Planetary Interaction at Mars: Implication for Magnetic Reconnection
Authors: Bowers Charles F. , DiBraccio Gina A. , Slavin James A. , Gruesbeck Jacob R. , Weber Tristan , Xu Shaosui , Romanelli Norberto , Harada Yuki
Published: February 2023

The Martian crustal magnetic anomalies present a varied, asymmetric obstacle to the imposing draped interplanetary magnetic field (IMF) and solar wind plasma. Magnetic reconnection, a ubiquitous plasma phenomenon responsible for transferring energy and changing magnetic field topology, has been observed throughout the Martian magnetosphere. More specifically, reconnection can occur as a result of the interaction between crustal fields and the IMF, however, the global implications and changes to the overall magnetospheric structure of Mars have yet to be fully understood. Here, we present an analysis to determine these global implications by investigating external conditions that favor reconnection with the underlying crustal anomalies at Mars. To do so, we plot a map of the crustal anomalies' strength and orientation compiled from magnetic field data collected throughout the Mars Atmosphere and Volatile EvolutioN (MAVEN) mission. Then, we create “shear maps” which calculate and plot the angle of shear between the crustal fields and a chosen external field orientation. From there we define a “shear index” to quantify the susceptibility of a region to undergo reconnection based on a given overlaid, external field orientation and the resulting shear map for that region. We demonstrate that the shear analysis technique augments analysis of local reconnection events and suggests southward IMF conditions should favor dayside magnetic reconnection on a more global scale at Mars.
Age‐Independent Oceanic Plate Thickness and Asthenosphere Melting From SS Precursor Imaging
Authors: Sun Shuyang , Zhou Ying
Published: February 2023

The Earth's asthenosphere is a mechanically weak layer characterized by low seismic velocity and high attenuation. The nature of this layer has been strongly debated. In this study, we process 12 years of seismic data recorded at the global seismological network stations to investigate SS waves reflected at the upper and lower boundaries of this layer in global oceanic regions. We observe strong reflections from both the top and the bottom of the asthenosphere, dispersive across all major oceans. The average depths of the two discontinuities are 120 and 255 km, respectively. The SS waves reflected at the lithosphere and asthenosphere boundary are characterized by anomalously large amplitudes, which require a ∼12.5% reduction in seismic velocity across the interface. This large velocity drop can not be explained by a thermal cooling model but indicates 1.5%–2% localized melt in the oceanic asthenosphere. The depths of the two discontinuities show large variations, indicating that the asthenosphere is far from a homogeneous layer but likely associated with strong and heterogeneous small‐scale convection in the oceanic mantle. The average depths of the two boundaries are largely constant across different age bands. In contrast to the half‐space cooling model, this observation supports the existence of a constant‐thickness plate in oceanic regions with a complex and heterogeneous origin.
Effect of Marine and Land Convection on Wet Scavenging of Ozone Precursors Observed During a SEAC4RS Case Study
Authors: Cuchiara G. C. , Fried A. , Barth M. C. , Bela M. M. , Homeyer C. R. , Walega J. , Weibring P. , Richter D. , Woods S. , Beyersdorf A. , Bui T. V. , Dean‐Day J.
Published: February 2023

Convective clouds are important for both the vertical redistribution of tropospheric trace gases and the removal, via microphysical scavenging, of soluble trace gas precursors of ozone. We investigate wet scavenging of formaldehyde (CH2O), hydrogen peroxide (H2O2), and methyl hydrogen peroxide (CH3OOH) in quasi‐marine and land convective storms over Texas, USA observed on 18 September 2013 during the 2013 SEAC4RS campaign. Cloud‐resolving simulations using the Weather Research and Forecasting model with Chemistry (WRF‐Chem) were performed to understand the effect of entrainment, scavenging efficiency (SE), and ice physics processes on these trace gases with varying solubility. While marine and land convection can have distinctly different microphysical properties, we did not find significant differences in the SEs of CH2O, H2O2, or CH3OOH. The SEs of 44%–53% for CH2O and 85%–90% for H2O2 are consistent with our previous studies from SEAC4RS and the 2012 DC3 field experiment storms. Using WRF‐Chem simulations, the ice retention factor (rf) for CH2O was determined to be 0.5–0.9, which is higher than found in previous studies. We show that the CH2O rf is higher in airmass and multicell storms than in severe storms and hypothesize that ice shattering may affect CH2O rf values. The CH3OOH SEs (39%–73%) were higher than expected from Henry's Law equilibrium. While recent studies suggest that CH3OOH measurements have interference due to methane diol, we find that this interference cannot fully explain the higher‐than‐expected CH3OOH SEs determined here and during DC3, suggesting further research is needed to understand CH3OOH vertical redistribution.
Vertical‐Wind‐Induced Cloud Opacity Variation in Low Latitudes Simulated by a Venus GCM
Authors: Karyu Hiroki , Kuroda Takeshi , Itoh Kazunari , Nitta Akira , Ikeda Kohei , Yamamoto Masaru , Sugimoto Norihiko , Terada Naoki , Kasaba Yasumasa , Takahashi Masaaki , Hartogh Paul
Published: February 2023

Venusian cloud structure and variation are strongly linked to atmospheric dynamics. Past near‐infrared measurements have found cloud variation such as zonal‐wavenumber‐1 cloud marking and cloud discontinuity. However, their formation mechanism is still not well understood. To investigate the Venusian cloud structure and its variation, we have developed a Venus GCM incorporating cloud condensation, evaporation, sedimentation, and simple atmospheric chemistry to represent the H2SO4 cycle. The GCM takes into account cloud particles with radii of 0.3, 1.0, 1.26, and 3.13 μm (Modes 1, 2, 2', and 3, respectively) based on past in situ observations. The simulated latitudinal trends of the cloud top and bottom structures are qualitatively consistent with past observations. Zonally averaged cloud mass loading was the largest and smallest in low and middle latitudes, respectively, and maintained by a mechanism similar to that of past 2‐D numerical studies. At the equator, the column integrated optical depth at 1 μm varied between 33 and 50, which is in good agreement with past observations. This variation consists of two types of cloud mass loading changes between 46 and 52 km. One is a rapid small‐scale variation induced by gravity waves. The other is a quasi‐periodic zonal‐wavenumber‐1 variation coupled with an equatorial Kelvin wave, which is similar to the observed cloud marking. Our results showed that the vertical wind associated with the Kelvin wave is essential for maintaining the quasi‐periodic variation, along with the condensation/evaporation by the temperature variation. The vertical‐wind‐induced cloud generation also suggests a relationship to the cloud discontinuity.
Surface Uplift and Topographic Rejuvenation of a Tectonically Inactive Range: Insights From the Anti‐Atlas and the Siroua Massif (Morocco)
Authors: Clementucci R. , Ballato P. , Siame L. , Fox M. , Lanari R. , Sembroni A. , Faccenna C. , Yaaqoub A. , Essaifi A.
Published: February 2023

The Atlas‐Meseta intracontinental orographic system of Morocco experienced recent, large‐scale surface uplift as documented by elevated late Miocene, shallow‐water marine deposits exposed in the Middle Atlas Mountains. The Anti‐Atlas Mountains do not present any stratigraphic records that document regional vertical movements, however, the presence of a high‐standing, erosional surface, and the transient state of the river network, provides insights into the uplift history of the belt and the mechanisms that drove it. Here, we combine geomorphic and stream profiles analyses, celerity of knickpoints and linear inverse landscape modeling with available geological evidence, to decipher the spatial and temporal variations of surface uplift in the Anti‐Atlas and the Siroua Massif. Our results highlight the presence of a transient landscape and document a long wave‐length topographic swell (∼100 × 600 km) with a maximum surface uplift of ∼1,500 m in the Siroua Massif and ∼1,100 m in the central Anti‐Atlas most likely starting from ∼14 to 10 Ma. Surface uplift occurred in association with the onset of late Miocene magmatism in the Siroua and Saghro Massif and contractional deformation in the High Atlas. Regional surface uplift was most likely due to deep‐seated mechanism, such as asthenospheric upwelling. Additional processes such as magma injection and faulting contributed to the surface uplift of the Siroua Massif. Overall, our approach allows to quantitatively constrain the transient state of the landscape and the contribution of regional surface uplift on mountain building processes.
BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression
Authors: Zeng Furong , Li Yayun , Meng Yu , Sun Huiyan , He Yi , Yin Mingzhu , Chen Xiang , Deng Guangtong
Published: February 2023

Targeting bromodomain and extra-terminal domain (BET) proteins has shown a promising therapeutic effect on melanoma. The development of strategies to better kill melanoma cells with BET inhibitor treatment may provide new clinical applications. Here, we used a drug synergy screening approach to combine JQ1 with 240 antitumor drugs from the Food and Drug Administration (FDA)-approved drug library and found that sunitinib synergizes with BET inhibitors in melanoma cells. We further demonstrated that BET inhibitors synergize with sunitinib in melanoma by inducing apoptosis and cell cycle arrest. Mechanistically, BET inhibitors sensitize melanoma cells to sunitinib by inhibiting GDF15 expression. Strikingly, GDF15 is transcriptionally regulated directly by BRD4 or indirectly by the BRD4/IL6/STAT3 axis. Xenograft assays revealed that the combination of BET inhibitors with sunitinib causes melanoma suppression in vivo. Altogether, these findings suggest that BET inhibitor-mediated GDF15 inhibition plays a critical role in enhancing sunitinib sensitivity in melanoma, indicating that BET inhibitors synergize with sunitinib in melanoma.
Effects of bilateral sequential theta-burst stimulation on 5-HT1A receptors in the dorsolateral prefrontal cortex in treatment-resistant depression: a proof-of-concept trial
Authors: Murgaš Matej , Unterholzner Jakob , Stöhrmann Peter , Philippe Cécile , Godbersen Godber M. , Nics Lukas , Reed Murray B. , Vraka Chrysoula , Vanicek Thomas , Wadsak Wolfgang , Kranz Georg S. , Hahn Andreas , Mitterhauser Markus , Hacker Marcus , Kasper Siegfried , Lanzenberger Rupert , Baldinger-Melich Pia
Published: February 2023

Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT1A) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [carbonyl-11C]WAY-100635 including arterial blood sampling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation (n = 8 and n = 3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted of excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere, time, and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group, time, and HAMD on specific distribution volume (VS) of 5-HT1A receptor. While post-hoc comparisons showed no significant changes of 5-HT1A receptor VS in either group, higher 5-HT1A receptor VS after treatment correlated with greater difference in HAMD (r = −0.62). The results of this proof-of-concept trial hint towards potential effects of TBS on the distribution of the 5-HT1A receptor. Due to the small sample size, all results must, however, be regarded with caution.
Low protein-induced intrauterine growth restriction as a risk factor for schizophrenia phenotype in a rat model: assessing the role of oxidative stress and neuroinflammation interaction
Authors: Allgäuer Larissa , Cabungcal Jan-Harry , Yzydorczyk Catherine , Do Kim Quang , Dwir Daniella
Published: February 2023

A large body of evidence suggests that intrauterine growth restriction (IUGR) impedes normal neurodevelopment and predisposes the offspring to cognitive and behavioral deficits later in life. A significantly higher risk rate for schizophrenia (SZ) has been reported in individuals born after IUGR. Oxidative stress and neuroinflammation are both involved in the pathophysiology of SZ, particularly affecting the structural and functional integrity of parvalbumin interneurons (PVI) and their perineuronal nets (PNN). These anomalies have been tightly linked to impaired cognition, as observed in SZ. However, these pathways remain unexplored in models of IUGR. New research has proposed the activation of the MMP9-RAGE pathway to be a cause of persisting damage to PVIs. We hypothesize that IUGR, caused by a maternal protein deficiency during gestation, will induce oxidative stress and neuroinflammation. The activation of these pathways during neurodevelopment may affect the maturation of PVIs and PNNs, leading to long-term consequences in adolescent rats, in analogy to SZ patients. The level of oxidative stress and microglia activation were significantly increased in adolescent IUGR rats at postnatal day (P)35 as compared to control rats. PVI and PNN were decreased in P35 IUGR rats when compared to the control rats. MMP9 protein level and RAGE shedding were also increased, suggesting the involvement of this mechanism in the interaction between oxidative stress and neuroinflammation. We propose that maternal diet is an important factor for proper neurodevelopment of the inhibitory circuitry, and is likely to play a crucial role in determining normal cognition later in life, thus making it a pertinent model for SZ.
LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1–TINCR-USP20-PD-L1 axis
Authors: Wang Qin , Li Guozheng , Ma Xin , Liu Lei , Liu Jiena , Yin Yanling , Li Hui , Chen Yihai , Zhang Xin , Zhang Lei , Sun Liyang , Ai Jing , Xu Shouping
Published: February 2023

Although programmed death-ligand 1 (PD-L1) inhibitors have achieved some therapeutic success in breast cancer, their efficacy is limited by low therapeutic response rates, which is closely related to the immune escape of breast cancer cells. Tissue differentiation inducing non-protein coding RNA (TINCR), a long non-coding RNA, as an oncogenic gene associated with the progression of various malignant tumors, including breast cancer; however, the role of TINCR in tumor immunity, especially in breast cancer, remains unclear. We confirmed that TINCR upregulated PD-L1 expression in vivo and in vitro, and promoted the progression of breast cancer. Next, we revealed that TINCR knockdown can significantly improve the therapeutic effect of PD-L1 inhibitors in breast cancer in vivo. Mechanistically, TINCR recruits DNMT1 to promote the methylation of miR-199a-5p loci and inhibit its transcription. Furthermore, in the cytoplasm, TINCR potentially acts as a molecular sponge of miR-199a-5p and upregulates the stability of USP20 mRNA through a competing endogenous RNA (ceRNA) regulatory mechanism, thus promoting PD-L1 expression by decreasing its ubiquitination level. IFN-γ stimulation activates STAT1 by phosphorylation, which migrates into the nucleus to promote TINCR transcription. This is the first study to describe the regulatory role of TINCR in breast cancer tumor immunity, broadening the current paradigm of the functional diversity of TINCR in tumor biology. In addition, our study provides new research directions and potential therapeutic targets for PD-L1 inhibitors in breast cancer.
Reaction profiles for quantum chemistry-computed [3 + 2] cycloaddition reactions
Authors: Stuyver Thijs , Jorner Kjell , Coley Connor W.
Published: February 2023

Bio-orthogonal click chemistry based on [3 + 2] dipolar cycloadditions has had a profound impact on the field of biochemistry and significant effort has been devoted to identify promising new candidate reactions for this purpose. To gauge whether a prospective reaction could be a suitable bio-orthogonal click reaction, information about both on- and off-target activation and reaction energies is highly valuable. Here, we use an automated workflow, based on the autodE program, to compute over 5000 reaction profiles for [3 + 2] cycloadditions involving both synthetic dipolarophiles and a set of biologically-inspired structural motifs. Based on a succinct benchmarking study, the B3LYP-D3(BJ)/def2-TZVP//B3LYP-D3(BJ)/def2-SVP level of theory was selected for the DFT calculations, and standard conditions and an (aqueous) SMD model were imposed to mimic physiological conditions. We believe that this data, as well as the presented workflow for high-throughput reaction profile computation, will be useful to screen for new bio-orthogonal reactions, as well as for the development of novel machine learning models for the prediction of chemical reactivity more broadly.
Effects of medwakh smoking on salivary metabolomics and its association with altered oral redox homeostasis among youth
Authors: Aghila Rani K. G. , Soares Nelson C. , Rahman Betul , Al-Hroub Hamza M. , Semreen Mohammad H. , Al Kawas Sausan
Published: February 2023

The use of alternative tobacco products, particularly medwakh, has expanded among youth in the Middle East and around the world. The present study is conducted to investigate the biochemical and pathophysiological changes caused by medwakh smoking, and to examine the salivary metabolomics profile of medwakh smokers. Saliva samples were collected from 30 non-smokers and 30 medwakh smokers and subjected to metabolomic analysis by UHPLC-ESI-QTOF-MS. The CRP and Glutathione Peroxidase 1 activity levels in the study samples were quantified by ELISA and the total antioxidant capacity (TAC) by TAC assay kits. Statistical measurements and thorough validation of data obtained from untargeted metabolomics identified 37 uniquely and differentially abundant metabolites in saliva of medwakh smokers. The levels of phthalate, L-sorbose, cytosine, uridine, alpha-hydroxy hippurate, and L-nicotine were noticeably high in medwakh smokers. Likewise, 20 metabolic pathways were differentially altered in medwakh smokers. This study identified a distinctive saliva metabolomics profile in medwakh smokers associated with altered redox homeostasis, metabolic pathways, antioxidant system, and CRP levels. The impact of the altered metabolites in medwakh smokers and their diagnostic utility require further research in large cohorts.
In silico protein engineering shows that novel mutations affecting NAD+ binding sites may improve phosphite dehydrogenase stability and activity
Authors: Baammi Soukayna , Daoud Rachid , El Allali Achraf
Published: February 2023

Pseudomonas stutzeri phosphite dehydrogenase (PTDH) catalyzes the oxidation of phosphite to phosphate in the presence of NAD, resulting in the formation of NADH. The regeneration of NADH by PTDH is greater than any other enzyme due to the substantial change in the free energy of reaction (G°′ = − 63.3 kJ/mol). Presently, improving the stability of PTDH is for a great importance to ensure an economically viable reaction process to produce phosphite as a byproduct for agronomic applications. The binding site of NAD+ with PTDH includes thirty-four residues; eight of which have been previously mutated and characterized for their roles in catalysis. In the present study, the unexplored twenty-six key residues involved in the binding of NAD+ were subjected to in silico mutagenesis based on the physicochemical properties of the amino acids. The effects of these mutations on the structure, stability, activity, and interaction of PTDH with NAD+ were investigated using molecular docking, molecular dynamics simulations, free energy calculations, and secondary structure analysis. We identified seven novel mutations, A155I, G157I, L217I, P235A, V262I, I293A, and I293L, that reduce the compactness of the protein while improving PTDH stability and binding to NAD+.
Method for 3D atomic structure determination of multi-element nanoparticles with graphene liquid-cell TEM
Authors: Heo Junyoung , Kim Dongjun , Choi Hyesung , Kim Sungin , Chun Hoje , Reboul Cyril F. , Van Cong T. S. , Elmlund Dominika , Choi Soonmi , Kim Kihyun , Park Younggil , Elmlund Hans , Han Byungchan , Park Jungwon
Published: February 2023

Determining the 3D atomic structures of multi-element nanoparticles in their native liquid environment is crucial to understanding their physicochemical properties. Graphene liquid cell (GLC) TEM offers a platform to directly investigate nanoparticles in their solution phase. Moreover, exploiting high-resolution TEM images of single rotating nanoparticles in GLCs, 3D atomic structures of nanoparticles are reconstructed by a method called “Brownian one-particle reconstruction”. We here introduce a 3D atomic structure determination method for multi-element nanoparticle systems. The method, which is based on low-pass filtration and initial 3D model generation customized for different types of multi-element systems, enables reconstruction of high-resolution 3D Coulomb density maps for ordered and disordered multi-element systems and classification of the heteroatom type. Using high-resolution image datasets obtained from TEM simulations of PbSe, CdSe, and FePt nanoparticles that are structurally relaxed with first-principles calculations in the graphene liquid cell, we show that the types and positions of the constituent atoms are precisely determined with root mean square displacement values less than 24 pm. Our study suggests that it is possible to investigate the 3D atomic structures of synthesized multi-element nanoparticles in liquid phase.
Modeling the impact of national and regional lockdowns on the 2020 spring wave of COVID-19 in France
Authors: Roux Jonathan , Massonnaud Clément R. , Colizza Vittoria , Cauchemez Simon , Crépey Pascal
Published: February 2023

Several countries have implemented lockdowns to control their COVID-19 epidemic. However, questions like “where” and “when” still require answers. We assessed the impact of national and regional lockdowns considering the French first epidemic wave of COVID-19 as a case study. In a regional lockdown scenario aimed at preventing intensive care units (ICU) saturation, almost all French regions would have had to implement a lockdown within 10 days and 96% of ICU capacities would have been used. For slowly growing epidemics, with a lower reproduction number, the expected delays between regional lockdowns increase. However, the public health costs associated with these delays tend to grow with time. In a quickly growing pandemic wave, defining the timing of lockdowns at a regional rather than national level delays by a few days the implementation of a nationwide lockdown but leads to substantially higher morbidity, mortality, and stress on the healthcare system.
Association between low handgrip strength and obesity with mortality in peritoneal dialysis patients
Authors: Do Jun Young , Kang Seok Hui
Published: February 2023

The association between sarcopenia and obesity in peritoneal dialysis (PD) patients is more complex than that of the general population. The aim of this study was, therefore, to evaluate the association of patient survival with sarcopenia or sarcopenic components and obesity in groups of patients with PD. We retrospectively analyzed a dataset from 199 prevalent PD patients. Measurements including handgrip strength (HGS), appendicular lean mass index, and baseline characteristics, were obtained during the period of study. Patients were divided into four groups according to their HGS and obesity: NH-NO (normal HGS and non-obesity, n = 60), NH-O (normal HGS and obesity, n = 31), LH-NO (low HGS and non-obesity, n = 71), and LH-O (low HGS and obesity, n = 37). The median follow-up interval was 17 months. The Kaplan–Meier curve analysis showed that the LH-O group had the poorest patient survival outcome among the four groups (P < 0.001). The NH-NO group had a better patient survival outcome compared with the LH-NO group. Univariate and multivariate Cox regression analyses showed that the LH-O group had the highest mortality rate compared with the other groups. The NH-NO group had lower mortality compared with the LH-NO group. The present study demonstrated that obesity with low HGS was associated with the greatest mortality rate in groups defined by HGS and obesity.
Prediction model for the compressive strength of green concrete using cement kiln dust and fly ash
Authors: Bakhoum Emad S. , Amir Arsani , Osama Fady , Adel Mohamed
Published: February 2023

Integrating artificial intelligence and green concrete in the construction industry is a challenge that can help to move towards sustainable construction. Therefore, this research aims to predict the compressive strength of green concrete that includes a ratio of cement kiln dust (CKD) and fly ash (FA), then recommend the optimum sustainable mixture design. The artificial neural network (ANN) and multiple linear regression techniques are used to build prediction models and statistics using MATLAB and IBM SPSS software. The input parameters are based on 156 data points of concrete components and compressive strengths that are collected from the literature. The developed models have been trained, validated, and tested for each technique. TOPSIS method is used to assign the optimum mixture design according to three sustainable criteria: compressive strength, carbon dioxide (CO2) emission, and cost. The results of ANN models showed a better prediction of the compressive strength with regression (R) equal to 0.928 and 0.986. The optimum mixture includes CKD 10–20% and FA 0–30%. Predicting the compressive strength of green concrete is a non-destructive approach that has sustainable returns including preservation of natural resources, reduction of greenhouse gas emissions, cost, time, and waste to landfill as well as saving energy.