bluuebunny/crossref_metadata_2025 huggingface dataset:
WNT ligands in non-small cell lung cancer: from pathogenesis to clinical practice
Authors: Xue Wanting , Cai Lihong , Li Su , Hou Yujia , Wang Yan-Dong , Yang Dongbin , Xia Yubing , Nie Xiaobo
Published: July 2023

Non-small cell lung cancer (NSCLC) is the malignant tumor with the highest morbidity and leading cause of death worldwide, whereas its pathogenesis has not been fully elucidated. Although mutations in some crucial genes in WNT pathways such as β-catenin and APC are not common in NSCLC, the abnormal signal transduction of WNT pathways is still closely related to the occurrence and progression of NSCLC. WNT ligands (WNTs) are a class of secreted glycoproteins that activate WNT pathways through binding to their receptors and play important regulatory roles in embryonic development, cell differentiation, and tissue regeneration. Therefore, the abnormal expression or dysfunction of WNTs undoubtedly affects WNT pathways and thus participates in the pathogenesis of diseases. There are 19 members of human WNTs, WNT1, WNT2, WNT2b, WNT3, WNT3a, WNT4, WNT5a, WNT5b, WNT6, WNT7a, WNT7b, WNT8a, WNT8b, WNT9a, WNT9b, WNT10a, WNT10b, WNT11 and WNT16. The expression levels of WNTs, binding receptors, and activated WNT pathways are diverse in different tissue types, which endows the complexity of WNT pathways and multifarious biological effects. Although abundant studies have reported the role of WNTs in the pathogenesis of NSCLC, it still needs further study as therapeutic targets for lung cancer. This review will systematically summarize current research on human WNTs in NSCLC, from molecular pathogenesis to potential clinical practice.
Simultaneous posthydrolysis and liquid–liquid extraction: a SIMPLLE process to detoxify eucalyptus prehydrolysis liquor
Authors: Almhofer Lukas , Paulik Christian , Bischof Robert H.
Published: July 2023

The prehydrolysis liquor from the prehydrolysis Kraft process is rich in sugars and could thus serve as a sustainable feedstock for the production of various chemicals. However, its industrial utilization is impeded by the presence of fermentation inhibitors and extensive lignin precipitation, the latter receiving only little attention in the literature.

In order to provide a feedstock suitable for biotechnological or chemical conversion, the prehydrolysis liquor from eucalyptus wood must be detoxified whilst preventing the precipitation of lignin. To increase the yield of monomeric sugars, acid posthydrolysis should be investigated.

Various solvents and solvent mixtures were screened for the high temperature liquid–liquid extraction of isothermally separated prehydrolysis liquor. Their capability to prevent lignin precipitation and to extract fermentation inhibitors was assessed using mass balances and size-exclusion chromatography. Based on the solvent screening, a process for simultaneous posthydrolysis and liquid–liquid extraction of eucalyptus prehydrolysis liquor was proposed and investigated using statistic experimental design.

Liquid–liquid extraction using aliphatic alcohols effectively prevents lignin precipitation, and the addition of 25% (w/w) tri-n-octylamine was found to increase the overall inhibitor extraction efficiency. The conditions for the simultaneous posthydrolysis were investigated using a Box-Behnken experimental design, allowing for a maximum monomeric sugar yield of 83.0% at a sugar purity of 91.6%.

The simultaneous posthydrolysis and liquid-liquid extraction (SIMPLLE) process thus avoids industrial-level problems associated with lignin precipitation. It provides a carbohydrate-rich stream with low levels of fermentation inhibitors, enabling further conversion to value added products.
Do guided mosque tours alleviate the prejudice of non-Muslims against Islam and Muslims? Evidence from a quasi-experimental panel study from Germany
Authors: Janzen Olga , Diekmann Isabell , Tsolak Dorian , Salentin Kurt
Published: July 2023

Background

Anti-Muslim and anti-Islam attitudes are widespread in contemporary western societies. A grassroots movement of mosques tries to reduce prejudice by organizing guided mosque tours for non-Muslims. While this is an opportunity for intergroup contact in a social psychological sense, contact occurs under sometimes difficult conditions. As yet, its effects have not been investigated empirically.

Objective

We examine (a) whether visits have an immediate and medium-term effect on prejudice toward Islam and (b) how they change the visitors’ subjective images of Muslims.

Methods

(a) We survey N = 324 secondary school students in a three-wave panel study in 6 guided mosque tours in different parts of Germany, including a control sample. The tour programme was in line with common practice in the mosques. Standardized measurements were taken immediately before and after the tour and again several months later. (b) We asked about subjective images of Muslims and had subjects report their spontaneous associations with the term Muslim.

Results

(a) Most, but not all, mosque visits significantly alleviate anti-Islam prejudice in the short term. The effects fall off after several months. (b) After the visit, the image of Muslims possessed more concrete religious content, while negative and menacing associations, such as oppression of women, threat, or so-called Islamic State have decreased.

Conclusions

Outgroup contact in a mosque works as predicted by the intergroup contact research, even under less than optimal conditions. However, there is potential for improvement of the setup of tours in the interest of a more sustainable impact.
Cheetah spatiotemporal overlap with other large carnivores and prey at camera-trap sites: do they fit the niche-complementarity hypothesis?
Authors: Cornhill Kristina L. , Balme Guy A. , Hunter Luke T. B. , Kerley Graham I. H.
Published: July 2023

In guilds, such as the large predators, species compete over multiple resources that are both consumable and non-consumable. The niche complementary hypothesis states that competitors can overlap in resource use if there is low overlap for at least one shared resource. In Africa, cheetah, Acinonyx jubatus, compete with other large carnivores across space, time and prey and are known to be subordinate; however, rarely has the entire guild been considered when assessing resource partitioning by cheetah. Using camera-trap data from four areas sampled over 4 years, we compared spatial and temporal overlap between cheetah and other large carnivores. Moreover, we estimated short-term avoidance of sites by cheetah after another large carnivore had visited. We show that cheetah align with the niche complementary hypothesis to avoid other large carnivores. Cheetah experienced high overlap with African wild dog, Lycaon pictus, activity patterns but avoided sites that were used frequently by them. The inverse was observed for lion, Panthera leo, and spotted hyena, Crocuta crocuta, with cheetah avoiding them across time but not space. Cheetah experienced moderate overlap with leopard, Panthera pardus, across both space and time, with only possible short-term avoidance occurring. Finally, cheetah exhibited high levels of spatial and temporal overlap with preferred prey species, suggesting a novel demonstration of the trade-off between resource acquisition and predator avoidance. Our results showcase the importance of taking multiple scales and resource axes into consideration when determining species abilities to co-exist and provides tools for managers working in highly managed systems.
Technical challenges and perception: does AI have a PR issue?
Authors: Oldfield Marie
Published: July 2023

Increasingly, models have been highlighted that not only disadvantage society but those whom the model was originally designed to benefit. An increasing number of legal challenges around the world illustrates this. A surge of recent work has focussed on the technical, legal or regulatory challenges but not necessarily the real-world day to day challenges for practitioners such as data collection or fairness by design. Since the publication of the Holstein et al.’s study in 2019, additional legislation, regulation and multiple bodies have been created to address practitioner challenge. This study asks what, if anything, has improved for practitioners between 2019 and 2022. Study 1 conducts an investigation into real-world needs within industry and asks whether practitioners are now able to mitigate challenges in a more robust manner. A further pilot study on the perception of AI examines whether perception of AI impacts practitioner work. The results show increasing and continuing interdisciplinary issues. Where increased regulation and legislation might have seemed reasonable, the result for practitioners is indecision and overwhelm. Based on these findings, we highlight directions for future research in this area. The most problematic area being human factors.
A leadership model supporting maturation of high-performance translational teams
Authors: Brasier Allan R. , Casey Shannon L. , Hatfield Peggy , Kelly Patrick W. , Sweeney Whitney A. , Schweizer Marin , Liu Bo , Burnside Elizabeth S.
Published: July 2023

Despite understanding its impact on organizational effectiveness, practical guidance on how to train translational team (TT) leaders is lacking. Previously, we developed an evolutionary learning model of TT maturation consisting of three goal-directed phases: (1). team assembly (Formation); (2). conducting research (Knowledge Generation); and (3). dissemination and implementation (Translation). At each phase, the team acquires group-level knowledge, skills, and attitudes (KSAs) that enhance its performance. Noting that the majority of team-emergent KSAs are promoted by leadership behaviors, we examine the SciTS literature to identify the relevant behaviors for each phase. We propose that effective team leadership evolves from a hierarchical, transformational model early in teamFormationto a shared, functional leadership model duringTranslation. We synthesized an integrated model of TT leadership, mapping a generic “functional leadership” taxonomy to relevant leadership behaviors linked to TT performance, creating an evidence-informed Leadership and Skills Enhancement for Research (LASER) training program. Empirical studies indicate that leadership behaviors are stable across time; to enhance leadership skills, ongoing reflection, evaluation, and practice are needed. We provide a comprehensive multi-level evaluation framework for tracking the growth of TT leadership skills. This work provides a framework for assessing and training relevant leadership behaviors for high-performance TTs.
COFINAL TYPES BELOW
Authors: SHALEV ROY
Published: July 2023

It is proved that for every positive integer n, the number of non-Tukey-equivalent directed sets of cardinality

$\leq \aleph _n$

is at least

$c_{n+2}$

, the

$(n+2)$

-Catalan number. Moreover, the class

$\mathcal D_{\aleph _n}$

of directed sets of cardinality

$\leq \aleph _n$

contains an isomorphic copy of the poset of Dyck

$(n+2)$

-paths. Furthermore, we give a complete description whether two successive elements in the copy contain another directed set in between or not.
A DOUBLE TRAGIC ALLUSION IN AMMIANUS MARCELLINUS 14.1.3
Authors: Alonso Francisco J.
Published: July 2023

This article identifies a double allusion to the tragic characters of Phaedra and Eriphyle in Amm. Marc. 14.1.3 and considers its possible meanings. In combination, these allusions evoke the double nature of the story of Eriphyle, therefore functioning as a reference to the double nature of Caesar Gallus’ depiction in Ammianus. The double allusion consequently forms part of Ammianus’ tragic style throughout Book 14. Having identified the presence of this double allusion, the article illuminates its possible meaning by connecting Ammianus’ passage to the Virgilian rewriting of the description of Eriphyle in Homer.
Inverse cascade based on nonlinear Schrödinger equation analysis with nonlinear feedback control
Authors: Cui Shaoyan , Hu Xin , Xie Peng , Yang Jialin , Feng Shuwen
Published: July 2023

This paper focuses on the wave inverse cascade instability analysis with self-regulating feedback control for a fixed external potential field and a highly localized finite-amplitude initial pulse. The wave inverse cascade instability analysis is carried out by solving the corresponding two-dimensional generalized nonlinear Schrödinger equation. The wave field firstly suffers from the modulation instability, followed by collapse into turbulence containing the shortest-wavelength modes in the system. This is followed by inverse cascade of the shortest wavelength modes back to the longer-wavelength ones, until a statistical stationary turbulent state is reached. It is found that the inverse cascade is limited to the shorter-wavelength modes with the wavenumber

$\left |k\right |\geq 100$

. This shows that the viscous damping

$p_i$

acts like a control switch to the inverse cascade, and the feedback control can also regulate the intensity of the inverse cascade mode.
Functional connectivity during tic suppression predicts reductions in vocal tics following behavior therapy in children with Tourette syndrome
Authors: Morand-Beaulieu Simon , Crowley Michael J. , Grantz Heidi , Leckman James F. , Sukhodolsky Denis G.
Published: July 2023

Background

Comprehensive Behavioral Intervention for Tics (CBIT) is recommended as a first-line treatment for Tourette syndrome in children and adults. While there is strong evidence proving its efficacy, the mechanisms of reduction in tic severity during CBIT are still poorly understood. In a recent study, our group identified a functional brain network involved in tic suppression in children with TS. We reasoned that voluntary tic suppression and CBIT may share some mechanisms and thus we wanted to assess whether functional connectivity during tic suppression was associated with CBIT outcome.

Methods

Thirty-two children with TS, aged 8 to 13 years old, participated in a randomized controlled trial of CBIT v. a treatment-as-usual control condition. EEG was recorded during tic suppression in all participants at baseline and endpoint. We used a source-reconstructed EEG connectivity pipeline to assess functional connectivity during tic suppression.

Results

Functional connectivity during tic suppression did not change from baseline to endpoint. However, baseline tic suppression-related functional connectivity specifically predicted the decrease in vocal tic severity from baseline to endpoint in the CBIT group. Supplementary analyses revealed that the functional connectivity between the right superior frontal gyrus and the right angular gyrus was mainly driving this effect.

Conclusions

This study revealed that functional connectivity during tic suppression at baseline predicted reduction in vocal tic severity. These results suggest probable overlap between the mechanisms of voluntary tic suppression and those of behavior therapy for tics.
On the maximum number of edges in -critical graphs
Authors: Luo Cong , Ma Jie , Yang Tianchi
Published: July 2023

A graph is called
$k$
-critical if its chromatic number is
$k$
but every proper subgraph has chromatic number less than
$k$
. An old and important problem in graph theory asks to determine the maximum number of edges in an
$n$
-vertex
$k$
-critical graph. This is widely open for every integer
$k\geq 4$
. Using a structural characterisation of Greenwell and Lovász and an extremal result of Simonovits, Stiebitz proved in 1987 that for
$k\geq 4$
and sufficiently large
$n$
, this maximum number is less than the number of edges in the
$n$
-vertex balanced complete
$(k-2)$
-partite graph. In this paper, we obtain the first improvement in the above result in the past 35 years. Our proofs combine arguments from extremal graph theory as well as some structural analysis. A key lemma we use indicates a partial structure in dense
$k$
-critical graphs, which may be of independent interest.
Factors Associated with Symptom-to-Door Delay in Patients with ST-Segment Myocardial Infarction: A Systematic Review
Authors: Lu Xiuyan , Xia Wei , Wang Xinru , Xie Fangyu , Sun Xiujie
Published: July 2023

Background:

Decreasing symptom-to-door (S2D) delay is of vital importance for reducing morbidity and mortality in patients with ST-segment elevation myocardial infarction (STEMI). The factors associated with S2D delay in STEMI patients have not been well-characterized.

Objectives:

The aim of this study was to identify factors associated with S2D delay in patients with STEMI.

Methods:

The PubMed, CINAHL, and Embase databases were searched for data. References from the selected articles and relevant background papers were also manually searched to identify additional eligible studies. The included articles were reviewed and assessed for risk of bias. The level of evidence for each identified factor was evaluated using a semiquantitative synthesis.

Results:

Twelve (12) papers were included in the review. Factors associated with S2D delay were complex and could be divided into sociodemographic, clinical history, and onset characteristics. The level of evidence regarding female sex and diabetes was strong, and the evidence was moderate regarding older age, smoking, history of hypertension, self-transport, or referral.

Conclusions:

Female sex, older age, previous diabetes, previous hypertension, smoking, and self-transport are all strong or moderate risk factors for S2D time delay in patients with ST-segment myocardial infarction. More efforts should be made to educate at-risk populations concerning symptoms of STEMI and the importance of seeking early medical assistance.
Mindfulness and Character Strengths
Authors: Niemiec Ryan M.
Published: July 2023

This new, fully revised, and expanded second edition of the handbook for the groundbreaking, evidence-based Mindfulness-Based Strengths Practice (MBSP) program is the guide you need in your professional practice. Developed by author Dr. Ryan M. Niemiec, scientist, educator, practitioner, and a global leader in mindfulness and character strengths, the MBSP approach is about the discovery, deepening awareness, exploration, and application of character strengths. It is about understanding and improving how we pay attention in life – the quality by which we eat, walk, work, listen, and experience joy and peace. And it is about seeing our potential – which sits underneath our strengths of perseverance, bravery, curiosity, hope, kindness, fairness, and leadership – and which, unleashed, could benefit the world. MBSP is not only about our clients’ own happiness, it is about the happiness of others too. And it is an evolving, evidence-based program that can help people to relieve their suffering by using mindfulness and character strengths to cope with, overcome, or transcend problems, stressors, and conflicts.
Counselors, coaches, psychologists, researchers, educators, and managers will discover the “how-to” delivery of mindfulness and character strengths. Following primers on the two strands of MBSP and deeper discussions about their integration, practitioners are then led step-by-step through the 8 sessions of the popular MBSP program. The session structure, scripts, tips, lecture material, processes, examples, and audio files are all there ready for use. This time-tested manual can bring beginners up-to-date on these topics while also serving to stimulate, inform, and provide valuable tools to the intermediate and most advanced students of mindfulness and character strengths.
A companion workbook is also available for clients.
An Improved Satellite‐Based Evapotranspiration Procedure for China
Authors: Huang Lei , Luo Yong , Steenhuis Tammo , Tang Qiuhong , Cheng Wei , Shi Wen , Xia Xin , Zhao Dingchi , Liao Zhouyi
Published: July 2023

Evapotranspiration (ET) is a critical process that regulates the transfer of heat and water between land and the atmosphere. While satellite‐based ET algorithms can provide area‐wide daily ET estimates, few are independent of local meteorological measurements. The Variant of the Moderate Resolution Imaging Spectroradiometer Standard Evapotranspiration Algorithm (VISEA) can potentially run without ground‐based observations. However, the surface energy budgets used in VISEA generally overpredict daily net radiation and related ET. To improve the accuracy of net radiation and ET, we incorporated Brutsaert's atmosphere emissivity model and corrected the routine to calculate the downward long‐wave radiation on cloudy days (which we called VISEA2023 model). The VISEA2023 model predicted net radiation and ET that agreed well with measurements at seven ChinaFlux sites, with an R2 of 0.8 and an Root Mean Square Error (RMSE) of 30 W m−2 for net radiation, and an R2 of 0.6 and an RMSE of 1 mm day−1 for ET, respectively. Additionally, the VISEA2023 model is more robust in comparison to the Variable Infiltration Capacity hydrologic model output in 10 major river basins and 80 sub‐river basins, with an R2 of 0.91 (0.78) and an RMSE of 85 (127.4) mm year−1, than MOD16, which has an R2 of 0.81 (0.82) and an RMSE of 134.8 (157.7) mm year−1, and Advanced Very High Resolution Radiometer ET, which has an R2 of 0.92 (0.62) and an RMSE of 90.1 (136.1) mm year−1. The improved VISEA2023 model can offer near‐real‐time ET on a larger scale, improving our understanding of water cycles and their relation to climate change.
Spectral Analysis of Ionospheric Density Variations Measured With the Large Radio Telescope in the Low‐Latitude Region
Authors: Mangla Sarvesh , Datta Abhirup
Published: July 2023

The low‐latitude ionosphere is a dynamic region with a wide range of disturbances in temporal and spatial scales. The Giant Metrewave Radio Telescope (GMRT) situated in the low‐latitude region has demonstrated its ability to detect various ionospheric phenomena. It can detect total electron content (TEC) variation with precision of 10−3 TECU and also can measure TEC gradient with an accuracy of about 7 × 10−4 TECU km−1. This paper describes the spectral analysis of previously calculated TEC gradient measurements and validates them by comparing their properties using two bands. The analysis tracked individual waves associated with medium‐scale traveling ionospheric disturbances (MSTIDs) and smaller waves down to wavelengths of ∼10 km. The ionosphere is found to have unanticipated changes during sunrise hours, with waves changed propagation direction as the sun approached the zenith. Equatorial spread F disturbances during sunrise hours is observed, along with smaller structures moving in the same direction.
Streamlined and on-demand preparation of mRNA products on a universal integrated platform
Authors: Wei Hongjuan , Rong Zhen , Liu Liyan , Sang Ye , Yang Jing , Wang Shengqi
Published: July 2023

Vaccines are used to protect human beings from various diseases. mRNA vaccines simplify the development process and reduce the production cost of conventional vaccines, making it possible to respond rapidly to acute and severe diseases, such as coronavirus disease 2019. In this study, a universal integrated platform for the streamlined and on-demand preparation of mRNA products directly from DNA templates was established. Target DNA templates were amplified in vitro by a polymerase chain reaction module and transcribed into mRNA sequences, which were magnetically purified and encapsulated in lipid nanoparticles. As an initial example, enhanced green fluorescent protein (eGFP) was used to test the platform. The expression capacity and efficiency of the products were evaluated by transfecting them into HEK-293T cells. The batch production rate was estimated to be 200–300 μg of eGFP mRNA in 8 h. Furthermore, an mRNA vaccine encoding the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein was produced by this platform. The proposed integrated platform shows advantages for the universal and on-demand preparation of mRNA products, offering the potential to facilitate broad access to mRNA technology and enable the development of mRNA products, including the rapid supply of new mRNA-based vaccines in pandemic situations and personalized mRNA-based therapies for oncology and chronic infectious diseases, such as viral hepatitis and acquired immune deficiency syndrome.
μeV electron spectromicroscopy using free-space light
Authors: Auad Yves , Dias Eduardo J. C. , Tencé Marcel , Blazit Jean-Denis , Li Xiaoyan , Zagonel Luiz Fernando , Stéphan Odile , Tizei Luiz H. G. , García de Abajo F. Javier , Kociak Mathieu
Published: July 2023

The synergy between free electrons and light has recently been leveraged to reach an impressive degree of simultaneous spatial and spectral resolution, enabling applications in microscopy and quantum optics. However, the required combination of electron optics and light injection into the spectrally narrow modes of arbitrary specimens remains a challenge. Here, we demonstrate microelectronvolt spectral resolution with a sub-nanometer probe of photonic modes with quality factors as high as 104. We rely on mode matching of a tightly focused laser beam to whispering gallery modes to achieve a 108-fold increase in light-electron coupling efficiency. By adapting the shape and size of free-space optical beams to address specific physical questions, our approach allows us to interrogate any type of photonic structure with unprecedented spectral and spatial detail.
Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib
Authors: Coombes R. C. , Howell Sacha , Lord Simon R. , Kenny Laura , Mansi Janine , Mitri Zahi , Palmieri Carlo , Chap Linnea I. , Richards Paul , Gradishar William , Sardesai Sagar , Melear Jason , O’Shaughnessy Joyce , Ward Patrick , Chalasani Pavani , Arkenau Tobias , Baird Richard D. , Jeselsohn Rinath , Ali Simak , Clack Glen , Bahl Ashwani , McIntosh Stuart , Krebs Matthew G.
Published: July 2023

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2− breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.
Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice
Authors: Bai Yunhu , Li Kenan , Li Xiaodong , Chen Xiyu , Zheng Jie , Wu Feifei , Chen Jinghao , Li Ze , Zhang Shuai , Wu Kun , Chen Yong , Wang Yayun , Yang Yanling
Published: July 2023

Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNrGAD2) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNrGAD2 and SNrGAD2-targeted chemogenetic inhibition targeted to SNrGAD2 rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE.
ORC1 binds to cis-transcribed RNAs for efficient activation of replication origins
Authors: Mas Aina Maria , Goñi Enrique , Ruiz de los Mozos Igor , Arcas Aida , Statello Luisa , González Jovanna , Blázquez Lorea , Lee Wei Ting Chelsea , Gupta Dipika , Sejas Álvaro , Hoshina Shoko , Armaos Alexandros , Tartaglia Gian Gaetano , Waga Shou , Ule Jernej , Rothenberg Eli , Gómez María , Huarte Maite
Published: July 2023

Cells must coordinate the activation of thousands of replication origins dispersed throughout their genome. Active transcription is known to favor the formation of mammalian origins, although the role that RNA plays in this process remains unclear. We show that the ORC1 subunit of the human Origin Recognition Complex interacts with RNAs transcribed from genes with origins in their transcription start sites (TSSs), displaying a positive correlation between RNA binding and origin activity. RNA depletion, or the use of ORC1 RNA-binding mutant, result in inefficient activation of proximal origins, linked to impaired ORC1 chromatin release. ORC1 RNA binding activity resides in its intrinsically disordered region, involved in intra- and inter-molecular interactions, regulation by phosphorylation, and phase-separation. We show that RNA binding favors ORC1 chromatin release, by regulating its phosphorylation and subsequent degradation. Our results unveil a non-coding function of RNA as a dynamic component of the chromatin, orchestrating the activation of replication origins.
Two point mutations in protocadherin-1 disrupt hantavirus recognition and afford protection against lethal infection
Authors: Slough Megan M. , Li Rong , Herbert Andrew S. , Lasso Gorka , Kuehne Ana I. , Monticelli Stephanie R. , Bakken Russell R. , Liu Yanan , Ghosh Agnidipta , Moreau Alicia M. , Zeng Xiankun , Rey Félix A. , Guardado-Calvo Pablo , Almo Steven C. , Dye John M. , Jangra Rohit K. , Wang Zhongde , Chandran Kartik
Published: July 2023

Andes virus (ANDV) and Sin Nombre virus (SNV) are the etiologic agents of severe hantavirus cardiopulmonary syndrome (HCPS) in the Americas for which no FDA-approved countermeasures are available. Protocadherin-1 (PCDH1), a cadherin-superfamily protein recently identified as a critical host factor for ANDV and SNV, represents a new antiviral target; however, its precise role remains to be elucidated. Here, we use computational and experimental approaches to delineate the binding surface of the hantavirus glycoprotein complex on PCDH1’s first extracellular cadherin repeat domain. Strikingly, a single amino acid residue in this PCDH1 surface influences the host species-specificity of SNV glycoprotein-PCDH1 interaction and cell entry. Mutation of this and a neighboring residue substantially protects Syrian hamsters from pulmonary disease and death caused by ANDV. We conclude that PCDH1 is a bona fide entry receptor for ANDV and SNV whose direct interaction with hantavirus glycoproteins could be targeted to develop new interventions against HCPS.
An osteoinductive and biodegradable intramedullary implant accelerates bone healing and mitigates complications of bone transport in male rats
Authors: Lin Sien , Maekawa Hirotsugu , Moeinzadeh Seyedsina , Lui Elaine , Alizadeh Hossein Vahid , Li Jiannan , Kim Sungwoo , Poland Michael , Gadomski Benjamin C. , Easley Jeremiah T. , Young Jeffrey , Gardner Michael , Mohler David , Maloney William J. , Yang Yunzhi Peter
Published: July 2023

Bone transport is a surgery-driven procedure for the treatment of large bone defects. However, challenging complications include prolonged consolidation, docking site nonunion and pin tract infection. Here, we develop an osteoinductive and biodegradable intramedullary implant by a hybrid tissue engineering construct technique to enable sustained delivery of bone morphogenetic protein-2 as an adjunctive therapy. In a male rat bone transport model, the eluting bone morphogenetic protein-2 from the implants accelerates bone formation and remodeling, leading to early bony fusion as shown by imaging, mechanical testing, histological analysis, and microarray assays. Moreover, no pin tract infection but tight osseointegration are observed. In contrast, conventional treatments show higher proportion of docking site nonunion and pin tract infection. The findings of this study demonstrate that the novel intramedullary implant holds great promise for advancing bone transport techniques by promoting bone regeneration and reducing complications in the treatment of bone defects.
The OsSGS3-tasiRNA-OsARF3 module orchestrates abiotic-biotic stress response trade-off in rice
Authors: Gu Xueting , Si Fuyan , Feng Zhengxiang , Li Shunjie , Liang Di , Yang Pei , Yang Chao , Yan Bin , Tang Jun , Yang Yu , Li Tai , Li Lin , Zhou Jinling , Li Ji , Feng Lili , Liu Ji-Yun , Yang Yuanzhu , Deng Yiwen , Wu Xu Na , Zhao Zhigang , Wan Jianmin , Cao Xiaofeng , Song Xianwei , He Zuhua , Liu Junzhong
Published: July 2023

Recurrent heat stress and pathogen invasion seriously threaten crop production, and abiotic stress often antagonizes biotic stress response against pathogens. However, the molecular mechanisms of trade-offs between thermotolerance and defense remain obscure. Here, we identify a rice thermo-sensitive mutant that displays a defect in floret development under high temperature with a mutation in SUPPRESSOR OF GENE SILENCING 3a(OsSGS3a). OsSGS3a interacts with its homolog OsSGS3b and modulates the biogenesis oftrans-acting small interfering RNA (tasiRNA) targetingAUXIN RESPONSE FACTORS(ARFs). We find that OsSGS3a/b positively, while OsARF3a/b and OsARF3la/lb negatively modulate thermotolerance. Moreover, OsSGS3a negatively, while OsARF3a/b and OsARF3la/lb positively regulate disease resistance to the bacterial pathogenXanthomonas oryzaepv.oryzae(Xoo) and the fungal pathogenMagnaporthe oryzae(M. oryzae). Taken together, our study uncovers a previously unknown trade-off mechanism that regulates distinct immunity and thermotolerance through the OsSGS3-tasiRNA-OsARF3 module, highlighting the regulation of abiotic-biotic stress response trade-off in plants.
A tripartite microbial co-culture system for de novo biosynthesis of diverse plant phenylpropanoids
Authors: Brooks Sierra M. , Marsan Celeste , Reed Kevin B. , Yuan Shuo-Fu , Nguyen Dustin-Dat , Trivedi Adit , Altin-Yavuzarslan Gokce , Ballinger Nathan , Nelson Alshakim , Alper Hal S.
Published: July 2023

Plant-derived phenylpropanoids, in particular phenylpropenes, have diverse industrial applications ranging from flavors and fragrances to polymers and pharmaceuticals. Heterologous biosynthesis of these products has the potential to address low, seasonally dependent yields hindering ease of widespread manufacturing. However, previous efforts have been hindered by the inherent pathway promiscuity and the microbial toxicity of key pathway intermediates. Here, in this study, we establish the propensity of a tripartite microbial co-culture to overcome these limitations and demonstrate to our knowledge the first reported de novo phenylpropene production from simple sugar starting materials. After initially designing the system to accumulate eugenol, the platform modularity and downstream enzyme promiscuity was leveraged to quickly create avenues for hydroxychavicol and chavicol production. The consortia was found to be compatible with Engineered Living Material production platforms that allow for reusable, cold-chain-independent distributed manufacturing. This work lays the foundation for further deployment of modular microbial approaches to produce plant secondary metabolites.
3D printing titanium grid scaffold facilitates osteogenesis in mandibular segmental defects
Authors: Li Yongfeng , Liu Huawei , Wang Chao , Yan Rongzeng , Xiang Lei , Mu Xiaodan , Zheng Lingling , Liu Changkui , Hu Min
Published: July 2023

Bone fusion of defect broken ends is the basis of the functional reconstruction of critical maxillofacial segmental bone defects. However, the currently available treatments do not easily achieve this goal. Therefore, this study aimed to fabricate 3D-printing titanium grid scaffolds, which possess sufficient pores and basic biomechanical strength to facilitate osteogenesis in order to accomplish bone fusion in mandibular segmental bone defects. The clinical trial was approved and supervised by the Medical Ethics Committee of the Chinese PLA General Hospital on March 28th, 2019 (Beijing, China. approval No. S2019–065–01), and registered in the clinical trials registry platform (registration number: ChiCTR2300072209). Titanium grid scaffolds were manufactured using selective laser melting and implanted in 20 beagle dogs with mandibular segmental defects. Half of the animals were treated with autologous bone chips and bone substances incorporated into the scaffolds; no additional filling was used for the rest of the animals. After 18 months of observation, radiological scanning and histological analysis in canine models revealed that the pores of regenerated bone were filled with titanium grid scaffolds and bone broken ends were integrated. Furthermore, three patients were treated with similar titanium grid scaffold implants in mandibular segmental defects; no mechanical complications were observed, and similar bone regeneration was observed in the reconstructed patients’ mandibles in the clinic. These results demonstrated that 3D-printing titanium grid scaffolds with sufficient pores and basic biomechanical strength could facilitate bone regeneration in large-segment mandibular bone defects.
A TLR7/8 agonist increases efficacy of anti-fentanyl vaccines in rodent and porcine models
Authors: Crouse Bethany , Miller Shannon M. , Muelken Peter , Hicks Linda , Vigliaturo Jennifer R. , Marker Cheryl L. , Guedes Alonso G. P. , Pentel Paul R. , Evans Jay T. , LeSage Mark G. , Pravetoni Marco
Published: July 2023

Opioid use disorders (OUD) and overdose are public health threats worldwide. Widespread access to highly potent illicit synthetic opioids such as fentanyl is driving the recent rise in fatal overdoses. Vaccines containing fentanyl-based haptens conjugated to immunogenic carrier proteins offer a long-lasting, safe, and cost-effective strategy to protect individuals from overdose upon accidental or deliberate exposure to fentanyl and its analogs. Prophylactic or therapeutic active immunization with an anti-fentanyl vaccine induces the production of fentanyl-specific antibodies that bind the drug in the blood and prevent its distribution to the brain, which reduces its reinforcing effects and attenuates respiratory depression and bradycardia. To increase the efficacy of a lead anti-fentanyl vaccine, this study tested whether the incorporation of synthetic toll-like receptor (TLR) 4 and TLR7/8 agonists as vaccine adjuvants would increase vaccine efficacy against fentanyl challenge, overdose, and self-administration in either rats or Hanford miniature pigs. Formulation of the vaccine with a nucleolipid TLR7/8 agonist enhanced its immunogenicity and efficacy in preventing fentanyl-induced respiratory depression, analgesia, bradycardia, and self-administration in either rats or mini-pigs. These studies support the use of TLR7/8 adjuvants in vaccine formulations to improve their clinical efficacy against OUD and potentially other substance use disorders (SUD).
Controlling the Solo12 quadruped robot with deep reinforcement learning
Authors: Aractingi Michel , Léziart Pierre-Alexandre , Flayols Thomas , Perez Julien , Silander Tomi , Souères Philippe
Published: July 2023

Quadruped robots require robust and general locomotion skills to exploit their mobility potential in complex and challenging environments. In this work, we present an implementation of a robust end-to-end learning-based controller on the Solo12 quadruped. Our method is based on deep reinforcement learning of joint impedance references. The resulting control policies follow a commanded velocity reference while being efficient in its energy consumption and easy to deploy. We detail the learning procedure and method for transfer on the real robot. We show elaborate experiments. Finally, we present experimental results of the learned locomotion on various grounds indoors and outdoors. These results show that the Solo12 robot is a suitable open-source platform for research combining learning and control because of the easiness in transferring and deploying learned controllers.
Research on surrogate model of dam numerical simulation with multiple outputs based on adaptive sampling
Authors: Liang Jiaming , Li Zhanchao , Pan Litan , Khailah Ebrahim Yahya , Sun Linsong , Lu Weigang
Published: July 2023

Dam numerical simulation is an important method to research the dam structural behavior, but it often takes a lot of time for calculation when facing problems that require many simulations, such as structural parameter back analysis. The surrogate model is widely used as a technology to reduce computational cost. Although various methods have been widely investigated, there are still problems in designing the surrogate model's optimal Design of Experiments (DoE). In addition, most of the current DoE focuses on establishing a single-output problem. Designing a reasonable DoE for high-dimensional outputs is also a problem that needs to be solved. Based on the above issues, this research proposes a sequential surrogate model based on the radial basis function model (RBFM) with multi-outputs adaptive sampling. The benchmark function demonstrates the applicability of the proposed method to single-input & multi-outputs and multi-inputs & multi-outputs problems. Then, this method is applied to establishing a surrogate model for dam numerical simulation with multi-outputs. The result demonstrates that the proposed technique can be sampled adaptively and samples can be targeted based on the function form of the surrogate model, which significantly reduces the required sampling and calculation cost.
Knockdown of protein interacting with C α kinase 1 aggravates sepsis-induced acute liver injury by regulating the TLR4/NF-κB pathway
Authors: Wang Huijun , Ma Ting , Bao Qianqian , Zhu Lijun , Ying Tingting , Yu Yulong
Published: July 2023

Acute liver injury (ALI) may manifest at any phase of sepsis, yet an explicit therapeutic approach remains elusive. In this study, LPS and cecum ligation and puncture (CLP) were utilized to establish an inflammatory cell model and a murine model of sepsis-induced liver injury, respectively, aiming to explore the potential protective effect of protein interacting with C α kinase 1 (PICK1) on sepsis-induced ALI and its underlying mechanisms. In both the cell supernatant and the murine whole blood, the concentrations of inflammatory factors were quantified by ELISA, while the protein and mRNA expressions of PICK1, cleaved-PARP-1, caspase1, TLR4, IκBα, and NF-κB were assessed via western blot and qRT-PCR. The outcomes revealed that the knockdown of PICK1 increased the levels of inflammatory factors and apoptosis, alongside activation of TLR4/NF-κB signaling pathway-related factors in both in vivo and in vitro models. Moreover, the murine liver samples were subjected to Hematoxylin–Eosin (HE) staining for assessment of histopathological morphology. The HE staining and liver injury scoring results manifested a markedly exacerbated hepatic damage in PICK1 knockout mice as compared to WT mice following CLP. Furthermore, the liver macrophages were isolated from murine livers, and the expression and activity of the factors associated with the TLR4/NF-κB signaling pathway were verified through RT-qPCR and western blot, and EMSA assay demonstrated an augmented NF-κB activity subsequent to PICK1 knockout. Finally, the expression and localization of PICK1 in macrophages were further scrutinized via immunofluorescence, and the interaction between PICK1 and TLR4 was identified through co-immunoprecipitation. In conclusion, the knockdown of PICK1 appeared to modulate inflammatory factors by activating the TLR4/NF-κB signaling pathway, thereby exacerbating hepatic damage induced by sepsis.
Expandable ELAST for super-resolution imaging of thick tissue slices using a hydrogel containing charged monomers
Authors: La Woonggi , Seo Junyoung , Heo Eunseok , Chang Jae-Byum
Published: July 2023

Hydrogels have been utilized extensively as a material for retaining position information in tissue imaging procedures, such as tissue clearing and super-resolution imaging. Immunostaining thick biological tissues, however, poses a bottleneck that restricts sample size. The recently developed technique known as entangled link-augmented stretchable tissue-hydrogel (ELAST) accelerates the immunostaining process by embedding specimens in long-chain polymers and stretching them. A more advanced version of ELAST, magnifiable entangled link-augmented stretchable tissue-hydrogel (mELAST), achieves rapid immunostaining and tissue expansion by embedding specimens in long-chain neutral polymers and subsequently hydrolyzing them. Building on these techniques, we introduce a variant of mELAST called ExELAST. This approach uses charged monomers to stretch and expand tissue slices. Using ExELAST, we first tested two hydrogel compositions that could permit uniform expansion of biological specimens. Then, we apply the tailored hydrogel to the 500-μm-thick mouse brain slices and demonstrated that they can be stained within two days and imaged with a resolution below the diffraction limit of light.
Climate-driven marmot-plague dynamics in Mongolia and China
Authors: Xu Lei , Wang Qian , Yang Ruifu , Ganbold Dalantai , Tsogbadrakh Nyamdorj , Dong Kaixing , Liu Min , Altantogtokh Doniddemberel , Liu Qiyong , Undrakhbold Sainbileg , Boldgiv Bazartseren , Liang Wannian , Stenseth Nils Chr.
Published: July 2023

The incidence of plague has rebounded in the Americas, Asia, and Africa alongside rapid globalization and climate change. Previous studies have shown local climate to have significant nonlinear effects on plague dynamics among rodent communities. We analyzed an 18-year database of plague, spanning 1998 to 2015, in the foci of Mongolia and China to trace the associations between marmot plague and climate factors. Our results suggested a density-dependent effect of precipitation and a geographic location-dependent effect of temperature on marmot plague. That is, a significantly positive relationship was evident between risk of plague and precipitation only when the marmot density exceeded a certain threshold. The geographical heterogeneity of the temperature effect and the contrasting slopes of influence for the Qinghai-Tibet Plateau (QTP) and other regions in the study (nQTP) were primarily related to diversity of climate and landscape types.