bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural, Frequency and Temperature Dependent Dielectric Properties of Zn2+ Substituted Ni-Co Based Spinel Ferrite (ZnxNi0.8−xCo0.2Fe2O4)
Authors: Oumezzine Marwène , Iuga Alin , Enculescu Monica , Galca Aurelian Catalin
Published: May 2023

Zinc substituted nickel-cobalt ferrites, i.e., ZnxNi0.8−xCo0.2Fe2O4 (x = 0.0, 0.05, 0.10 and 0.20) with average crystallite size 100 nm were synthesized by citrate-gel auto-combustion method to investigate effects of Zn2+ substitution on the structural and dielectric properties. Both X-ray diffraction (XRD) and IR spectroscopy studies confirms the formation of pure cubic spinel structure. Variation of lattice parameter infers Vegard’s law linear dependence with the addition of Zn2+ concentration. The temperature-dependent behavior of dielectric and modulus spectra has been studied within the frequency range 100 Hz-100 kHz for different temperatures between 100 K and 400 K. It was concluded that the dielectric responses of ZnxNi0.8−xCo0.2Fe2O4 are found to be frequency dependent and thermally activated. Also, In the Zn doped ferrites variations of dielectric loss (tan δ) and the imaginary part of electric modulus (M") show the presence of the non-Debye type of dielectric relaxation. Rise in Zinc concentration leads to a decrease in dielectric constant (ε
r) due to the declining of Fe3+–O–M2+ conducting network (M is Co or Ni). Here, we report a low loss tangent factor of the order of

8
×

10

−
3

for the sample Ni0.6Zn0.2Co0.2Fe2O4 make this composition suitable for high frequency-applications at room temperature. The activation energy is calculated from electric modulus formalism and DC electrical conductivity and found to increase with further substitution of Zn2+ concentration.
Optimization Analysis for Innovative Inputs under the Objective Discrepancy between Government and Enterprise
Authors: Kai Wu , Huiying Zhang
Published: May 2023

Aiming at the improvement of innovation efficiency after enterprise obtaining subsidies, this paper constructs two-stage innovation benefit model about research and development (R&D) and transformation and achieves Nash equilibrium of innovative inputs to solve the objective discrepancy of innovation between government and enterprise. The main conclusions are as follows: there are three kinds of resource allocation structure in the way of achieving Nash equilibrium. The allocation structure is determined by the sensitivity of benefits (differentiated by social benefits and enterprise benefits) to R&D and transformation. After obtaining subsidies, enterprise optimizes resource allocation and results in crowding out effect, which is the inevitable choice for enterprise to seek benefits. Relative to the enterprise budget, when the proportion of government subsidies is few, the way of subsidies does not affect benefits. When the government invests more subsidies, which are designated for R&D, there is the possibility of dual losses of social benefits and enterprise benefits. The conclusion defines the proportion of subsidies to enterprise budgets so as to differentiate the allocation structure of innovative inputs. The practical significance is to provide a precise method of resource allocation from the microlevel of enterprise project, which alleviates the objective discrepancy between the government and enterprise.
A Study on the Abrasion Resistance of Hydraulic Structures with Different Repair Mortars
Authors: Melesse Getinet , Kaske Kassa Hibretu , Geta Minale , Simachew Tigist , Mamo Tewodros , Mengesha Adal , Asale Tegegn
Published: May 2023

One of the main problems with hydraulic structures is that floating silt, gravel, ice sand, boulders, and other materials circulating over a concrete surface have an abrasive effect that causes hydraulic structures to abrade. Abrasion causes concrete to degrade, which could eventually expose the reinforcing to corrosion. In addition to section loss, reinforced concrete hydraulic structures’ endurance may also be a problem. Repair mortars are used to restore surfaces that have been abraded. The suitability of various repair materials for use as a repair layer on concrete surfaces is examined in this study. In order to apply different repair mortars to concrete specimens and subject them to abrasive forces, this work employs an experimental methodology. The ASTM C 1138 standard was followed for testing the abrasion resistance of the samples repaired using repair mortars underwater. Both silica fume mortar and polymer-modified mortar were employed in the study as forms of repair mortar. For each type of repair mortar, three cylindrical concrete specimens were cast, along with control specimens. Hence, nine cylindrical concrete samples in total were employed in this study. In order to quantify the effect of abrasion and, consequently, to assess the efficacy of various repair materials, abrasion volume loss was measured. Important findings about each type of repair material’s resistance to underwater abrasion are included in the study. The findings show that in terms of abrasion resistance underwater, the polymer-modified mortar performs better than the silica fume mortar.
Learning Curve Analyses for Left Bundle Branch Area Pacing with Conventional Stylet-Driven Pacing Leads
Authors: Yu Ga-In , Kim Tae-Hoon , Yu Hee Tae , Joung Boyoung , Pak Hui-Nam , Lee Moon-Hyoung
Published: May 2023

Background. Physiological conduction system pacing has attracted attention to overcome the dyssynchrony problems of conventional right ventricular pacing (RVP). Left bundle branch area pacing (LBBAP), which complements short combing of His bundle pacing (HBP), has emerged and has proven its efficiency and safety. In addition, initial experiences of LBBAP were mainly using lumen-less pacing lead, and the feasibility of stylet-driven pacing lead (SDL) was also established. The purpose of this study is to evaluate the learning curve for LBBAP using SDL. Methods. The study enrolled 265 patients who underwent LBBAP or RVP performed by operators without previous LBBAP experience at Yonsei University Severance Hospital in Korea between December 2020 and October 2021. LBBAP was performed using SDL with an extendable helix. The learning curve was evaluated by analyzing fluoroscopy and procedure times. And, before and after reaching the learning curve, we evaluated how much the time required for the LBBAP differed from the time required for the RVP. Results. LBBAP was successful in 50 of 50 (100.0%) patients left bundle branch pacing was successful in 49 of 50 (98.0%). In 50 patients who underwent LBBAP, mean fluoroscopy and procedural times were 15.1 ± 13.5 minutes and 59.9 ± 24.8 minutes, respectively. The plateau of fluoroscopy time reached in the 25th case and the plateau of procedure time reached in the 24th case. Conclusion. During the initial experience with LBBAP, fluoroscopy and procedural times improved with increasing operator experience. For operators who were experienced in cardiac pacemaker implantation, the steepest part of the learning curve was over the first 24-25 cases. It is shorter than the previously reported learning curves of HBP.
Mobile Robot Path Planning Based on Improved Particle Swarm Optimization and Improved Dynamic Window Approach
Authors: Yang Zhenjian , Li Ning , Zhang Yunjie , Li Jin
Published: May 2023

To enable mobile robots to effectively complete path planning in dynamic environments, a hybrid path planning method based on particle swarm optimization (PSO) and dynamic window approach (DWA) is proposed in this paper. First, an improved particle swarm optimization (IPSO) is proposed to enhance the exploration capability and search accuracy of the algorithm by improving the velocity update method and inertia weight. Secondly, a particle initialization strategy is used to increase population diversity, and an addressing local optimum strategy is used to make the algorithm overcome the local optimum. Thirdly, a method of selecting navigation points is proposed to guide local path planning. The robot selects the appropriate navigation points as the target points for local path planning based on the position of the robot and the risk of collision with dynamic obstacles. Finally, an improved dynamic window approach (IDWA) is proposed by combining the velocity obstacle (VO) with the DWA, and the evaluation function of the DWA is improved to enhance trajectory tracking and dynamic obstacle avoidance capabilities. The simulation and experimental results show that IPSO has greater exploration capability and search accuracy; IDWA is more effective in trajectory tracking and dynamic obstacle avoidance; and the hybrid algorithm enables the robot to efficiently complete path planning in dynamic environments.
Causes, Effects, and Mitigation Measures of Time and Cost Overruns in Water Supply Projects: Case of Tigrai Region, Northern Ethiopia
Authors: Berihu Lielti Gebreegziabher , Grum Berhane , Tariku Zeru , Abebe Bizuneh Asfaw
Published: May 2023

Project cost overrun and schedule delay are major and widespread problems in the construction industry. In Tigrai, most water supply construction projects are not completed within the predetermined contract time and planned budget. Hence, this research was carried out to investigate the causes and effects of time and cost overrun in water supply projects in Tigrai, northern Ethiopia and further recommend effective mitigation measures. A total of 87 questionnaires were distributed, 50 of them were collected, and desk study of 12 water supply projects were conducted. Data were analyzed using relative importance index and statistical software SPSS version 20. Results showed that the most important causes of time overrun were design errors and changes, lack of consistency between bill of quantities and drawings, and change order. Similarly, the most important causes of cost overrun were design errors and changes, lack of consistency between bill of quantities and drawings, and shortage of construction materials and electromechanical equipment in local market. The most effective mitigation measure of the overruns was complete and proper design. Time and cost overrun of the projects ranged between 0 and 203% and between 0 and 25%, respectively. The regression model showed that time overrun was estimated well (r2 = 0.95) using delays caused by design errors and changes and material import. Similarly, cost overrun was estimated well (r2 = 0.98) using factors that affect cost. Overall, the major cause for the overruns was design problem, hence clients and consultants should give due attention for the design process.
A MIMO-Enabled Free Space Optical Link under Log-Normal Fading/Gamma-Gamma Channel: Exploring an Optimal Modulation Scheme
Authors: Adardour Haroun Errachid , Kameche Samir , Singh Mehtab
Published: May 2023

The technology of free-space optical communication (FSOC) systems has some distinctive merits compared to other technologies. Its use is extremely beneficial to meet the exigencies of optical telecommunications and wireless networks (OTWNs). However, since the OTWNs transport a lot of data, the choice of a reliable modulation scheme is highly crucial. To this end, the focus of this paper is an in-depth study of a Point-to-Point Optical Link (P2P-OL) system under a FSOC-Multiple-Input Multiple-Output (MIMO) channel using an optimal modulation scheme. Furthermore, atmospheric turbulence (AT) effects over the FSOC-MIMO channel are incorporated in the proposed system to obtain substantial results. The performance analysis test of the proposed high-rate P2P-OL system is validated under the case that the channel decreases significantly when the AT gets strong regimes. Finally, the proposed system uses an optimal Non-Return to Zero Pulse Generator-Mach-Zehnder Modulator ((NRZPG-MZM)) scheme, which displays acceptable performance levels in a dust-fog meteorological environment under a LNF FSOC-9 × 9 channel with the attenuation value of 59.66 dB/km (i.e., max OSNR = 24.9 dB, min BER = 1e − 09, and max Q-factor = 6), whereas with the same environment under a G-G FSOC-9 × 9 channel, the attenuation value is 58.55 dB/km (i.e., max OSNR = 24.67 dB, min BER = 1e − 09, and max Q-factor = 6).
Supplementary Data from Comprehensive DNA Methylation Analysis Indicates That Pancreatic Intraepithelial Neoplasia Lesions Are Acinar-Derived and Epigenetically Primed for Carcinogenesis
Authors: Lo Emily K.W. , Mears Brian M. , Maurer H. Carlo , Idrizi Adrian , Hansen Kasper D. , Thompson Elizabeth D. , Hruban Ralph H. , Olive Kenneth P. , Feinberg Andrew P.
Published: May 2023

Supplementary figures and captions for supplementary tables
Supplementary Table 3 from ANO1 Reprograms Cholesterol Metabolism and the Tumor Microenvironment to Promote Cancer Metastasis
Authors: Deng Chun-Miao , Zhang Guo-Geng , Liu Qin-Wen , Xu Jiao-Jiao , Liu Zhi-Chao , Yang Jing , Xu Tao-Yang , Li Zhi-Gang , Zhang Fan , Li Bin
Published: May 2023

Supplementary Table 3 shows DEGs between ESCC primary tumors and matched lymph node metastatic tumors
Supplementary Figures from Extrachromosomal Amplification of Human Papillomavirus Episomes Is a Mechanism of Cervical Carcinogenesis
Authors: Rossi Nicole M. , Dai Jieqiong , Xie Yi , Wangsa Darawalee , Heselmeyer-Haddad Kerstin , Lou Hong , Boland Joseph F. , Yeager Meredith , Orozco Roberto , Freites Enrique Alvirez , Mirabello Lisa , Gharzouzi Eduardo , Dean Michael
Published: May 2023

Supplementary figures
Data from DAB2IP is a bifunctional tumor suppressor that regulates wildtype RAS and inflammatory cascades in KRAS mutant colon cancer
Authors: Miller Abigail L. , Perurena Naiara , Gardner Alycia , Hinoue Toshinori , Loi Patrick , Laird Peter W. , Cichowski Karen
Published: May 2023

Abstract
The DAB2IP tumor suppressor encodes a RAS GTPase-activating protein (RASGAP). Accordingly, DAB2IP has been shown to be mutated or suppressed in tumor types that typically lack RAS mutations. However, here we report that DAB2IP is mutated or selectively silenced in the vast majority of KRAS and BRAF mutant CRCs. In this setting, DAB2IP loss promoted tumor development by activating wild-type H- and NRAS proteins, which was surprisingly required to achieve robust activation of RAS effector pathways in KRAS-mutant tumors. DAB2IP loss also triggered production of inflammatory mediators and the recruitment of pro-tumorigenic macrophages in vivo. Importantly, tumor growth was suppressed by depleting macrophages or inhibiting cytokine/inflammatory mediator expression with a JAK/TBK1 inhibitor. In human tumors DAB2IP was lost at early stages of tumor development, and its depletion was associated with an enrichment of macrophage and inflammatory signatures. Together, these findings demonstrate that DAB2IP restrains the activation of the RAS pathway and inflammatory cascades in the colon and that its loss represents a common and unappreciated mechanism for amplifying these two critical oncogenic signals in colorectal cancer.
Data from DAB2IP Is a Bifunctional Tumor Suppressor That Regulates Wild-Type RAS and Inflammatory Cascades in KRAS Mutant Colon Cancer
Authors: Miller Abigail L. , Perurena Naiara , Gardner Alycia , Hinoue Toshinori , Loi Patrick , Laird Peter W. , Cichowski Karen
Published: May 2023

Abstract
The DAB2IP tumor suppressor encodes a RAS GTPase-activating protein. Accordingly, DAB2IP has been shown to be mutated or suppressed in tumor types that typically lack RAS mutations. However, here we report that DAB2IP is mutated or selectively silenced in the vast majority of KRAS and BRAF mutant colorectal cancers. In this setting, DAB2IP loss promoted tumor development by activating wild-type H- and N-RAS proteins, which was surprisingly required to achieve robust activation of RAS effector pathways in KRAS-mutant tumors. DAB2IP loss also triggered production of inflammatory mediators and the recruitment of protumorigenic macrophages in vivo. Importantly, tumor growth was suppressed by depleting macrophages or inhibiting cytokine/inflammatory mediator expression with a JAK/TBK1 inhibitor. In human tumors, DAB2IP was lost at early stages of tumor development, and its depletion was associated with an enrichment of macrophage and inflammatory signatures. Together, these findings demonstrate that DAB2IP restrains the activation of the RAS pathway and inflammatory cascades in the colon and that its loss represents a common and unappreciated mechanism for amplifying these two critical oncogenic signals in colorectal cancer.
Significance:
DAB2IP is lost in early-stage tumors, which amplifies RAS signaling, triggers inflammatory mediators, and recruits macrophages in KRAS-mutant colon cancers.
Data from ANO1 Reprograms Cholesterol Metabolism and the Tumor Microenvironment to Promote Cancer Metastasis
Authors: Deng Chun-Miao , Zhang Guo-Geng , Liu Qin-Wen , Xu Jiao-Jiao , Liu Zhi-Chao , Yang Jing , Xu Tao-Yang , Li Zhi-Gang , Zhang Fan , Li Bin
Published: May 2023

Abstract
Tumor metastasis is a complex process. A better understanding of the mechanistic underpinnings of the metastatic cascade could uncover approaches to better prevent and target metastases. Here, we integrated transcriptomic profiling in primary esophageal squamous cell carcinoma (ESCC) and matched lymph node metastatic tissues and genome-wide CRISPR/Cas9 functional screening to identify the key drivers of cancer metastasis. Anoctamin 1 (ANO1) expression was found to be elevated in primary tumors and further increased in metastatic tissues. High expression of ANO1 was associated with poor patient survival, and ANO1 overexpression promoted cancer invasion and metastasis. Mechanistically, ANO1 inactivated the LXR pathway and increased intracellular cholesterol accumulation by interacting with JUN to repress the transcription of cholesterol hydroxylase, CYP27A1. In a paracrine manner, IL1β secreted from ANO1-expressing ESCC cancer cells activated NF-κB signaling in fibroblasts to stimulate production of the chemokine CCL1, which in turn enhanced invasion of ESCC cancer cells. Furthermore, molecular docking and in silico screening of 1,500,000 small molecules identified K786–4469 as a lead compound that targeted ANO1 and suppressed cancer metastasis in vitro and in vivo. Overall, these findings uncover a noncanonical function of ANO1 in regulating cholesterol metabolism and fibroblast function, revealing ANO1 as a potential prognostic biomarker and therapeutic target for metastatic ESCC.
Significance:
Metastatic cancer cells upregulate ANO1 to activate cell-intrinsic and -extrinsic mechanisms that alter cholesterol metabolism and stimulate fibroblasts, which can be targeted with ANO1 inhibitors to inhibit metastatic growth.

See related commentary by Singh and Mehla, p. 1759
Data from Large B-cell Lymphomas of Immune-Privileged Sites Relapse via Parallel Clonal Evolution from a Common Progenitor B Cell
Authors: Los-de Vries G. Tjitske , Stathi Phylicia , Rutkens Ryanne , Hijmering Nathalie J. , Luijks Jeroen A.C.W. , Groenen Patricia J.T.A. , de Jong Daphne , Ylstra Bauke , Roemer Margaretha G.M.
Published: May 2023

Abstract
Large B-cell lymphoma of immune-privileged sites (LBCL-IP) arise in immune sanctuaries including the testis and central nervous system (CNS). After initially reaching complete response, relapses occur in almost 50% of patients, typically at other immune-privileged sites. Resolution of the clonal relationships and evolutionary patterns of LBCL-IP is required to understand the unique clinical behavior. We collected a unique set of 33 primary–relapse LBCL-IP sample pairs and performed next-generation sequencing for copy number, mutation, translocation, and immunoglobulin clonality analysis. All LBCL-IP sample pairs were clonally related, and both tumors developed from a common progenitor cell (CPC) with MYD88 and TBL1XR1 mutations and/or BCL6 translocations in 30/33 cases, indicating that these are early genetic events. This was succeeded by intermediate genetic events including shared, as well as unique alterations in targets of aberrant somatic hypermutation (aSHM), CD79B mutations, and 9p21.3/CDKN2A loss. Genetic alterations in genes involved in immune escape (HLA, CD274/PDCD1LG2) were predominantly unique in primary and relapse samples and thus considered late genetic events. Together, this study indicates that primary and relapsed LBCL-IP follow an early parallel evolutionary pattern where the CPC contains genetic alterations that support prolonged survival/proliferation and retention in a memory B-cell state, followed by germinal center reentry, aSHM and immune escape.
Significance:
Genomic analyses reveal that primary and relapse LBCL-IP originate from a common progenitor cell with a small set of genetic alterations, followed by extensive parallel diversification, elucidating the clonal evolution of LBCL-IP.
Data from Extrachromosomal Amplification of Human Papillomavirus Episomes Is a Mechanism of Cervical Carcinogenesis
Authors: Rossi Nicole M. , Dai Jieqiong , Xie Yi , Wangsa Darawalee , Heselmeyer-Haddad Kerstin , Lou Hong , Boland Joseph F. , Yeager Meredith , Orozco Roberto , Freites Enrique Alvirez , Mirabello Lisa , Gharzouzi Eduardo , Dean Michael
Published: May 2023

Abstract
HPV16 is the most oncogenic type of human papillomaviruses (HPV). Integration of HPV into the human genome is an important mechanism of carcinogenesis but is absent in at least 30% of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors to characterize HPV16 carcinogenesis in the absence of integration. Large tandem arrays of full-length and unique truncated viral genomes integrated into multiple chromosomes were identified in two HPV16+ cell lines. The dispersion of characteristic viral variants to multiple integration sites indicates that viral deletions formed as extrachromosomal DNA (a phenomenon we term HPV superspreading). In addition, we identified an HPV16+ cell line with unintegrated (episomal) DNA that has tandem arrays of full-length, truncated, and rearranged HPV16 genomes (multimer episomes). Cytogenetic analysis of this cell line shows intense extrachromosomal HPV staining, including structures resembling double-minute chromosomes. WGS of HPV16+ cervical tumor samples from Latin America revealed that 11 of 20 tumors with only episomal HPV (EP) had intact monomer episomes. The remaining nine EP tumors had multimer and rearranged HPV genomes. The majority (80%) of HPV rearrangements and deletions disrupted the E1 and E2 genes, and EP tumors overexpressed the E6 and E7 viral oncogenes, a similar profile to tumors with HPV integration. Tumors with putative multimer HPV integrations display HPV multimers and concatemers of human and viral sequences. Our data uncovered a novel mechanism for HPV16 to cause cancer without integration through aberrant episomal replication, forming rearranged, mutated, and multimer episomes.
Significance:
Multimers of the HPV genome are generated in cervical tumors replicating as extrachromosomal episomes, which is associated with deletion and rearrangement of the HPV genome and provides a mechanism for oncogenesis without integration.
Data from Preclinical profile of BYON3521 predicts an effective and safe c-MET-antibody-drug conjugate
Authors: Groothuis Patrick G. , Jacobs Daniëlle C.H. , Hermens Inge A.T. , Damming Désirée , Berentsen Kim , Mattaar-Hepp Ellen , Stokman Marloes E.M. , Van Boekel Tinie , Rouwette Myrthe , Van der Vleuten Monique A.J. , Sesink Aloys , Dijcks Fred A. , Coumans Ruud G.E. , Schouten Jan , Glaudemans Dirk H. , van Wijk Daniëlle , Blomenröhr Marion , Kappers Wendela A. , Ubink Ruud , Van der Lee Miranda M.C. , Dokter Wim H.A.
Published: May 2023

Abstract
c-MET, the cell-surface receptor for the hepatocyte growth factor/scatter factor (HGF/SF), which is widely overexpressed in various solid cancer types, is an attractive target for the development of antibody-based therapeutics. BYON3521 is a novel site-specifically conjugated duocarmycin-based ADC, comprising a humanized cysteine-engineered IgG1 monoclonal antibody with low pM binding affinity towards both human and cynomolgus c-MET. In vitro studies showed that BYON3521 internalizes efficiently upon c-MET binding and induces both target- and bystander-mediated cell killing. BYON3521 showed good potency and full efficacy in MET-amplified and high c-MET-expressing cancer cell lines; in moderate and low c-MET-expressing cancer cell lines good potencies and partial efficacy were observed. In mouse xenograft models, BYON3521 showed significant anti-tumor activity upon single dose administration in multiple non-MET-amplified tumor types with low, moderate and high c-Met expression, including complete tumor remissions in models with moderate c-MET expression. In the repeat-dose GLP safety assessment in cynomolgus monkeys, BYON3521 was well tolerated and based on the observed toxicities and their reversibility, the highest non-severely toxic dose (HNSTD) was set at 15 mg/kg. A human pharmacokinetics (PK) model was derived from the PK data from the cynomolgus safety assessments, and the minimal efficacious dose in humans is estimated to be in the range of 3-4 mg/kg. In all, our nonclinical data suggests that BYON3521 is a safe ADC with potential for clinical benefit in patients. A first-in-human dose escalation study is currently ongoing to determine the maximum tolerated dose and recommended dose for expansion (NCT05323045).
Data from 3D-informed targeting of the Trop-2 signal-activation site drives selective cancer vulnerability
Authors: Guerra Emanuela , Trerotola Marco , Relli Valeria , Lattanzio Rossano , Tripaldi Romina , Ceci Martina , Boujnah Khouloud , Pantalone Ludovica , Sacchetti Andrea , Havas Kristina M. , Simeone Pasquale , Travali Nicole , Querzoli Patrizia , Pedriali Massimo , Roversi Pietro , Iezzi Manuela , Tinari Nicola , Antolini Laura , Alberti Saverio
Published: May 2023

Abstract
Next-generation Trop-2-targeted therapy against advanced cancers is hampered by expression of Trop-2 in normal tissues. We discovered that Trop-2 undergoes proteolytic activation by ADAM10 in cancer cells, leading to the exposure of a previously inaccessible protein groove flanked by two N-glycosylation sites. We designed a recognition strategy for this region, to drive selective cancer vulnerability in patients. Most undiscriminating anti-Trop-2 monoclonal antibodies (mAb) recognize a single immunodominant epitope. Hence, we removed it by deletion-mutagenesis. Cancer-specific, glycosylation-prone mAb were selected by ELISA, bio-layer interferometry, flow cytometry, confocal microscopy for differential binding to cleaved/activated, wild-type and glycosylation-site-mutagenized Trop-2. The resulting 2G10 mAb family binds Trop-2-expressing cancer cells, but not Trop-2 on normal cells. We humanized 2G10 by state-of-the-art CDR grafting/re-modeling, yielding Hu2G10. This antibody binds cancer-specific, cleaved/activated Trop-2 with Kd <10-12 M, and uncleaved/wtTrop-2 in normal cells with Kd 3.16x10-8 M, thus promising an unprecedented therapeutic index in patients. In vivo, Hu2G10 ablates growth of Trop-2-expressing breast, colon, prostate cancers, but shows no evidence of systemic toxicity, paving the way for a paradigm shift in Trop-2-targeted therapy.
Supplementary Figure 3 from MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2
Authors: Markovits Ettai , Harush Ortal , Baruch Erez N. , Shulman Eldad D. , Debby Assaf , Itzhaki Orit , Anafi Liat , Danilevsky Artem , Shomron Noam , Ben-Betzalel Guy , Asher Nethanel , Shapira-Frommer Ronnie , Schachter Jacob , Barshack Iris , Geiger Tamar , Elkon Ran , Besser Michal J. , Markel Gal
Published: May 2023

Supplementary Figure 3
Data from IL12/18/21 pre-activation enhances the anti-tumor efficacy of expanded γδT cells and overcomes resistance to anti-PD-L1 treatment
Authors: Teo Huey Yee , Song Yuan , Yong Kylie Su Mei , Liu Yonghao , Mei Yu , Hanafi Zuhairah Binte. , Zhu Ying , Chua Yen Leong , Gascoigne Nicholas R.J. , Chen Qingfeng , Liu Haiyan
Published: May 2023

Abstract
γδT cells are promising candidates for cellular immunotherapy due to their immune regulation through cytokine production and MHC-independent direct cytotoxicity against a broad spectrum of tumors. However, current γδT cell-based cancer immunotherapy has limited efficacy, and novel strategies are needed to improve clinical outcomes. Here, we report that cytokine pre-treatment with IL12/18, IL12/15/18, IL12/18/21, and IL12/15/18/21 effectively enhanced the activation and cytotoxicity of in vitro-expanded murine and human γδT cells. However, only adoptive transfer of IL12/18/21 pre-activated γδT cells significantly inhibited tumor growth in a murine melanoma model and a hepatocellular carcinoma model. Both IL12/18/21 pre-activated antibody-expanded and zoledronate-expanded human γδT cells effectively controlled tumor growth in a humanized mouse model. IL12/18/21 pre-activation promoted γδT cell proliferation and cytokine production in vivo and enhanced IFNγ production and activation of endogenous CD8+ T cells in a cell-cell contact- and ICAM-1-dependent manner. Furthermore, the adoptive transfer of IL12/18/21 pre-activated γδT cells could overcome the resistance to anti-PD-L1 therapy, and the combination therapy had a synergistic effect on the therapeutic outcomes. Moreover, the enhanced anti-tumor function of adoptively transferred IL12/18/21 pre-activated γδT cells was largely diminished in the absence of endogenous CD8+ T cells when administered alone or in combination with anti-PD-L1, suggesting a CD8+ T cell-dependent mechanism. Taken together, IL12/18/21 pre-activation can promote γδT cell anti-tumor function and overcome the resistance to checkpoint blockade therapy, indicating an effective combinational cancer immunotherapeutic strategy.
FIGURE 6 from Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy
Authors: Sah Vasu R. , Jespersen Henrik , Karlsson Joakim , Nilsson Lisa M. , Bergqvist Mattias , Johansson Iva , Carneiro Ana , Helgadottir Hildur , Levin Max , Ullenhag Gustav , Ståhlberg Anders , Olofsson Bagge Roger , Nilsson Jonas A. , Ny Lars
Published: May 2023

IHC magenta showing low mag of CD20 varied staining of TLS-like (borderline-tertiary lymphoid structures) followed by high magnification images of CD20, CD3, CCL21 within serial sections for Pt 2-027 (A), 3-010 (B). Also see Supplementary Fig. S5. Low and high magnification images of CD20+ TLS-like staining for Pt. 2-026 (C) and no TLS sample Pt. 4-017 (D). Kaplan–Meier analysis showing PFS (E) and OS (F), respectively dividing patient population into two groups based on IHC, no-TLS (n = 4) and TLS-like (n = 18). Also see Supplementary Fig. S5. G, Heatmap showing top 10% genes with highest log2 fold change, among all positively and negatively significantly regulated genes comparing no-TLS and TLS-like groups using bulk RNA-seq (log2 Reads Per Kilobase per Million mapped reads [RPKM] normalized values). Arrows represent relevant TLS-based gene signatures. Genes with FDR-adjusted P values <0.05 were considered statistically significant. H, Individual box plots showing CCL19, CCL21, CCR7, and CD79A changes in expression between the groups. Statistical tests were carried out using DESeq2 and FDR-adjusted P values were denoted with *, P < 0.05; **, P < 0.01; ***, P < 0.001.
História Literária antes de 1922, o caso de Ronald de Carvalho
Authors: Gagliardi Laura Rivas
Published: May 2023

Relegado a mero documento histórico, o volume Pequena história da literatura brasileira (1919), de Ronald de Carvalho, tem ganhado recentemente novas leituras. Os movimentos que levaram ao abandono e à revitalização de Pequena história serão iluminados aqui a partir da análise de trechos da obra e de documentos que compõem o panorama de sua recepção. A aura modernista que se colou a Ronald de Carvalho depois de sua participação na Semana de Arte Moderna de 1922 se expandiu para a Pequena história, produzida, contudo, nos moldes do conservadorismo academista contra o qual parte dos integrantes da Semana se voltava. Esse conservadorismo não foi superado na edição revista pelo autor, lançada postumamente em 1937 e parece não ser um dado relevante nas últimas reconsiderações feitas da obra.
Entre poemas e poesias: reflexões sobre a tradução de Meus poemas não mudarão o mundo
Authors: Alves Cláudia Tavares
Published: May 2023

Considerando que o ato de traduzir é um exercício de escolhas que implicam aspectos positivos e negativos, este artigo pretende refletir sobre a experiência de tradução, para o português brasileiro, de Le mie poesie non cambieranno il mondo (Einaudi, 1974), Meus poemas não mudarão o mundo (Edições Jabuticaba, 2021), de Patrizia Cavalli. As sutilezas e ironias das ambientações cavallianas – verbalizadas através da oralidade dos convívios rotineiros – precisaram ser recriadas na tradução para serem recebidas em outro tempo-espaço, buscando assim estabelecer por vezes um novo sentido para seus jogos lexicais, mas conservando tanto quanto possível seu efeito estético-poético original. Nesse sentido, desenhou-se uma travessia entre a poesia italiana e a tradução brasileira, sustentada, entre outros fatores, pela identificação de sensações compartilhadas, mas também por processos de diferenciação, que revelavam bagagens culturais muito próprias de cada país. A experiência aqui relatada se alinha a uma perspectiva que entende a tradução poética como um conjunto de escolhas que visam constituir uma atmosfera de trocas entre a voz do eu-lírico dos poemas e a voz desse eu-outro da língua de chegada, confiando na hipótese de que essa é uma troca possível e praticável, apesar das dificuldades e subjetividades intrínsecas ao processo.
Life’s Essential 8, Genetic Susceptibility, and Incident Cardiovascular Disease: A Prospective Study
Authors: Li Xiang , Ma Hao , Wang Xuan , Feng Han , Qi Lu
Published: May 2023

Background:

The American Heart Association recently released a new cardiovascular health (CVH) metric, Life’s Essential 8 (LE8), for health promotion. However, the association between levels of LE8 and the risk of cardiovascular disease (CVD) outcomes is not known from a large prospective cohort. We aim to analyze the relationship between CVH, indicated by LE8, and risks of coronary heart disease (CHD), stroke, and CVD. Moreover, we sought to test whether the genetic susceptibility to CHD or stroke could be modified by LE8.

Methods:

A total of 137 794 participants free of CVD from the UK Biobank were included. CVH was scored using LE8 and categorized as low, moderate, and high.

Results:

During a median of 10 years, 8595 CVD cases (6968 CHDs and 1948 strokes) were documented. A higher LE8 score was associated with remarkably lower risks of CHD, stroke, and CVD (
P
<0.001 for all). Comparing the high CVH to the low CVH, the hazard ratios (95% CI) were 0.34 (0.30–0.38) for CHD, 0.45 (0.37–0.54) for stroke, and 0.36 (0.33–0.40) for CVD. Moreover, the model with LE8 achieved higher accuracy and outperformed the model with Life’s Simple 7 for CHD, stroke, and CVD (
P
<0.001 for all). The protective associations of the LE8 score with CVD outcomes were more pronounced among women (
P
interaction, <0.001 for CHD and 0.0013 for CVD, respectively) and among younger adults (
P
interaction, <0.001, 0.007, and <0.001 for CHD, stroke, and CVD, respectively). In addition, a significant interaction was found between the genetic risk of CHD and the LE8 score (
P
interaction, <0.001). The inverse association was stronger among those with a lower genetic risk of CHD.

Conclusions:

High level of CVH, defined by LE8, was associated with significantly lower risks of CHD, stroke, and CVD.
Tongue-flicking: an idiosyncratic displacement behaviour in a free-ranging and urban-dwelling population of Balinese long-tailed macaques
Authors: Chertoff Sydney , Wandia I Nengah , Leca Jean-Baptiste
Published: May 2023

This brief report describes the occurrence of an idiosyncratic behaviour, labelled tongue-flicking, that was performed by one subadult male long-tailed macaque living in a free-ranging population in Bali, Indonesia. Tongue-flicking may serve a similar purpose as a displacement behaviour in which the subject sticks his tongue out of his mouth and moves it either slightly up and down or in and out without bringing it all the way back into the mouth. Additionally, while abnormal behaviours in non-human animals are almost exclusively reported in captive individuals, the investigation of idiosyncratic behaviours such as tongue-flicking allows us to explore the potential occurrence of abnormal behaviours in free-ranging populations. This preliminary descriptive analysis of tongue-flicking aims to highlight the need for understanding the motivational bases and affective implications (e.g., welfare) of abnormal behaviours in captive and free-living animals.
Kinetic Energy Spectra and Spectral Budget of Radiative–Convective Equilibrium
Authors: Lai Kwan Tsaan , Waite Michael L.
Published: May 2023

The atmospheric kinetic energy spectrum and energy cascade are investigated in idealized simulations of radiative–convective equilibrium (RCE). WRF is employed to perform cloud-resolving simulations of an idealized radiative–convective equilibrium with and without aggregation with Δx = 4 km. The horizontal kinetic energy (HKE) spectrum for the aggregated simulation in the upper troposphere is steeper than the nonaggregated case and closer to −5/3. The HKE spectra for the nonaggregated simulation in the upper troposphere and the lower stratosphere are much shallower than the −5/3 spectrum. In the upper troposphere, the divergent kinetic energy has a similar magnitude to the rotational kinetic energy in both the nonaggregated simulation and aggregated simulation. Energy is mainly gained from the buoyancy flux and mainly lost from the vertical energy flux for scales larger than 20 km. Downscale energy transfer is found in the upper troposphere. Numerical dissipation is the main source of energy loss at small scales. In the lower stratosphere, the divergent kinetic energy dominates the kinetic energy spectrum in both simulations. Energy is mainly gained from the vertical energy flux and is balanced by the loss from the buoyancy flux term, transfer term, and dissipation. An Eliassen–Palm flux analysis suggests that wave–mean-flow interaction may be responsible for the upscale energy transfer found in the lower stratosphere. The magnitudes of our kinetic energy spectra are similar to spectra calculated from aircraft data. Rotation is found to promote aggregation and steepen the energy spectrum.
Varying Relationship between La Niña and SST Anomalies in the Kuroshio and Adjacent Regions during Boreal Winter: Role of the East Asian Winter Monsoon
Authors: Chen Sheng , Chen Jiepeng , Wang Xin , Xiao Ziniu
Published: May 2023

The winter sea surface temperature (SST) anomalies in the Kuroshio and adjacent regions (KAR), which greatly influence the East Asian–North Pacific–North American climate, are closely related to El Niño–Southern Oscillation (ENSO). This SST relationship between the KAR and the equatorial eastern-central Pacific is widely assumed to be symmetric between El Niño and La Niña. Compared to previous studies indicating the significant and strong KAR warming during El Niño winters, this study indicates weakly negative KAR SST anomalies in the composite analysis for all La Niña events. Positive winter KAR SST anomalies unexpectedly appear in approximately half of La Niña events, which counteract negative SST anomalies in the rest of La Niña events. Further analysis suggests that the impact of La Niña on KAR SST anomalies is modulated by the East Asian winter monsoon (EAWM) during early winter. The weaker-than-normal EAWM offsets the anomalous northeasterly winds in the KAR induced by La Niña and then reinforces the KAR warming through warm oceanic advection. As for strong EAWM, it enhances the northeasterly winds to the west of an anomalous Philippine Sea cyclone associated with La Niña, leading to KAR cooling with more latent heat flux loss from the ocean and anomalous cold oceanic advection. Additionally, when the EAWM is independent of ENSO and is associated with the western Pacific pattern, it also can exhibit a pronounced influence on the KAR SST anomalies via the major processes of surface latent flux and horizontal heat advection in the ocean, accompanied by a change in Kuroshio transport.

Significance Statement

The interannual variability of SST from Philippine Sea to the Kuroshio and adjacent regions is considered an important forecast factor of the eastern China climate. Previous studies have reported a dipole SST pattern with Philippine Sea cooling and warming in the Kuroshio and adjacent regions during El Niño winter is dominant, and simply regarded that the effect of La Niña on western North Pacific SST anomalies was a mirror image of that of El Niño events. Here, we have found two distinctive SST patterns in the western North Pacific during La Niña winter. One type is the dipole SST pattern, characterized by Philippine Sea warming and by cooling in the Kuroshio and adjacent regions. The other type is the monopole SST pattern with uniform warming expanding from the Philippine Sea to the Kuroshio and adjacent regions. The dipole (monopole) SST pattern in western North Pacific is modulated by La Niña and a strong (weak) EAWM. Analysis shows that the above two SST patterns during La Niña winter are equally important during 1950–2021. This study has identified the influence of the EAWM independent of ENSO on the SST anomalies in the Kuroshio and adjacent regions.
Molecular characteristics of carbapenem-resistant gram-negative bacilli in pediatric patients in China
Authors: Yin Lijun , Lu Lu , He Leiyan , Lu Guoping , Cao Yun , Wang Laishuan , Zhai Xiaowen , Wang Chuanqing
Published: May 2023

Background

Carbapenem-resistant gram-negative bacilli (CR-GNB) have been increasingly reported in China. However, dynamic monitoring data on molecular epidemiology of CR-GNB are limited in pediatric patients.

Results

300 CR-GNB isolates (200 Carbapenem-resistant K. pneumoniae (CRKP), 50 carbapenem-resistant A.baumannii (CRAB) and 50 carbapenem-resistant P. aeruginosa (CRPA)) were investigated. The predominant carbapenemase gene was blaNDM−1 (73%) and blaKPC−2 (65%) in neonates and non-neonates. Meanwhile, the predominant STs were ST11 (54%) in neonates and ST17 (27.0%) and ST278 (20.0%) in non-neonates. Notably, a shift in the dominant sequence type of CRKP infections from ST17 /ST278-NDM-1 to ST11-KPC-2 was observed during the years 2017–2021 and KPC-KP showed relatively higher resistance to aminoglycosides and quinolones than NDM-KP.BlaOXA−23 was isolated from all the CRAB isolates while only one isolate expressing blaBIC and 2 isolates expressing blaVIM−2 were found in CRPA isolates. ST195 (22.0%) and ST244 (24.0%) were the most common in CRAB and CRPA isolates and all the STs of CRAB belonged to CC92 while CRPA presents ST types with diversity distribution.

Conclusion

CRKP showed different molecular phenotypes in neonates and non-neonates and was changing dynamically and high-risk clone of ST11 KPC-KP should be paid more attention. Most CRKP and CRAB strains shared the same CCs, suggesting that intrahospital transmission may occur, and large-scale screening and more effective measures are urgently needed.
Leaf litter chemistry and its effects on soil microorganisms in different ages of Zanthoxylum planispinum var. Dintanensis
Authors: Song Yanping , Yu Yanghua , Li Yitong , Du Mingfeng
Published: May 2023

Background

Leaf litter is the products of metabolism during the growth and development of plantation, and it is also an important component of nutrient cycling in plantation ecosystems. However, leaf litter chemistry and its effects on soil microorganisms in different ages, as well as the interactions between chemical components in leaf litter have been rarely reported. Based on this, this paper took Zanthoxylum planispinum var. dintanensis (hereafter Z. planispinum) plantations of 5–7, 10–12, 20–22, and 28–32 years old as the objects. By using one-way ANOVA, Pearson correlation analysis and redundancy analysis, we investigated leaf litter chemistry and its effects on soil microorganisms in different ages, and to reveal internal correlation of various chemical components in leaf litter, which can provide a scientific basis for the regulation of soil microbial activity in plantations.

Results

The variation of organic carbon with plantation age was more stable compared to total nitrogen and phosphorus of leaf litter. Nitrogen resorption was stronger than phosphorus resorption efficiency in Z. planispinum, and resorption efficiencies of leaf nitrogen and phosphorus for different ages were lower than the global average. Total nitrogen was highly significantly positively correlated with lignin, and total potassium was significantly positively correlated with tannin, suggesting the increase of inorganic substances in leaf litter would promote the accumulation of secondary metabolites. The leaf litter chemical traits explained up to 72% of soil microorganisms, where lignin was positively correlated with fungi and negatively correlated with bacteria, indicating that fungi are able to decompose lower quality litter and can break down complex and stable organic compounds more rapidly than bacteria. The nutrient elements carbon and nitrogen in the leaf litter and their interrelationship also have a great impact on soil microorganisms, because carbon is not only the element that provides energy, but also the element with the largest content in the microbiota.

Conclusions

The sustained increase in inorganic nutrients of leaf litter did not favor the decomposition of secondary metabolites, but rather inhibited the degradation of leaf litter. The significant positive effect of the leaf litter chemistry on soil microorganisms indicates the important role of leaf litter in promoting nutrient cycling in Z. planispinum plantations.
Joint effect of human papillomavirus exposure, smoking and alcohol on risk of oral squamous cell carcinoma
Authors: Yang Zheng , Sun Peng , Dahlstrom Kristina R. , Gross Neil , Li Guojun
Published: May 2023

Background

Smoking, alcohol consumption, and human papillomavirus (HPV) infection are known risk factors for oral squamous cell carcinoma (OSCC) including SCC of oropharynx (SCCOP) and SCC of oral cavity (SCCOC). Researchers have examined each of these risk factors independently, but few have observed the potential risk of their interaction. This study investigated the interactions among these risk factors and risk of OSCC.

Methods

Totally 377 patients with newly diagnosed SCCOP and SCCOC and 433 frequency-matched cancer-free controls by age and sex were included. Multivariable logistic regression was performed to calculate ORs and 95% CIs.

Results

We found that overall OSCC risk was independently associated with smoking (adjusted OR(aOR), 1.4; 95%CI, 1.0–2.0), alcohol consumption (aOR, 1.6; 95%CI, 1.1–2.2), and HPV16 seropositivity (aOR, 3.3; 95%CI, 2.2–4.9), respectively. Additionally, we found that HPV16 seropositivity increased the risk of overall OSCC in ever-smokers (aOR, 6.8; 95%CI, 3.4–13.4) and ever-drinkers (aOR, 4.8; 95%CI, 2.9–8.0), while HPV16-seronegative ever-smokers and ever-drinkers had less than a twofold increase in risk of overall OSCC (aORs, 1.2; 95%CI, 0.8–1.7 and 1.8; 95%CI, 1.2–2.7, respectively). Furthermore, the increased risk was particularly high for SCCOP in HPV16-seropositive ever-smokers (aOR, 13.0; 95%CI, 6.0–27.7) and in HPV16-seropositive ever-drinkers (aOR, 10.8; 95%CI, 5.8–20.1), while the similar increased risk was not found in SCCOC.

Conclusion

These results suggest a strong combined effect of HPV16 exposure, smoking, and alcohol on overall OSCC, which may indicate a strong interaction between HPV16 infection and smoking and alcohol consumption, particularly for SCCOP.