bluuebunny/crossref_metadata_2025 huggingface dataset:
Fully Kernected Neural Networks
Authors: Zhang Wei , Han Zhi , Chen Xiai , Liu Baichen , Jia Huidi , Tang Yandong
Published: June 2023

In this paper, we apply kernel methods to deep convolutional neural network (DCNN) to improve its nonlinear ability. DCNNs have achieved significant improvement in many computer vision tasks. For an image classification task, the accuracy comes to saturation when the depth and width of network are enough and appropriate. The saturation accuracy will not rise even by increasing the depth and width. We find that improving nonlinear ability of DCNNs can break through the saturation accuracy. In a DCNN, the former layer is more inclined to extract features and the latter layer is more inclined to classify features. Therefore, we apply kernel methods at the last fully connected layer to implicitly map features to a higher-dimensional space to improve nonlinear ability so that the network achieves better linear separability. Also, we name the network as fully kernected neural networks (fully connected neural networks with kernel methods). Our experiment result shows that fully kernected neural networks achieve higher classification accuracy and faster convergence rate than baseline networks.
Learning Attentional Communication with a Common Network for Multiagent Reinforcement Learning
Authors: Yu Wenwu , Wang Rui , Hu Xiaohui
Published: June 2023

For multiagent communication and cooperation tasks in partially observable environments, most of the existing works only use the information contained in hidden layers of a network at the current moment, limiting the source of information. In this paper, we propose a novel algorithm named multiagent attentional communication with the common network (MAACCN), which adds a consensus information module to expand the source of communication information. We regard the best‐performing overall network in the historical moment for agents as the common network, and we extract consensus knowledge by leveraging such a network. Especially, we combine current observation information with the consensus knowledge to infer more effective information as input for decision‐making through the attention mechanism. Experiments conducted on the StarCraft multiagent challenge (SMAC) demonstrate the effectiveness of MAACCN in comparison to a set of baselines and also reveal that MAACCN can improve performance by more than 20% in a super hard scenario especially.
Development of a Novel Vaccine Candidates against Cardiobacterium valvarum through Reverse Vaccinology and Computational Approaches
Authors: Albaqami Faisal F. , Altharawi Ali , Althurwi Hassan N. , Alharthy Khalid M. , Tahir ul Qamar Muhammad , Muhseen Ziyad Tariq , Iqbal Madiha
Published: June 2023

Antibiotic resistance is a major public health concern that has resulted in high healthcare costs, increased mortality, and the emergence of novel bacterial diseases. Cardiobacterium valvarum, an antibiotic‐resistant bacterium, is one of the leading causes of heart disease. Currently, there is no licensed vaccination against C. valvarum. In this research, an in silico‐based vaccine was designed against C. valvarum using reverse vaccinology, bioinformatics, and immunoinformatics techniques. 4206 core proteins, 2027 nonredundant proteins, and 2179 redundant proteins were predicted. Among nonredundant proteins, 23 proteins were predicted in an extracellular membrane, 30 in the outer membrane, and 62 in the periplasmic membrane region. After applying several subtractive proteomics filters, two proteins, TonB‐dependent siderophore receptor and hypothetical protein, were chosen for epitope prediction. In the epitope selection phase, B and T‐cellepitopes were analyzed and shortlisted for vaccine design. The vaccine model was designed by linking selected epitopes with GPGPG linkers to avoid flexibility. Furthermore, the vaccine model was linked to cholera toxin B adjuvant to induce a proper immune response. The docking approach was utilized to analyze binding affinity to immune cell receptors. Molecular docking results predicted 12.75 kcal/mol for a Vaccine with MHC‐I, 6.89 for a vaccine with MHC‐II, and 19.51 vaccine with TLR‐4. The MMGBSA estimated ‐94, ‐78, and ‐76 kcal/mol for TLR‐4 and vaccine, MHC‐I and vaccine, and MHC‐II and vaccine, while the MMPBSA analysis estimated ‐97, ‐61, and ‐72 kcal/mol for TLR‐4 with the vaccine, MHC‐I with vaccine, and MHC‐II with a vaccine. Molecular dynamic simulation analysis revealed that the designed vaccine construct has proper stability with immune cell receptors as it is essential for inducing an immune response. In conclusion, we observed that the model vaccine candidate has the potency to induce an immune response in the host. However, the study is designed purely on a computational basis; hence, experimental validation is strongly recommended.
Optimization of Edible Coating Formulation Using Response Surface Methodology for Delaying the Ripening and Preserving Tomato (Solanum lycopersicum) Fruits
Authors: Tchouala Tazo Franck Laurins , Kanmegne Gabriel , Ngotio Tchinda Alain , Kenfack Odelonne Justine , Tafré Phounzong Eugéne
Published: June 2023

Tomato is a climacteric fruit that has a short shelf life under natural conditions. However, some treatments can be applied in order to extend the shelf life and improve the quality of fruits. The present study aimed at formulating a coating solution based on coffee leaf extract, starch, and Gum Arabic in order to extend the postharvest shelf life of tomato. The response surface methodology (RSM) was used to determine the optimal concentrations of the different abovementioned components in the coating, for better delay the ripening process of tomatoes. The central composite design (CCD) was generated, and the effect of different factors on the shelf life and quality (percent ripening, firmness, physiological loss of mass, pH, chlorophylls a and b contents, lycopene, and β-carotene contents) of tomato fruits were determined 14 days after treatment and stored at room temperature. Chlorophyll a and chlorophyll b contents as well as firmness of treated fruits were higher than those of control fruits. In addition, treated fruits recorded low lycopene and β-carotene contents, physiological loss of mass, pH, and ripening percentage compared to control fruits. Coffee leaf extract had a significant effect (

p
<
0.05

) on chl a content, pH, and ripening percentage. On the other hand, starch and Gum Arabic did not significantly (

p
>
0.05

) influence pH, physiological loss of mass, and percentage of ripening. The interaction between coffee leaf extract and starch (X1X2) had the most significant effect (

p
<
0.05

) on the studied parameters. The results showed that the experimental data could be adequately fitted into a second-order polynomial model with coefficients of determination greater than 80% for all variables studied. The optimal coating formulation consisted of 78.5 g/l coffee leaves extract, 56 g/l starch, and 9.5% Gum Arabic. There was no significant difference between the experimental and predicted data.
Virtual Machine Replica Placement Using a Multiobjective Genetic Algorithm
Authors: Mohamed Marwa F. , Dahshan Mai , Li Kenli , Salah Ahmad
Published: June 2023

Virtual machine (VM) replication is a critical task in any cloud computing platform to ensure the availability of the cloud service for the end user. In this task, one primary VM resides on a physical machine (PM) and one or more replicas reside on separate PMs. In cloud computing, VM placement (VMP) is a well‐studied problem in terms of different goals, such as power consumption reduction. The VMP problem can be solved by using heuristics, namely, first‐fit and meta‐heuristics such as the genetic algorithm. Despite extensive research into the VMP problem, there are few works that consider VM replication when choosing a VMP. In this context, we proposed studying the problem of optimal VMP considering VM replication requirements. The proposed work frames the problem at hand as a multiobjective problem and adapts a nondominated sorting genetic algorithm (NSGA‐III) to address the problem. VM replicas’ placement should consider several dimensions such as the geographical distance between the PM hosting the primary VM and the other PMs hosting the replicas. In addition, to this end, the proposed model aims to minimize (1) power consumption, (2) performance degradation, and (3) the distance between the PMs hosting the primary VM and its replica(s). The proposed method is thoroughly tested on a variety of computing environments with various heterogeneous VMs and PMs, including compute‐intensive and memory‐intensive environments. The obtained results illustrate the performance disparity between the adapted NSGA‐III and MOEA/D methods and other methods of comparison, including heuristic and meta‐heuristic approaches, with NSGA‐III outperforming other comparison methods. For instance, in memory‐intensive and in heterogeneous environments, the NSGA‐III method’s performance was superior to the first‐fit, next‐fit, best‐fit, PSO, and MOEA/D methods by 58%, 62%, 64%, 55%, and 31%, respectively.
Material Characteristics and Electrical Performance of Perovskite Solar Cells with Different Carbon-Based Electrodes Mixed with CuSCN
Authors: Barruna Elang , Saniah Atya , Rahman Siti Fauziyah , Poespawati Nji Raden
Published: June 2023

Perovskite solar cells are the most cutting-edge photovoltaic technology having high efficiency and short fabrication time. In recent decades, there has been a significant rise in the study of the usage of carbon materials in perovskite solar cells because of low cost and earth abundance. Several studies have been conducted to mix hole transport materials with carbon materials to improve the hole extraction capability. Nevertheless, no research has reported using CuSCN on different carbon electrodes on perovskite solar cells. In this research, various carbon materials, including carbon nanotubes (CNT), graphite, activated carbon, and reduced graphene oxide (rGO), are mixed with CuSCN. The carbon materials and CuSCN were mixed by ball mill and then deposited using the doctor blading method to become an electrode layer. The existence of CuSCN in carbon materials was proved by conducting the energy dispersive X-ray test. CNT mixed with CuSCN material exhibits the highest electrical conductivity indicated by ID/IG ratio of 1.22 using Raman spectroscopy. Perovskite solar cell with a mix of CNT and CuSCN electrode exhibits the lowest series resistance of 76.69 Ω, resulting in the optimum solar cell performance such as a short-circuit current density (JSC) of 0.199 mA/cm2, open-circuit voltage (VOC) of 0.52 V, fill-factor (FF) of 0.369, and efficiency of 0.0735.
Figure S5 from A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galvan Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: June 2023

Supplementary Figure S5. Decision tree algorithm to construct the multiparameter classifier of response in PAMELA.
Figure S3 from A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galvan Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: June 2023

Supplementary Figure S3. Distribution of intrinsic subtypes in (A) TBCRC023 and (B) PAMELA cohort.
Supplementary Fig. 3 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling
Authors: Ghukasyan Razmik , Liang Keke , Chau Kevin , Li Luyi , Chan Charlotte , Abt Evan R. , Le Thuc , Park Joon Y. , Wu Nanping , Premji Alykhan , Damoiseaux Robert , Luu Tony , Labora Amanda , Rashid Khalid , Link Jason M. , Radu Caius G. , Donahue Timothy R.
Published: June 2023

Supplementary Fig. 3 MEK inhibition amplifies STING-induced transcription of IFNB1, IL-6, and TNFA in multiple PDAC cell lines.
Supplementary Data 1 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling
Authors: Ghukasyan Razmik , Liang Keke , Chau Kevin , Li Luyi , Chan Charlotte , Abt Evan R. , Le Thuc , Park Joon Y. , Wu Nanping , Premji Alykhan , Damoiseaux Robert , Luu Tony , Labora Amanda , Rashid Khalid , Link Jason M. , Radu Caius G. , Donahue Timothy R.
Published: June 2023

Supplementary Resources and Table
Supplementary Table S1 from A Bifunctional PARP-HDAC Inhibitor with Activity in Ewing Sarcoma
Authors: Ramos Louise , Truong Sarah , Zhai Beibei , Joshi Jay , Ghaidi Fariba , Lizardo Michael M. , Shyp Taras , Kung Sonia H.Y. , Rezakhanlou Alireza M. , Oo Htoo Zarni , Adomat Hans , Le Bihan Stephane , Collins Colin , Bacha Jeffrey , Brown Dennis , Langlands John , Shen Wang , Lallous Nada , Sorensen Poul H. , Daugaard Mads
Published: June 2023

Blood cell panel counts and weight loss percentage of in vivo toxicity study
Supplementary Figure S4 from A Bifunctional PARP-HDAC Inhibitor with Activity in Ewing Sarcoma
Authors: Ramos Louise , Truong Sarah , Zhai Beibei , Joshi Jay , Ghaidi Fariba , Lizardo Michael M. , Shyp Taras , Kung Sonia H.Y. , Rezakhanlou Alireza M. , Oo Htoo Zarni , Adomat Hans , Le Bihan Stephane , Collins Colin , Bacha Jeffrey , Brown Dennis , Langlands John , Shen Wang , Lallous Nada , Sorensen Poul H. , Daugaard Mads
Published: June 2023

Replicate data of DNA damage assays
Figure S2 from BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer
Authors: Lim Sun Min , Fujino Toshio , Kim Chulwon , Lee Gwanghee , Lee Yong-Hee , Kim Dong-Wan , Ahn Jin Seok , Mitsudomi Tetsuya , Jin Taiguang , Lee Sang-Yoon
Published: June 2023

Supplementary Figure 2. Activity of BBT-176 in EGFR WT and EGFR exon 20 insertion models.
Data from BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer
Authors: Lim Sun Min , Fujino Toshio , Kim Chulwon , Lee Gwanghee , Lee Yong-Hee , Kim Dong-Wan , Ahn Jin Seok , Mitsudomi Tetsuya , Jin Taiguang , Lee Sang-Yoon
Published: June 2023

AbstractPurpose:
Resistance to third-generation EGFR inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting the C797S mutation.
Patients and Methods:
Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells, and patient-derived xenografts expressing mutant EGFRs were used to test the inhibitory potency and the anticancer efficacy of BBT-176 both in vitro and in vivo. Patient case data are also available from an ongoing phase I clinical trial (NCT04820023).
Results:
The half maximal inhibitory concentration (IC50) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S proteins were measured at 4.36, 1.79, and 5.35 nmol/L, respectively (vs. 304.39, 124.82, and 573.72 nmol/L, for osimertinib). IC50 values of BBT–176 against Ba/F3 cells expressing EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, EGFR L858R/C797S, and EGFR L858R/T790M/C797S were 42, 49, 183, and 202 nmol/L, respectively (vs. 869, 1,134, 2,799, and 2,685 nmol/L for osimertinib). N-ethyl-N-nitrosourea mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the EGFR gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT-176 effectively suppressed the growth of BBT-176–resistant clones. BBT-176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients harboring EGFR 19Del/T790M/C797S in blood showed tumor shrinkage and radiologic improvements.
Conclusions:
BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKI, with early clinical efficacy and safety.
Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma
Authors: Lee Juyeun , Nicosia Michael , Hong Ellen S. , Silver Daniel J. , Li Cathy , Bayik Defne , Watson Dionysios C. , Lauko Adam , Kay Kristen E. , Wang Sabrina Z. , Johnson Sadie , McGraw Mary , Grabowski Matthew M. , Kish Danielle D. , Desai Amar B. , Goodman Wendy A. , Cameron Scott J. , Okada Hideho , Valujskikh Anna , Fairchild Robert L. , Ahluwalia Manmeet S. , Lathia Justin D.
Published: June 2023

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti–PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell–mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response.

Significance:

Immunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM.

See related commentary by Alspach, p. 1966.

This article is featured in Selected Articles from This Issue, p. 1949
Supplementary Table S8 from Immunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function
Authors: Renauer Paul , Park Jonathan J. , Bai Meizhu , Acosta Arianny , Lee Won-Ho , Lin Guang Han , Zhang Yueqi , Dai Xiaoyun , Wang Guangchuan , Errami Youssef , Wu Terence , Clark Paul , Ye Lupeng , Yang Quanjun , Chen Sidi
Published: June 2023

Supplementary Table S8
Supplementary Table S3 from Immunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function
Authors: Renauer Paul , Park Jonathan J. , Bai Meizhu , Acosta Arianny , Lee Won-Ho , Lin Guang Han , Zhang Yueqi , Dai Xiaoyun , Wang Guangchuan , Errami Youssef , Wu Terence , Clark Paul , Ye Lupeng , Yang Quanjun , Chen Sidi
Published: June 2023

Supplementary Table S3
Supplementary Table S2 from Immunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function
Authors: Renauer Paul , Park Jonathan J. , Bai Meizhu , Acosta Arianny , Lee Won-Ho , Lin Guang Han , Zhang Yueqi , Dai Xiaoyun , Wang Guangchuan , Errami Youssef , Wu Terence , Clark Paul , Ye Lupeng , Yang Quanjun , Chen Sidi
Published: June 2023

Supplementary Table S2
Supplementary Video 2 from Metronomic administration of topotecan alone and in combination with docetaxel inhibits epithelial-mesenchymal transition in aggressive variant prostate cancers
Authors: MITRA GHOSH TARASWI , Mazumder Suman , Davis Joshua , YADAV JYOTI , AKINPELU AYUBA , ALNAIM AHMED , KUMAR HARISH , WALIAGHA RAZAN , Church Bird Allison E , Rais-Bahrami Soroush , Bird R. Curtis , Mistriotis Panagiotis , MISHRA AMARJIT , Yates Clayton C. , MITRA AMIT K , Arnold Robert D
Published: June 2023

Supplementary Video 2
Supplementary Figure 8 from Metronomic administration of topotecan alone and in combination with docetaxel inhibits epithelial-mesenchymal transition in aggressive variant prostate cancers
Authors: MITRA GHOSH TARASWI , Mazumder Suman , Davis Joshua , YADAV JYOTI , AKINPELU AYUBA , ALNAIM AHMED , KUMAR HARISH , WALIAGHA RAZAN , Church Bird Allison E , Rais-Bahrami Soroush , Bird R. Curtis , Mistriotis Panagiotis , MISHRA AMARJIT , Yates Clayton C. , MITRA AMIT K , Arnold Robert D
Published: June 2023

Supplementary Fig. 8 shows Flow Cytometry; Prostate cancer cell lines stained with stemness markers (CD44, CD133 and CD44/133) to determine the percent of CD44+, CD133+ and double positive cells among PCa subtypes. 
Treatments with CONV-TOPO, METRO-TOPO and CONV-DTX+METRO-TOPO reduced stemness. METRO-TOPO reduced CD44+ cells to a greater extent compared to CONV-TOPO and CONV-DTX treatments, whereas combination treatment with CONV-DTX+METRO-TOPO reduced stemness (CD44+ cells) the most in ARHigh/mCRPC/NEPC. A) PC-3M, B) DU145 cell lines.
Supplementary Figure 1 from Metronomic administration of topotecan alone and in combination with docetaxel inhibits epithelial-mesenchymal transition in aggressive variant prostate cancers
Authors: MITRA GHOSH TARASWI , Mazumder Suman , Davis Joshua , YADAV JYOTI , AKINPELU AYUBA , ALNAIM AHMED , KUMAR HARISH , WALIAGHA RAZAN , Church Bird Allison E , Rais-Bahrami Soroush , Bird R. Curtis , Mistriotis Panagiotis , MISHRA AMARJIT , Yates Clayton C. , MITRA AMIT K , Arnold Robert D
Published: June 2023

Supplementary Fig. 1 shows Differentially expressed gene signature (DEGs) based on next gene sequencing (mRNA sequencing) for ARLow /mCRPC/NEPC (PC-3, PC-3M, DU145) vs ARHigh /mCSPC (LNCaP, VCAP, 22RV1) prostate cancer (PCa) cell lines and normal prostate cell lines RWPE1 and RWPE2.

Volcano plots representing mRNA expression for all cell lines. (blue p<0.05 and gray>0.05)
HeatMap representing Differentially Expressed Gene Signature (DEGs) for ARLow/mCRPC/NEPC (PC-3, PC-3M, DU145) vs ARHigh/mCSPC (LNCaP, VCAP, 22RV1) PCa and normal prostate cell lines RWPE1 and RWPE2 (FDR<0.05 and TOP-100).
Supplementary Methods 1 from Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer
Authors: Cecchini Michael , Zhang Janie Y. , Wei Wei , Sklar Jeffrey , Lacy Jill , Zhong Minghao , Kong Yong , Zhao Hongyu , DiPalermo Jassim , Devine Lesley , Stein Stacey M. , Kortmansky Jeremy , Johung Kimberly L. , Bindra Ranjit S. , LoRusso Patricia , Schalper Kurt A.
Published: June 2023

Supplementary Methods 1: Clinical trial protocol.
Data from Metronomic administration of topotecan alone and in combination with docetaxel inhibits epithelial-mesenchymal transition in aggressive variant prostate cancers
Authors: MITRA GHOSH TARASWI , Mazumder Suman , Davis Joshua , YADAV JYOTI , AKINPELU AYUBA , ALNAIM AHMED , KUMAR HARISH , WALIAGHA RAZAN , Church Bird Allison E , Rais-Bahrami Soroush , Bird R. Curtis , Mistriotis Panagiotis , MISHRA AMARJIT , Yates Clayton C. , MITRA AMIT K , Arnold Robert D
Published: June 2023

Abstract
Prostate cancer (PCa) is the second leading cause of non-cutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and radiation therapy remain the primary treatment for early-stage PCa patients (castration-sensitive: CSPC). Following ADT, many patients ultimately develop metastatic castration-resistant PCa (mCRPC). Standard chemotherapy options for CRPC are Docetaxel (DTX) and Cabazitaxel (CBZ), which increase median survival, although the development of resistance is common. Cancer-stem-like cells possess mesenchymal phenotypes (EMT) and play crucial roles in tumor initiation and progression of mCRPC. We have shown that low-dose continuous administration of topotecan (METRO-TOPO) inhibits PCa growth by interfering with key cancer-pathway genes. This study utilized bulk and single-cell or whole-transcriptome analysis (RNA-sequencing and scRNAseq), and we observed greater expression of several EMT markers, including VIM, HAS3, S100A6, TGFB1, CD44, CD55, and CD109 in European American and African American aggressive variant PCa (AVPC) subtypes - mCRPC, neuroendocrine variant (NEPC), and taxane-resistant. The taxane-resistant gene FSCN1 was also expressed highly in single-cell sub-clonal populations in mCRPC. Further, metronomic-topotecan single-agent and combinations with DTX downregulated these EMT markers as well as CD44+ and CD44+/CD133+ “stem-like” cell populations. A microfluidic chip-based cell invasion assay revealed that METRO-TOPO treatment as a single-agent or in combination with DTX was potentially effective against invasive PCa spread. Our RNAseq and scRNAseq analysis were supported by in silico and in vitro studies, suggesting METRO-TOPO combined with DTX may inhibit oncogenic progression by reducing cancer stemness in AVPC through the inhibition of EMT markers and multiple oncogenic factors/pathways.
Data from Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer
Authors: Cecchini Michael , Zhang Janie Y. , Wei Wei , Sklar Jeffrey , Lacy Jill , Zhong Minghao , Kong Yong , Zhao Hongyu , DiPalermo Jassim , Devine Lesley , Stein Stacey M. , Kortmansky Jeremy , Johung Kimberly L. , Bindra Ranjit S. , LoRusso Patricia , Schalper Kurt A.
Published: June 2023

Purpose:
O6-methylguanine DNA methyltransferase (MGMT)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer.
Experimental Design:
Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m2 days 1–7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers.
Results:
MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8+ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2). Flow cytometry identified peripheral expansion of effector T cells.
Conclusions:
Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8+ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations.
Significance:
TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.
Mitochondrial GSNOR Alleviates Cardiac Dysfunction via ANT1 Denitrosylation
Authors: Tang Xin , Zhao Shuang , Liu Jieqiong , Liu Xiameng , Sha Xinqi , Huang Changgao , Hu Lulu , Sun Shixiu , Gao Yuanqing , Chen Hongshan , Zhang Zhiren , Wang Dongjin , Gu Yuexi , Chen Shaoliang , Wang Liansheng , Gu Aihua , Chen Feng , Pu Jun , Chen Xin , Yu Bo , Xie Liping , Huang Zhengrong , Han Yi , Ji Yong
Published: June 2023

BACKGROUND:

The cardiac-protective role of GSNOR (S-nitrosoglutathione reductase) in the cytoplasm, as a denitrosylase enzyme of S-nitrosylation, has been reported in cardiac remodeling, but whether GSNOR is localized in other organelles and exerts novel effects remains unknown. We aimed to elucidate the effects of mitochondrial GSNOR, a novel subcellular localization of GSNOR, on cardiac remodeling and heart failure (HF).

METHODS:

GSNOR subcellular localization was observed by cellular fractionation assay, immunofluorescent staining, and colloidal gold particle staining. Overexpression of GSNOR in mitochondria was achieved by mitochondria-targeting sequence-directed adeno-associated virus 9. Cardiac-specific knockout of GSNOR mice was used to examine the role of GSNOR in HF. S-nitrosylation sites of ANT1 (adenine nucleotide translocase 1) were identified using biotin-switch and liquid chromatography-tandem mass spectrometry.

RESULTS:

GSNOR expression was suppressed in cardiac tissues of patients with HF. Consistently, cardiac-specific knockout mice showed aggravated pathological remodeling induced by transverse aortic constriction. We found that GSNOR is also localized in mitochondria. In the angiotensin II–induced hypertrophic cardiomyocytes, mitochondrial GSNOR levels significantly decreased along with mitochondrial functional impairment. Restoration of mitochondrial GSNOR levels in cardiac-specific knockout mice significantly improved mitochondrial function and cardiac performance in transverse aortic constriction–induced HF mice. Mechanistically, we identified ANT1 as a direct target of GSNOR. A decrease in mitochondrial GSNOR under HF leads to an elevation of S-nitrosylation ANT1 at cysteine 160 (C160). In accordance with these findings, overexpression of either mitochondrial GSNOR or ANT1 C160A, non-nitrosylated mutant, significantly improved mitochondrial function, maintained the mitochondrial membrane potential, and upregulated mitophagy.

CONCLUSIONS:

We identified a novel species of GSNOR localized in mitochondria and found mitochondrial GSNOR plays an essential role in maintaining mitochondrial homeostasis through ANT1 denitrosylation, which provides a potential novel therapeutic target for HF.
NGAL is a Novel Target in Hypertension by Modulating the NCC-Mediated Renal Na Balance
Authors: Bonnard Benjamin , El Moghrabi Soumaya , Ueda Kohei , Lattenist Lionel , Soulie Matthieu , López-Andrés Natalia , Xhaard Constance , Shimosawa Tatsuo , Rossignol Patrick , Jaisser Frédéric
Published: June 2023

BACKGROUND:

The expression of NGAL/lcn2 (neutrophil gelatinase-associated lipocalin) is directly modulated by mineralocorticoid receptor activation but its role in blood pressure control is unclear.

METHODS:

a potential relationship between NGAL plasma levels, systolic blood pressure and urinary Na excretion was assessed in the STANISLAS cohort. The specific role of NGAL/lcn2 in salt-sensitive hypertension was studied using lcn2-knockout mice (lcn2 KO) fed with low-Na diet (0Na).

RESULTS:

we show that NGAL plasma levels positively correlate with systolic blood pressure, whereas they negatively correlate with urinary Na excretion in subjects of the STANISLAS cohort. Prolonged feeding of lcn2 KO mice with a 0Na diet induced lower systolic blood pressure than that of the control group (wildtype), suggesting a role for NGAL/lcn2 in Na-balance homeostasis. Short-term or prolonged 0Na increased Na-Cl cotransporter (NCC) phosphorylation in the cortex of wildtype mice, which was prevented in lcn2 KO mice. Recombinant mouse lcn2 injections in lcn2 KO mice induced NCC phosphorylation in the kidney cortex, associated with decreased urinary Na excretion. Ex vivo experiments using kidney slices from lcn2 KO mice showed increased NCC phosphorylation by recombinant murine lcn2. In addition, recombinant murine lcn2 induced activation of CamK2β (calcium/calmodulin-dependent protein kinase II β subunit) phosphorylation in lcn2 KO mice and in kidney slices, providing an underlying mechanism involved in lcn2-induced NCC phosphorylation. Indeed, the inhibition of CamK2β prevented NCC phosphorylation induced by recombinant lcn2 in kidney slices.

CONCLUSIONS:

we highlight a novel role of NGAL/lcn2 as a modulator of the activity of the renal sodium transporter NCC affecting salt-sensitive blood pressure
Computer-Aided Composition Using a Sound-Based Notation
Authors: Sköld Mattias
Published: June 2023

This article describes the music data format of the recently introduced Sound Notation system, and how it makes possible computer-aided composition of scores representing sound-based music. The Sound Notation system is an adaptation of Lasse Thoresen's spectromorphological analysis notation, developed for composition and analysis. A detailed description of the data format is followed by two examples of its application in a computer-aided composition process resulting in the sounding interpretation of two score excerpts of an electroacoustic composition. Generating sound structures as symbolic notation data in this way provided possibilities for the creation of sound-based music otherwise limited to works of traditional notation.
Protestant Hermeneutics and the Persistence of Moral Meanings in Early Modern Natural Histories
Authors: Blank Andreas
Published: June 2023

Peter Harrison explains the disappearance of symbolic meanings of animals from seventeenth-century works in natural history through what he calls the “literalist mentality of the reformers.” By contrast, the present article argues in favor of a different understanding of the connection between hermeneutics and Protestant natural history. Martin Luther, Philipp Melanchthon, Johannes Brenz, Johannes Oecolampadius, and Jean Calvin continued to assign moral meanings to natural particulars, and moral interpretations can still be found in the writings of Protestant naturalists such as Conrad Gesner, Caspar Heldelinus, Jeremias Wilde, Thomas Penny, and Thomas Moffett. If there are differences between Protestant and Catholic interpretations of animals, then these differences derive from the reformer’s greater insistence on providing textual support for assigning symbolic meanings, their resulting greater reluctance in assigning prophetic meanings to animals, and their elimination of spiritual interpretations of animals that are in tension with central tenets of Protestant theology. These differences in hermeneutics and theology may explain some of the divergences between the symbolic interpretations of animals proposed by Protestant natural historians and their Catholic colleague, Ulisse Aldrovandi.
Impetus aestheticus. Baumgarten on Physics and Aesthetics
Authors: Nannini Alessandro
Published: June 2023

In this essay, I analyze the role of physics in Baumgarten’s founding of aesthetics. After examining for the first time his courses on physics and their relationship with aesthetics, I explore the importance of physical metaphors in the issues of aesthetic experiments and aesthetic enthusiasm, with special regard to the influence of Bacon, Boyle, and Leibniz’s doctrine of vis viva.
Atmospheric Response to Antarctic Sea-Ice Reductions Drives Ice Sheet Surface Mass Balance Increases
Authors: Trusel Luke D. , Kromer Jessica D. , Datta Rajashree Tri
Published: June 2023

The mass balance of the Antarctic ice sheet is intricately linked to the state of the surrounding atmosphere and ocean. As a direct result, improving projections of future sea level change requires understanding change in the Antarctic atmosphere and Southern Ocean, and the processes that couple these systems. Here, we examine the influence of sea ice cover on the overlying atmosphere and subsequently the surface mass balance (SMB) of the adjacent Antarctic ice sheet. We investigate these processes both over the observational era using the ERA5 atmospheric reanalysis and in ensemble simulations of the Community Earth System Model 2.1 (CESM2) where only sea ice coverage is altered. Comparing extreme high and low sea ice over the satellite era in ERA5 reveals atmospheric and ice sheet SMB anomalies that largely mirror anomalies simulated by CESM2 in response to sea ice loss. Results highlight significant near-surface atmospheric warming in response to sea ice reductions that are particularly pronounced in nonsummer seasons and driven by significant ocean-to-atmosphere turbulent heat fluxes. In areas of sea ice loss, significant ocean surface evaporation increases occur. On the eastern flank of climatological low pressure systems, moisture is readily advected toward the ice sheet, driving positive anomalies in the ice sheet SMB. These results indicate that underestimation of Antarctic sea ice, which is common in many current-generation coupled climate models, may lead to overestimation of the ice sheet SMB and therefore underestimation of Antarctica’s contributions to global sea level.

Significance Statement

The Antarctic ice sheet is the largest potential source of global sea level rise. Its sea level contributions depend in part on how much snow accumulates across its surface. Through observation-incorporating reanalysis data and climate model sensitivity studies, we find that Southern Ocean sea ice coverage exerts an important influence on the near-surface climate and mass balance of the Antarctic ice sheet. Our results show that reductions in Antarctic sea ice promote enhanced ocean surface evaporation and subsequent increases in snowfall across the Antarctic ice sheet. Because current climate models tend to simulate too little Antarctic sea ice, we conclude they may therefore overestimate Antarctic ice sheet snowfall, leading to underprediction of future sea level rise.
Hashtag nationalism: a discursive and networked digital activism
Authors: He Renyi
Published: June 2023

Shinzo Abe, Japan’s former and longest-serving prime minister was assassinated on 8 July 2022. As the world expressed sorrow of the human tragedy, nationalists in China were celebrating the disappearance of a hardline Chinese hawk with great enthusiasm. When a Chinese journalist sobbed for Abe’s death during a live report of the assassination, the surging anti-Japan sentiment exploded and soon developed into a hashtag-based nationalist protest attacking Abe and the journalist. Drawing from cyber nationalism and hashtag activism literature, the author coined a concept ‘hashtag nationalism’ to analyze this protest﻿, the interactions between state-led nationalism and popular nationalism, and the role of digital media in the public-state relation. This article also generalized three affordances of hashtag – interconnectivity, intertextuality, and interdiscursivity – to approach the role of social media in digital activism from a relational perspective. Finally, the analysis revealed the discursive and networked nature of hashtag nationalism.
A new framework for metabolic connectivity mapping using bolus [18F]FDG PET and kinetic modeling
Authors: Volpi Tommaso , Vallini Giulia , Silvestri Erica , Francisci Mattia De , Durbin Tony , Corbetta Maurizio , Lee John J , Vlassenko Andrei G , Goyal Manu S , Bertoldo Alessandra
Published: June 2023

Metabolic connectivity (MC) has been previously proposed as the covariation of static [18F]FDG PET images across participants, i.e., across-individual MC (ai-MC). In few cases, MC has been inferred from dynamic [18F]FDG signals, i.e., within-individual MC (wi-MC), as for resting-state fMRI functional connectivity (FC). The validity and interpretability of both approaches is an important open issue. Here we reassess this topic, aiming to 1) develop a novel wi-MC methodology; 2) compare ai-MC maps from standardized uptake value ratio ( SUVR) vs. [18F]FDG kinetic parameters fully describing the tracer behavior (i.e., Ki, K1, k3); 3) assess MC interpretability in comparison to structural connectivity and FC. We developed a new approach based on Euclidean distance to calculate wi-MC from PET time-activity curves. The across-individual correlation of SUVR, Ki, K1, k3 produced different networks depending on the chosen [18F]FDG parameter ( k3 MC vs. SUVR MC, r = 0.44). We found that wi-MC and ai-MC matrices are dissimilar (maximum r = 0.37), and that the match with FC is higher for wi-MC (Dice similarity: 0.47–0.63) than for ai-MC (0.24–0.39). Our analyses demonstrate that calculating individual-level MC from dynamic PET is feasible and yields interpretable matrices that bear similarity to fMRI FC measures.
Association between time-dependent changes in cerebrovascular autoregulation after cardiac arrest and outcomes: A prospective cohort study
Authors: Tachino Jotaro , Nonomiya Yuta , Taniuchi Satsuki , Shintani Ayumi , Nakao Shunichiro , Takegawa Ryosuke , Hirose Tomoya , Sakai Tomohiko , Ohnishi Mitsuo , Shimazu Takeshi , Shiozaki Tadahiko
Published: June 2023

This prospective observational single-center cohort study aimed to determine an association between cerebrovascular autoregulation (CVAR) and outcomes in hypoxic-ischemic brain injury post-cardiac arrest (CA), and assessed 100 consecutive post-CA patients in Japan between June 2017 and May 2020 who experienced a return of spontaneous circulation. Continuous monitoring was performed for 96 h to determine CVAR presence. A moving Pearson correlation coefficient was calculated from the mean arterial pressure and cerebral regional oxygen saturation. The association between CVAR and outcomes was evaluated using the Cox proportional hazard model; non-CVAR time percent was the time-dependent, age-adjusted covariate. The non-linear effect of target temperature management (TTM) was assessed using a restricted cubic spline. Of the 100 participants, CVAR was detected using the cerebral performance category (CPC) in all patients with a good neurological outcome (CPC 1–2) and in 65 patients (88%) with a poor outcome (CPC 3–5). Survival probability decreased significantly with increasing non-CVAR time percent. The TTM versus the non-TTM group had a significantly lower probability of a poor neurological outcome at 6 months with a non-CVAR time of 18%–37% (p < 0.05). Longer non-CVAR time may be associated with significantly increased mortality in hypoxic-ischemic brain injury post-CA.
Effects of atorvastatin and rosuvastatin on dysfunctional coronary circulation in patients with ST-segment elevation myocardial infarction
Authors: Zhou Langping , Hu Xiangming , Zhang Haotian , Lu Haoyu , Lin Yan , Wang Weimian , Yu Bingyan , Liang Wensheng , Zhou Yingling , Li Guang , Dong Haojian
Published: June 2023

Objective

Evidence of therapy for dysfunctional coronary circulation in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) is limited. This study was performed to compare the effects of atorvastatin and rosuvastatin on dysfunctional coronary circulation.

Methods

This retrospective study enrolled 597 consecutive patients with STEMI who underwent pPCI in 3 centers from June 2016 to December 2019. Dysfunctional coronary circulation was defined by the thrombolysis in myocardial infarction (TIMI) grade and the TIMI myocardial perfusion grade (TMPG). Logistic regression analysis was used to evaluate the impact of different statin types on dysfunctional coronary circulation.

Results

The incidence of TIMI no/slow reflow did not differ between the two groups, but the incidence of TMPG no/slow reflow was significantly lower in the atorvastatin than rosuvastatin group (44.58% vs. 57.69%, respectively). After multivariate adjustment, the odds ratio with 95% confidence interval of rosuvastatin was 1.72 (1.17–2.52) for after pretreatment TMPG no/slow reflow and 1.73 (1.16–2.58) for after stenting TMPG no/slow reflow. Atorvastatin and rosuvastatin showed no significant differences in clinical outcomes during hospitalization.

Conclusions

Compared with rosuvastatin, atorvastatin was associated with better coronary microcirculatory perfusion in patients with STEMI who underwent pPCI.
Evidence for Modal Inertia in Multimodal Tours: An Integrated Choice and Latent Variable Modeling Approach
Authors: Jabbari Parastoo , Khan Nazmul Arefin , MacKenzie Don
Published: June 2023

In this paper, we aim to answer two main questions in the context of multimodal travel and new modes of transportation, such as autonomous vehicles: firstly, as travelers gain the ability to readily compare modes side by side for each trip, will they become more willing to select the option that best meets their needs in the moment, or will they continue to prefer using a single mode for a whole tour? Secondly, we compare two approaches to estimating mode choice models in the context of a typical workday tour: one in which we enumerate each possible sequence of modes, and one in which we calculate the expected utility given all modes available for each trip separately, and sum over all trips in the tour. We find that the latter approach returns similar estimation results to the former, but is much faster and easier to compute, an advantage that would only grow with more mode alternatives or more trips in the tour. In addition, we discovered a substantial “mode inertia” in our sample: the utility of the mode used for the previous trip is significantly higher for the present trip. This finding indicates that respondents in our sample are more likely to stick with unimodal tours than multimodal ones.
Safe, Efficient, and Comfortable Reinforcement-Learning-Based Car-Following for AVs with an Analytic Safety Guarantee and Dynamic Target Speed
Authors: ElSamadisy Omar , Shi Tianyu , Smirnov Ilia , Abdulhai Baher
Published: June 2023

Over the last decade, there has been rising interest in automated driving systems and adaptive cruise control (ACC). Controllers based on reinforcement learning (RL) are particularly promising for autonomous driving, being able to optimize a combination of criteria such as efficiency, stability, and comfort. However, RL-based controllers typically offer no safety guarantees. In this paper, we propose SECRM (the Safe, Efficient, and Comfortable RL-based car-following Model) for autonomous car-following that balances traffic efficiency maximization and jerk minimization, subject to a hard analytic safety constraint on acceleration. The acceleration constraint is derived from the criterion that the follower vehicle must have sufficient headway to be able to avoid a crash if the leader vehicle brakes suddenly. We critique safety criteria based on the time-to-collision (TTC) threshold (commonly used for RL controllers), and confirm in simulator experiments that a representative previous TTC-threshold-based RL autonomous-vehicle controller may crash (in both training and testing). In contrast, we verify that our controller SECRM is safe, in training scenarios with a wide range of leader behaviors, and in both regular-driving and emergency-braking test scenarios. We find that SECRM compares favorably in efficiency, comfort, and speed-following to both classical (non-learned) car-following controllers (intelligent driver model, Shladover, Gipps) and a representative RL-based car-following controller.