bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of the Effect of Ammonia Addition on the Two-Stage Ignition Process of Dimethyl Ether Based on Chemical Kinetic Analysis
Authors: Ou Juan , Yang Ruomiao , Yan Yuchao , Liu Zhentao , Liu Jinlong
Published: January 2024

Ammonia (NH3) has garnered considerable attention in recent years as a promising carbon-free hydrogen carrier fuel for internal combustion engines. However, directly using pure ammonia in compression-ignition engines poses challenges. To facilitate NH3 ignition, high-activity fuels are often employed to ignite the premixed NH3/air mixture and initiate combustion. This study specifically focuses on the ignition process of binary mixtures of NH3 and dimethyl ether (DME), considering that DME is a carbon-neutral high-activity fuel. By conducting zero-dimensional reaction kinetics analysis, we compare the ignition processes of DME and NH3/DME mixtures. The results reveal that the addition of NH3 has minimal impact on the control mechanism of DME’s two-stage ignition process. DME still heavily relies on the proliferation of OH radicals in the low-temperature oxidation pathway, releasing heat during the reaction progression. As the temperature increases, the low-temperature oxidation branching pathways are gradually replaced by chain propagation pathways, resulting in a decrease in overall reaction activity. The reactivity and temperature rise rate of the reaction system is then controlled by the H2O2 loop mechanism prior to the thermal ignition. However, the presence of ammonia noticeably extends the ignition delay period of DME. Ammonia competes with OH radicals, essential for DME oxidation, thereby inhibiting DME ignition. Additionally, as the ignition reaction advances, the involvement of NH3 kinetics increases. For instance, nitrogen-containing species generated from NH3 oxidation, such as NO, NO2, and NH2, react with CH3OCH2 to form CH3OCHO, reducing the flux through the low-temperature oxidation pathway of DME. While ammonia reaction pathways also generate OH radicals, this comes at the expense of HO2 radicals and H radicals, ultimately leading to H2O2 production. Overall, these findings clearly demonstrate the substantial impact of ammonia addition on the ignition process of DME, emphasizing the necessity for further fundamental research to enhance our understanding of NH3/DME binary fuel ignition. Such insights are pivotal for improving the design and operation strategies of NH3/DME dual-fuel engines, thereby improving engine efficiency and reliability.
Experimental Study and Analysis of Ultra-Low Temperature Fuel Spray With a Heavy-Duty Injector Under Vaporizing Conditions
Authors: Zhao Zhihao , Zhang Anqi , Schmidt Henry , Atkinson William , Naber Jeffrey
Published: January 2024

Despite efficiency and emission benefits, the Gasoline Compression Ignition (GCI) technology faces a key technical risk of deteriorated cold start performance. This study aims to provide experimental dataset and analysis of fuel sprays under ultra-low temperature (as low as −40 °C) adapted for GCI applications. Both RON92 gasoline and ultra-low sulfur diesel (ULSD) were tested in this study to investigate the effects of fuel properties and ambient conditions on the spray vaporization and mixing processes. The experiments were conducted in a constant-volume combustion vessel with various fuel temperatures, injection pressures, ambient densities, and charge gas temperatures, captured by simultaneous Mie scattering and schlieren imaging. A novel fuel chilling setup was introduced to control the fuel reservoir temperature by circulating of liquid-nitrogen-cooled methanol. Vapor penetration, liquid penetration, and spray cone angle from a heavy-duty multi-hole injector were obtained through image processing. The results showed comparable vapor penetration between RON92 and ULSD even with different fuel temperatures and charge gas temperatures. However, RON92 and ULSD differs in terms of liquid penetration at different ambient charge gas temperatures due to their different volatility. RON92 gasoline started to present saturated liquid length at 700K, while ULSD needed a higher temperature at 900K. A semi-quantitative analysis was practiced using single component surrogates to highlight the fuel volatility effect.
Spatial release from masking in the median plane with non-native speakers using individual and mannequin head related transfer functions
Authors: González-Toledo Daniel , Cuevas-Rodríguez María , Vicente Thibault , Picinali Lorenzo , Molina-Tanco Luis , Reyes-Lecuona Arcadio
Published: January 2024

Spatial release from masking (SRM) in speech-on-speech tasks has been widely studied in the horizontal plane, where interaural cues play a fundamental role. Several studies have also observed SRM for sources located in the median plane, where (monaural) spectral cues are more important. However, a relatively unexplored research question concerns the impact of head-related transfer function (HRTF) personalisation on SRM, for example, whether using individually-measured HRTFs results in better performance if compared with the use of mannequin HRTFs. This study compares SRM in the median plane in a speech-on-speech virtual task rendered using both individual and mannequin HRTFs. SRM is obtained using English sentences with non-native English speakers. Our participants show lower SRM performances compared to those found by others using native English participants. Furthermore, SRM is significantly larger when the source is spatialised using the individual HRTF, and this effect is more marked for those with lower English proficiency. Further analyses using a spectral distortion metric and the estimation of the better-ear effect, show that the observed SRM can only partially be explained by HRTF-specific factors and that the effect of the familiarity with individual spatial cues is likely to be the most significant element driving these results.
Learning from different disciplines
The Most Unknown
Ian Cheney, director
Vice/Motherboard, 2018, 88 minutes. Available on Netflix, August 2018.
Authors: Uzzi Brian
Published: January 2024

Conversations spark connections as scientists search for inspiration in other fields
Protecting the Achilles heel: three FolE_I-type GTP-cyclohydrolases needed for full growth of metal-resistant
Cupriavidus metallidurans
under a variety of conditions
Authors: Schulz Vladislava , Galea Diana , Herzberg Martin , Nies Dietrich H.
Published: January 2024

In
Cupriavidus metallidurans
and other bacteria, biosynthesis of the essential biochemical cofactor tetrahydrofolate (THF) initiates from guanosine triphosphate (GTP). This step is catalyzed by FolE_I-type GTP cyclohydrolases, which are either zinc-dependent FolE_IA-type or metal-promiscuous FolE_IB-type enzymes. As THF is also essential for GTP biosynthesis, GTP and THF synthesis form a cooperative cycle, which may be influenced by the cellular homeostasis of zinc and other metal cations. Metal-resistant
C. metallidurans
harbors one FolE_IA-type and two FolE_IB-type enzymes. All three proteins were produced in
Escherichia coli
. FolE_IA was indeed zinc dependent and the two FolE_IB enzymes metal-promiscuous GTP cyclohydrolases
in vitro
, the latter, for example, functioning with iron, manganese, or cobalt. Single and double mutants of
C. metallidurans
with deletions in the
folE_I
genes were constructed to analyze the contribution of the individual FolE_I-type enzymes under various conditions. FolE_IA was required in the presence of cadmium, hydrogen peroxide, metal chelators, and under general metal starvation conditions. FolE_IB1 was important when zinc uptake was impaired in cells without the zinc importer ZupT (ZIP family) and in the presence of trimethoprim, an inhibitor of THF biosynthesis. FolE_IB2 was needed under conditions of low zinc and cobalt but high magnesium availability. Together, these data demonstrate that
C. metallidurans
requires all three enzymes to allow efficient growth under a variety of conditions.

IMPORTANCE

Tetrahydrofolate (THF) is an important cofactor in microbial biochemistry. This “Achilles heel” of metabolism has been exploited by anti-metabolites and antibiotics such as sulfonamide and trimethoprim. Since THF is essential for the synthesis of guanosine triphosphate (GTP) and THF biosynthesis starts from GTP, synthesis of both compounds forms a cooperative cycle. The first step of THF synthesis by GTP cyclohydrolases (FolEs) is metal dependent and catalyzed by zinc- or metal-promiscuous enzymes, so that the cooperative THF and GTP synthesis cycle may be influenced by the homeostasis of several metal cations, especially that of zinc. The metal-resistant bacterium
C. metallidurans
needs three FolEs to grow in environments with both high and low zinc and cadmium content. Consequently, bacterial metal homeostasis is required to guarantee THF biosynthesis.
CREATE’ing improvements in first-year students’ science efficacy via an online introductory course experience
Authors: Garzke Jessica , Steinwand Blaire J.
Published: January 2024

With a primary objective to engage students in the process of science online, we transformed a long-standing laboratory course for first-year science students into a more accessible, immersive experience of current biological research using a narrow and focused set of primary literature and the Consider, Read, Elucidate a hypothesis, Analyze and interpret data, Think of the next Experiment (CREATE) pedagogy. The efficacy of the CREATE approach has been demonstrated in a diversity of higher education settings and courses. It is, however, not yet known if CREATE can be successfully implemented online with a large, diverse team of faculty untrained in the CREATE pedagogy. Here, we present the transformation of a large-enrollment, multi-section, multi-instructor course for first-year students in which the instructors follow different biological research questions but work together to reach shared goals and outcomes. We assessed students’ (i) science self-efficacy and (ii) epistemological beliefs about science throughout an academic year of instruction fully administered online as a result of ongoing threats posed by COVID-19. Our findings demonstrate that novice CREATE instructors with varying levels of teaching experience and ranks can achieve comparable outcomes and improvements in students’ science efficacy in the virtual classroom as a teaching team. This study extends the use of the CREATE pedagogy to large, team-taught, multi-section courses and shows its utility in the online teaching and learning environment.
Production of infectious reporter murine norovirus by VP2
trans
-complementation
Authors: Ishiyama Ryoka , Yoshida Kazuhiro , Oikawa Kazuki , Takai-Todaka Reiko , Kato Akiko , Kanamori Kumiko , Nakanishi Akira , Haga Kei , Katayama Kazuhiko
Published: January 2024

In this study, we revealed that some of the coding regions of ORF3 could be replaced by a foreign gene and infectious virus could be produced when VP2 was supplied. Propagation of this virus depended on VP2 being supplied
in trans
, indicating that this virus could infect only once. Our findings help to elucidate the functions of VP2 in the virus lifecycle and to develop other caliciviral vectors for recombinant attenuated live enteric virus vaccines or therapeutics tools.
Intrahepatic homeobox protein MSX-1 is a novel host restriction factor of hepatitis B virus
Authors: Shen Zhongliang , Zhang Shenyan , Gao Zixiang , Yu Xueping , Wang Jinyu , Pan Shaokun , Kang Ning , Liu Nannan , Xu Huijun , Liu Mu , Yang Yang , Deng Qiang , Liu Jing , Xie Youhua , Zhang Jiming
Published: January 2024

Covalently closed circular DNA plays a key role for the persistence of hepatitis B virus (HBV) since it serves as the template for viral transcription. Identification of transcription factors that regulate HBV transcription not only provides insights into molecular mechanisms of viral life cycle regulation but may also provide potential antiviral targets. In this work, we identified host MSX1 as a novel restriction factor of HBV transcription. Meanwhile, we observed higher intrahepatic MSX1 expression in chronic hepatitis B virus (CHB) patients in immune active phase compared to those in immune tolerant phase, suggesting possible involvement of MSX1 in the regulation of HBV activity by the host. Lastly, intrahepatic overexpression of MSX1 delivered by recombinant adenoviruses into two mouse models of HBV persistence demonstrated MSX1-mediated repression of HBV
in vivo
, and MSX1-induced clearance of intrahepatic HBV DNA in treated mice suggested its potential as a therapeutic target for the treatment of CHB.
The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer
Authors: Khalil Mohamed I. , Yang Canchai , Vu Lexi , Chadha Smriti , Nabors Harrison , James Claire D. , Morgan Iain M. , Pyeon Dohun
Published: January 2024

The human papillomavirus (HPV) oncoprotein E7 is a relatively short-lived protein required for HPV-driven cancer development and maintenance. E7 is degraded through ubiquitination mediated by cullin 1 (CUL1) and the ubiquitin-conjugating enzyme E2 L3 (UBE2L3). However, E7 proteins are maintained at high levels in most HPV-positive cancer cells. A previous proteomics study has shown that UBE2L3 and CUL1 protein levels are increased by the knockdown of the E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8). We have recently demonstrated that HPV16 upregulates MARCHF8 expression in HPV-positive keratinocytes and head and neck cancer (HPV+ HNC) cells. Here, we report that MARCHF8 stabilizes the HPV16 E7 protein by degrading the components of the S-phase kinase-associated protein 1-CUL1-F-box ubiquitin ligase complex in HPV+ HNC cells. We found that
MARCHF8
knockdown in HPV+ HNC cells drastically decreases the HPV16 E7 protein level while increasing the CUL1 and UBE2L3 protein levels. We further revealed that the MARCHF8 protein binds to and ubiquitinates CUL1 and UBE2L3 proteins and that MARCHF8 knockdown enhances the ubiquitination of the HPV16 E7 protein. Conversely, the overexpression of CUL1 and UBE2L3 in HPV+ HNC cells decreases HPV16 E7 protein levels and suppresses tumor growth
in vivo
. Our findings suggest that HPV-induced MARCHF8 prevents the degradation of the HPV16 E7 protein in HPV+ HNC cells by ubiquitinating and degrading CUL1 and UBE2L3 proteins.

IMPORTANCE

Since human papillomavirus (HPV) oncoprotein E7 is essential for virus replication; HPV has to maintain high levels of E7 expression in HPV-infected cells. However, HPV E7 can be efficiently ubiquitinated by a ubiquitin ligase and degraded by proteasomes in the host cell. Mechanistically, the E3 ubiquitin ligase complex cullin 1 (CUL1) and ubiquitin-conjugating enzyme E2 L3 (UBE2L3) components play an essential role in E7 ubiquitination and degradation. Here, we show that the membrane ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8) induced by HPV16 E6 stabilizes the E7 protein by degrading CUL1 and UBE2L3 and blocking E7 degradation through proteasomes. MARCHF8 knockout restores CUL1 and UBE2L3 expression, decreasing E7 protein levels and inhibiting the proliferation of HPV-positive cancer cells. Additionally, overexpression of CUL1 or UBE2L3 decreases E7 protein levels and suppresses
in vivo
tumor growth. Our results suggest that HPV16 maintains high E7 protein levels in the host cell by inducing MARCHF8, which may be critical for cell proliferation and tumorigenesis.
Whole-exome sequencing reveals causative genetic variants for several overgrowth syndromes in molecularly negative Beckwith-Wiedemann spectrum
Authors: Higashimoto Ken , Sun Feifei , Imagawa Eri , Saida Ken , Miyake Noriko , Hara Satoshi , Yatsuki Hitomi , Kubiura-Ichimaru Musashi , Fujita Atsushi , Mizuguchi Takeshi , Matsumoto Naomichi , Soejima Hidenobu
Published: January 2024

BackgroundBeckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by (epi)genetic alterations at 11p15. Because approximately 20% of patients test negative via molecular testing of peripheral blood leukocytes, the concept of Beckwith-Wiedemann spectrum (BWSp) was established to encompass a broader cohort with diverse and overlapping phenotypes. The prevalence of other overgrowth syndromes concealed within molecularly negative BWSp remains unexplored.

MethodsWe conducted whole-exome sequencing (WES) on 69 singleton patients exhibiting molecularly negative BWSp. Variants were confirmed by Sanger sequencing or quantitative genomic PCR. We compared BWSp scores and clinical features between groups with classical BWS (cBWS), atypical BWS or isolated lateralised overgrowth (aBWS+ILO) and overgrowth syndromes identified via WES.

ResultsTen patients, one classified as aBWS and nine as cBWS, showed causative gene variants for Simpson-Golabi-Behmel syndrome (five patients), Sotos syndrome (two), Imagawa-Matsumoto syndrome (one), glycosylphosphatidylinositol biosynthesis defect 11 (one) or 8q duplication/9p deletion (one). BWSp scores did not distinguish between cBWS and other overgrowth syndromes. Birth weight and height in other overgrowth syndromes were significantly larger than in aBWS+ILO and cBWS, with varying intergroup frequencies of clinical features.

ConclusionMolecularly negative BWSp encapsulates other syndromes, and considering both WES and clinical features may facilitate accurate diagnosis.
PADVG: A Simple Baseline of Active Protection for Audio-Driven Video Generation
Authors: Liu Huan , Liu Xiaolong , Tan Zichang , Li Xiaolong , Zhao Yao
Published: January 2024

Over the past few years, deep generative models have significantly evolved, enabling the synthesis of realistic content and also bringing security concerns of illegal misuse. Therefore, active protection for generative models has been proposed recently, aiming to generate samples with hidden messages for future identification while preserving the original generating performance. However, existing active protection methods are specifically designed for generative adversarial networks (GANs), restricted to handling unconditional image generation. We observe that they get limited identification performance and visual quality when handling audio-driven video generation conditioned on target audio and source input to drive video generation with consistent context, e.g., identity and movement, between frame sequences. To address this issue, we introduce a simple yet effective activeProtection framework forAudio-DrivenVideoGeneration, named PADVG. To be specific, we present a novel frame-shared embedding module in which messages to hide are first transformed into frame-shared message coefficients. Then, these coefficients are assembled with the intermediate feature maps of video generators at multiple feature levels to generate the embedded video frames. Besides, PADVG further considers two visual consistent losses: (i) intra-frame loss is utilized to keep the visual consistency with different hidden messages; (ii) inter-frame loss is used to preserve the visual consistency across different video frames. Moreover, we also propose an auxiliary denoising training strategy through perturbing the assembled features by learnable pixel-level noise to improve identification performance, while enhancing robustness against real-world disturbances. Extensive experiments demonstrate that our proposed PADVG for audio-driven video generation can effectively identify the generated videos and achieve high visual quality.
Rigorous Assessment of Model Inference Accuracy using Language Cardinality
Authors: Clun Donato , Shin Donghwan , Filieri Antonio , Bianculli Domenico
Published: January 2024

Models such as finite state automata are widely used to abstract the behavior of software systems by capturing the sequences of events observable during their execution. Nevertheless, models rarely exist in practice and, when they do, get easily outdated; moreover, manually building and maintaining models is costly and error-prone. As a result, a variety of model inference methods that automatically construct models from execution traces have been proposed to address these issues.

However, performing a systematic and reliable accuracy assessment of inferred models remains an open problem. Even when a reference model is given, most existing model accuracy assessment methods may return misleading and biased results. This is mainly due to their reliance on statistical estimators over a finite number of randomly generated traces, introducing avoidable uncertainty about the estimation and being sensitive to the parameters of the random trace generative process.

This article addresses this problem by developing a systematic approach based on analytic combinatorics that minimizes bias and uncertainty in model accuracy assessment by replacing statistical estimation with deterministic accuracy measures. We experimentally demonstrate the consistency and applicability of our approach by assessing the accuracy of models inferred by state-of-the-art inference tools against reference models from established specification mining benchmarks.
Aging Mechanism For Calendar Aging of Li-Ion Cells With Si/Graphite Anodes
Authors: Bischof Katharina , Flügel Marius , Hölzle Markus , Wohlfahrt-Mehrens Margret , Waldmann Thomas
Published: January 2024

Calendar aging of Li-ion batteries with Si/graphite electrodes was investigated within this study. A total of 121 single-layer pouch full cells with either graphite or Si/graphite (3.0 wt−%, 5.8 wt−% and 20.8 wt−% Si) anodes and NMC622 cathodes with the same N/P ratio were built on pilot-scale. Calendar aging was studied at SoC 30%, 60%, and 100%, as well as temperature (25 °C, 45 °C, 60 °C) and time dependence. The aging data was analyzed in terms of capacity fade and a square-root behavior was observed. Differential voltage analysis (DVA) has been performed as a function of aging time. The observed temperature and time dependence is best described by time dependent, 3D Arrhenius plots. Post-Mortem analysis (SEM, EDX, GD-OES) is applied to investigate the changes on electrode and material level. Conclusions are drawn on the main aging mechanisms for calendar aging of Li-ion cells with Si/graphite anodes and differences between Si/graphite and pure graphite anodes are discussed. The Si-containing cells show a combination of lithium inventory loss and a loss of accessible Si active material, both caused by SEI growth.
Beyond the Scoreboard: A Machine Learning Investigation of Online Games’ Influence on Jordanian University Students’ Grades
Authors: Alshraideh Mohammad , Abu-Zayed Abeer Abdel-Jabbar , Leiner Martin , AlDajani Iyad Muhsen
Published: January 2024

In the latter part of the 21st century, the prevalence of online games has significantly increased, encompassing titles connected to the Internet via smart devices, enabling multiplayer interaction. Recent media attention has shed light on the adverse effects associated with online gaming. This research paper explores the viewpoints of 4,700 university students in Jordan regarding the physical, psychological, and behavioural impacts of Internet games. Additionally, it predicts how these impacts may affect the academic performance of 1,410 students. To analyze student trends and forecast outcomes based on sustained game engagement, a convolutional neural network (CNN) was specifically developed for the neural network. The findings revealed student consensus with recommended university measures to limit online game usage, emphasizing a prevalent belief in the negative influence of games on the body, behaviour, and mental health. In terms of the prediction process, the training data encompassed 60%, 70%, and 80% of the dataset. The results revealed that the highest accuracy, 96.69%, was achieved at the 70% threshold for predicting students’ grade point average (GPA). The analysis suggested that projecting a decrease in the percentage of hours dedicated to playing online games could act as a mitigating factor to prevent GPA decline. Consequently, the system advises a range from 99.9% to 4.1%. This implies that a student with a maximum of 99.9% is encouraged to significantly reduce playing hours to preserve their GPA, while a student with a minimum of 4.1% is recommended to decrease playing hours by 4.1%. On average, for the 1,090 students, the system proposes a 48.36% reduction in playing hours to safeguard their GPAs and mitigate potential risks. This high level of accuracy played a crucial role in forecasting students’ GPA outcomes following a year of sustained daily engagement with online games. Notably, the results unveiled a concerning revelation that 80% of students would face a detrimental impact on their academic performance after one year of such consistent online game involvement.
Steroids for the Treatment of Misophonia and Misokinesia
Authors: Webb Jadon , Williamson Afton
Published: January 2024

Misophonia and misokinesia are disorders characterized by intensely negative physical and emotional reactions to specific auditory and visual stimuli. The availability of effective treatments, especially pharmacological ones, is limited. This report presents a case of a 35-year-old male with severe misophonia and misokinesia who experienced nearly complete resolution of symptoms while undergoing high-dose steroid therapy for an unrelated muscular injury. Two days after starting a 20 mg oral prednisone taper pack (in which the steroid dose is reduced by 4 mg daily), his Amsterdam Misophonia Scale (A-Miso-S) score drastically reduced from a baseline of 23 (i.e., extreme symptoms) to 1, with symptom relief persisting for approximately 2 weeks after completing the taper. Months later, a daily dose of prednisone (4 mg) was reintroduced. This again resulted in a marked reduction in symptoms (A-Miso-S of 6), enabling him to resume working in an office setting despite his triggers. Symptom improvement remained stable over several months. This case raises the possibility of the steroid prednisone as a novel treatment for misophonia and misokinesia. However, further investigation is needed to determine the generalizability of this observation.
Primary Peritoneal Serous Cancer: A Case Report of a Tumor in the Rectovaginal Septum
Authors: Herrera-Torres Analy , Parra-Torres Carlos Guadalupe , Alamilla García Gabriela C. , Thompson Bonilla María del Rocío , García Córdova Oscar Manuel , Padilla Martínez Alfredo , Lara Ruíz Rodolfo Iván , Ramírez Moreno Esther
Published: January 2024

Peritoneal cancer is the invasion by malignant cells of serous membrane that lines the abdominal cavity, the viscera, and the coelom of the amniotes. Histologically, it is indistinguishable from ovarian counterpart, although in the former, it commonly involves the ovary only superficially, or it may totally lack an ovarian component, but with extensive involvement of the peritoneum, calcified perihepatic peritoneal nodules, or involvement of the omentum, in most cases. The current study describes the case of a 54-year-old female patient referring a history of colitis and dairy intolerance. A transvaginal ultrasound and a computed tomography (CT) scan revealed a tumor measuring 70×61×63 mm. CA-125 serum levels were 880 U/ml. Laparotomy surgery was indicated, and tumor was found at the level of the rectovaginal septum without evidence of metastasis. Tumor dissection and protective colostomy with loop sigmoid colon were performed. A pathological study gave a diagnosis of a high-grade peritoneal serous carcinoma with a micropapillary pattern. The present study describes the case of papillary serous peritoneal cancer presented as a single tumor mass without extensive involvement of the peritoneum. Additionally, the need for routine tests for its diagnosis and documenting hormonal alterations as the cause of its origin are suggested.
Laypersons’ Esthetic Perception of Different Dentogingival Characteristics Based on Smile Dynamics: Cross‐Sectional Study
Authors: Malheiros Adriana S. , Barboza Julianne R. , Pinheiro Neto Sebastião M. , Dibai Daniela B. , Maia Filho Etevaldo M. , Pinzan-Vercelino Célia Maio , Ferreira Meire C. , Tavarez Rudys R. J.
Published: January 2024

This study aimed to evaluate laypersons’ esthetic perception of different dentogingival characteristics based on smile dynamics. Six voluntary models were selected, with only one presenting dentogingival characteristics within esthetic standards: white teeth, good alignment, and adequate gingival contour. Two videos were then produced. One video focused on the mouth, whereas the other focused on the entire face of the model, to ensure that the dynamics of the smile could be evaluated. For the evaluation, 200 laypeople were asked to rank the models from first to sixth place in their order of preference. Laypeople were required to justify their reasons for choosing the first and last places. The obtained data were subjected to descriptive and inferential statistical analyses. The results showed that smile and face dynamics influenced the perception of dentogingival characteristics and facial esthetics. No significant changes were observed. However, a gummy smile accompanied by dental alterations was observed in the video of the mouth and was masked by the facial set exposed in the video of the face. A diastema between the central incisors was decisive for negative evaluation of both the mouth and face. The standard model was rated as the most pleasing. Smiles and facial dynamics influence the perception of dentogingival characteristics. Smile and facial dynamics influence the perception of dentogingival alterations among Brazilian laypeople. Diastema is an alteration that interferes with the isolated evaluation of the lower third of the face and the facial set.
Impact of the COVID‐19 Epidemic on Inhalant Allergen Sensitization in Children
Authors: Huang Xueshan , Yang Min , Ye Ma , Qiu Jun , Chen Yanping
Published: January 2024

Objective. To explore the impact of non‐pharmacological interventions on inhaled allergen sensitization in children during the COVID‐19 pandemic. Methods. The positive rate of inhaled allergens, allergens sIgE grade, and multiple sensitization rates before and during the pandemic were analyzed retrospectively in this study. Logistic regression analysis was used to compare the positive rate of allergens before and during the pandemic, using odds ratio (OR) and OR 95% CI to investigate the impact of the pandemic on allergen sensitization. Results. Positive rates of d1 (49.5% vs. 38.5%), d2 (50.2% vs. 32.2%), e2 (10.1% vs. 6.1%), e1 (6.2% vs. 1.7%), mx2 (10.1% vs. 2.7%), sycamore (7.2% vs. 2.1%), w1 (4.0% vs. 1.7%), elm (3.1% vs. 0.6%), w6 (3.0% vs. 1.7%), and u80 (1.3% vs. 0.5%) increased significantly during the COVID‐19 pandemic. After adjusting gender, age, season, and other potential influencing factors, the COVID‐19 pandemic was found to be a risk factor for the positive rate of d1 (OR = 1.174, 95% CI = 1.015–1.358), d2 (OR = 1.301, 95% CI = 1.093–1.549), e2 (OR = 1.499, 95% CI = 1.280–1.756), mx2 (OR = 3.959, 95% CI = 3.358–4.446), w1 (OR = 1.828, 95% CI = 1.353–2.470, w6 (OR = 1.538, 95% CI = 1.123–2.106)), and u80 (OR = 2.521, 95% CI = 1.413–4.497) (P < 0.05). In addition, d1 and d2 allergen sIgE grades increased during the COVID‐19 pandemic (d1: χ2 = 9.576, P < 0.05; d2: χ2 = 39.063, P < 0.05). The proportion of multiple allergies was significantly higher than that before the pandemic, with a statistical significance (χ2 = 1621.815, P < 0.05). Conclusion. During the COVID‐19 pandemic, non‐pharmacological interventions increased the positive rate of both indoor and outdoor allergens in children. The sIgE grade of dust mite allergen and multiple sensitization rates were significantly higher than those before COVID‐19.
Hyperuricemia Induces Reproductive Damage in Male Rats through Zinc Homeostasis Imbalance and Oxidative Stress
Authors: Te Liger , Li Yuejia , Liu Junsheng , Liu Xuan , Zhao Ming , Wang Shusong , Ma Jing
Published: January 2024

Studies have reported the adverse effects of hyperuricemia on male reproduction, but the mechanism is still unclear. The purpose of this study is to explore the mechanism of hyperuricemia on reproductive system damage in male rats. The rats were divided into a control group and a model group. Rats were given hypoxanthine and potassium oxonate dissolved in 0.5% (w/v) sodium carboxymethyl cellulose solution to induce the hyperuricemia (HUA) model. After 6 weeks, the blood, testis, and epididymis tissues of the anesthetized rats were collected for further experiments and analysis. Compared with the control rats, the serum uric acid of HUA rats was significantly increased, and the serum testosterone, sperm count, and motility were significantly decreased. The protein expression of testosterone‐related molecules CYP11A1, 3β‐HSD, and StAR was downregulated in the testis of HUA rats. The protein expression of blood–testis barrier (BTB) related molecules ZO‐1 and Connexin43 was downregulated in the testis of HUA rats. Compared with the control group, the zinc content and zinc‐containing enzymes (ALP and LDH) were decreased, and the mRNA and protein expression of zinc transporters (ZnT4 and ZIP7) were downregulated in the testis of HUA rats. Furthermore, the level of MDA increased and the activities of CAT, GSH‐PX, and SOD decreased in the testicular tissue of HUA rats. The PI3K/AKT/mTOR pathway in the testis of HUA rats was activated. However, there was no significant change in the protein expression of autophagy associated molecules LC3, Beclin1, and ATG5 in the testis of HUA rats. Thus, the conclusion is that hyperuricemia can lead to the destruction of BTB, impaired testosterone synthesis, and decreased sperm count and motility in male rats, mainly by inducing zinc homeostasis imbalance and oxidative stress, rather than autophagy.
Supplementary Data from The Chromatin Remodeler CHD4 Sustains Ewing Sarcoma Cell Survival by Controlling Global Chromatin Architecture
Authors: Graca Marques Joana , Pavlovic Blaz , Ngo Quy A. , Pedot Gloria , Roemmele Michaela , Volken Larissa , Kisele Samanta , Perbet Romain , Wachtel Marco , Schäfer Beat W.
Published: January 2024

Supplementary Figures 1-7 and supplementary material and methods
Main supplemental file from Erythroid Differentiation Enhances RNA Mis-Splicing in SF3B1-Mutant Myelodysplastic Syndromes with Ring Sideroblasts
Authors: Moura Pedro L. , Mortera-Blanco Teresa , Hofman Isabel J. , Todisco Gabriele , Kretzschmar Warren W. , Björklund Ann-Charlotte , Creignou Maria , Hagemann-Jensen Michael , Ziegenhain Christoph , Cabrerizo Granados David , Barbosa Indira , Walldin Gunilla , Jansson Monika , Ashley Neil , Mead Adam J. , Lundin Vanessa , Dimitriou Marios , Yoshizato Tetsuichi , Woll Petter S. , Ogawa Seishi , Sandberg Rickard , Jacobsen Sten Eirik W. , Hellström-Lindberg Eva
Published: January 2024

Main supplemental file
Supplementary Table 5 from Small Cell Lung Cancer Plasticity Enables NFIB-Independent Metastasis
Authors: Ko Julie H. , Lambert Kyle E. , Bhattacharya Debadrita , Lee Myung Chang , Colón Caterina I. , Hauser Haley , Sage Julien
Published: January 2024

HOMER analysis ATAC-seq
Supplementary Tables S1 from CircMMP2(6,7) Cooperates with β-Catenin and PRMT5 to Disrupt Bone Homeostasis and Promote Breast Cancer Bone Metastasis
Authors: Xu Yingru , Li Xincheng , Zhang Shuxia , Tang Miaoling , Yu Ruyuan , Liao Xinyi , Li Ziwen , Li Man , Chen Suwen , Qian Wanying , Song Libing , Ke Zunfu , Li Jun
Published: January 2024

Clinicopathological Characteristics of Clinical Samples and Expression of CircMMP2(6, 7) and PRMT5 in Breast Cancer
Supplementary Figure 6 from Small Cell Lung Cancer Plasticity Enables NFIB-Independent Metastasis
Authors: Ko Julie H. , Lambert Kyle E. , Bhattacharya Debadrita , Lee Myung Chang , Colón Caterina I. , Hauser Haley , Sage Julien
Published: January 2024

NFIBneg SCLC metastases show chromatin and transcriptional features related to ASCL1 activity
Supplementary Figure 4 from Small Cell Lung Cancer Plasticity Enables NFIB-Independent Metastasis
Authors: Ko Julie H. , Lambert Kyle E. , Bhattacharya Debadrita , Lee Myung Chang , Colón Caterina I. , Hauser Haley , Sage Julien
Published: January 2024

Loss of CDH1 expression is not dependent on NFIB expression in RPR2 mutant mice
Data from CircMMP2(6,7) Cooperates with β-Catenin and PRMT5 to Disrupt Bone Homeostasis and Promote Breast Cancer Bone Metastasis
Authors: Xu Yingru , Li Xincheng , Zhang Shuxia , Tang Miaoling , Yu Ruyuan , Liao Xinyi , Li Ziwen , Li Man , Chen Suwen , Qian Wanying , Song Libing , Ke Zunfu , Li Jun
Published: January 2024

Abstract
The bone is the most common site of distant metastasis of breast cancer, which leads to serious skeletal complications and mortality. Understanding the mechanisms underlying breast cancer bone metastasis would provide potential strategies for the prevention and treatment of breast cancer bone metastasis. In this study, we identified a circular RNA that we named circMMP2(6,7) that was significantly upregulated in bone metastatic breast cancer tissues and correlated with breast cancer–bone metastasis. Upregulation of circMMP2(6,7) dramatically enhanced the metastatic capability of breast cancer cells to the bone via inducing bone metastatic niche formation by disrupting bone homeostasis. Mechanistically, circMMP2(6,7) specifically bound to the promoters of bone-remodeling factors calcium-binding protein S100A4 and carbohydrate-binding protein LGALS3 and formed a complex with β-catenin and arginine methyltransferase PRMT5, eliciting histone H3R2me1/H3R2me2s-induced transcriptional activation. Treatment with GSK591, a selective PRMT5 inhibitor, effectively inhibited circMMP2(6,7)/β-catenin/PRMT5 complex–induced breast cancer bone metastasis. These findings reveal a role for circMMP2(6,7) in bone homeostasis disruption and shed light on the mechanisms driving breast cancer bone metastasis.
Significance:
Upregulation of bone-remodeling factors S100A4 and LGALS3 mediated by a circMMP2(6,7)/β-catenin/PRMT5 complex generates a niche that supports breast cancer bone metastasis, identifying PRMT5 as a promising target for treating metastasis.
Abstract A009: Association between unstable diabetes mellitus and risk of pancreatic cancer
Authors: Ali Sitwat , Coory Michael , Donovan Peter , Na Renhua , Pandeya Nirmala , Pearson Sallie-Anne , Spilsbury Katrina , Stewart Louise , Thompson Bridie , Tuesley Karen , Waterhouse Mary , Webb Penelope , Jordan Susan , Neale Rachel
Published: January 2024

Worsening of hyperglycemia in people with pre-existing diabetes mellitus may be an indicator of undiagnosed pancreatic cancer. However, there is limited evidence from longitudinal studies regarding the association between deterioration of diabetes and pancreatic cancer in people with previously stable diabetes. The size of the association between deterioration of diabetes and pancreatic cancer, and how the association changes over time, needs further investigation. A population-based matched cohort study was conducted within Australian women with stable diabetes mellitus. Unstable diabetes, the exposure of interest, was defined as change in the type of antidiabetic medication or addition of another antidiabetic medication after at least 24 months of stable antidiabetic medication use. The date of exposure was defined as the index date. Each woman with unstable diabetes was matched to 4 women with stable diabetes by birth year (±1 year) at the index date. Flexible parametric survival models were used to estimate hazard ratios (HR) (overall and at different times) and 95% confidence intervals (CI), and absolute risk in both groups at different time points. We identified 134,954 women with unstable diabetes; these were matched to women who had not developed unstable diabetes at the index date. The mean age of the cohort was 68 years. Over a median follow-up period of 2.8 years, 1,315 pancreatic cancer cases were diagnosed. Overall, women who experienced deterioration in glycemic control had a 2.5-fold increased risk of developing pancreatic cancer (HR 2.55; 95% CI 2.29 – 2.85). The risk was very high during the initial few months [HRs at 3 months (5.76; 95% CI 4.72 – 7.04), 6 months (4.56; 95% CI 3.81 – 5.46), and 12 months (3.33; 95% CI 2.86 – 3.89)]. The risk then progressively declined with time. Worsening of glycemic control in those with previously stable diabetes may be an early clinical manifestation of pancreatic cancer. Further research is warranted to differentiate this pancreatic cancer-associated deterioration of glycemic control from other causes. The longer-term (3-7 years) weaker association between pancreatic cancer and deterioration of glycemic control suggests that poorly controlled hyperglycemia is a predisposing factor for pancreatic cancer.

Citation Format: Sitwat Ali, Michael Coory, Peter Donovan, Renhua Na, Nirmala Pandeya, Sallie-Anne Pearson, Katrina Spilsbury, Louise Stewart, Bridie Thompson, Karen Tuesley, Mary Waterhouse, Penelope Webb, Susan Jordan, Rachel Neale. Association between unstable diabetes mellitus and risk of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A009.
Abstract A018: Exercise stimulates anti-tumoral immunity in metastatic PDAC
Authors: Riachi Mansour E. , Hirsch Carolina G. Alcantara , Ma Erica , Shapiro Beny , Javed Ammar , Wolfgang Christopher L. , Bar-Sagi Dafna
Published: January 2024

The majority of pancreatic ductal adenocarcinoma (PDAC) patients are metastatic at presentation with limited treatment options and a poor overall 5-year survival of 3%. The liver is the predominant site of distant metastasis in PDAC. Our group has previously shown that aerobic exercise can inhibit tumorigenesis in a primary PDAC mouse model by promoting anti-tumor immunity, however, the effects of exercise in the metastatic setting have not been explored. As such, we developed a model of PDAC liver metastasis by isolating primary pancreatic and liver metastatic cell lines from 18–20-week-old LSL-KRasG12D/+; LSL-Trp53R172H/+; p48Cre; Rosa26LSL-tdTomato/+ (KPCTpancreas or KPCTliver, respectively) mice. KPCTpancreas cells were surgically implanted into the pancreata of syngeneic wild-type mice. One week after pancreatic implantation, KPCTliver cells were implanted into the liver either by direct injection into the parenchyma or via the portal vein. The portal vein method enables us to account for the extravasation step of the metastatic cascade, while the direct parenchymal injection offers a less invasive surgery. Both models preserve the spleen, which is the largest secondary lymphoid organ and essential to the immune response. Treadmill running was initiated in the aerobic exercise cohort 5 days per week for 2 weeks or mice were allowed to rest. Endpoint analysis revealed that aerobic exercise treatment decreased tumor burden in both primary tumors and liver metastasis as measured by tumor weights and tdTomato fluorescence imaging when compared to the rested controls. Immune profiling of the liver metastases revealed elevated IL-15Rɑ+ CD8+ T cells as well as CD19+ B cells in the exercise cohort. While identification of IL-15Rɑ+ CD8+ T cells is consistent with the immune changes we have previously reported in the primary pancreatic tumor of exercised mice, the latter changes reveal organ specific immune cell recruitment not observed in the primary pancreatic tumor of exercised mice. The combined immune profiling and phenotypic changes suggest that aerobic exercise reduces PDAC metastatic growth by modulating systemic and intra-tumoral immunity. The induction of an anti-tumorigenic immune response by aerobic exercise could open avenues for potential pharmacological intervention in downstream pathways to aid in the treatment of metastatic PDAC.

Citation Format: Mansour E. Riachi, Carolina G. Alcantara Hirsch, Erica Ma, Beny Shapiro, Ammar Javed, Christopher L. Wolfgang, Dafna Bar-Sagi. Exercise stimulates anti-tumoral immunity in metastatic PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A018.
Abstract A043: The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC
Authors: Guo Yifei , Finan Jennifer M. , Hedberg Madeline D. , Brody Jonathan R. , Eil Robert
Published: January 2024

Immunotherapies have shown limited effectiveness in pancreatic ductal adenocarcinoma (PDAC), despite successes in many other cancers. The RNA-binding protein HuR is known to play a critical role in the oncogenesis of PDAC through regulating key mRNA transcripts. Our lab has showed that tumor-intrinsic HuR is overexpressed in PDAC and regulates the tumor microenvironment composition and alters multiple tumor cytokine release. Thus, we hypothesized that HuR plays a role in immune evasion of PDAC. We disrupted the locus encoding HuR (Elavl1), using CRISPR Cas9 in Kras-p53 mutant-driven (KPC) murine PDAC to assess its function in tumor immune evasion. Here, we report that HuR, a known pro-survival factor for PDAC, has a role in tumor immune evasion by suppressing T cell infiltration and T cell activation. Specifically, HuR-knockout (KO) KPC tumors grew slower compared to KPC wildtype (WT) tumors in an orthotopically implantation model (p-value<0.0001), even though they grew at the same rate in vitro (in a non-compromised environment). Accordingly, HuR-KO tumors had more T cell infiltration and activated T cells comparing to HuR-WT tumors (p-value=0.0047). Furthermore, T cell depletion partially rescued the size of HuR-KO tumors. Collectively, these data support the hypothesis that HuR suppresses T cell activation and prevents T cells from infiltrating the PDAC microenvironment, which therefore leads to PDAC immune evasion. Ongoing experiments will transduce KPC cell lines with ovalbumin (OVA) antigen, which will selectively active CD8+ OT-I T cells through their transgenic TCR, to measure the ability of KPC HuR-WT or HuR-KO OVA cells in directly activating CD8+ OT-I T cells. We will also rescue HuR in HuR-KO cells to validate HuR’s role in immune evasion. These findings support the concept that HuR plays an important pro-survival role of PDAC in vivo, and that targeting strategies against HuR being developed (e.g., siHuR nanotherapies and small molecule inhibitors) could potentially enhance PDAC sensitivity to immune-based anti-cancer therapies such as checkpoint blockade and T cell transfer.

Citation Format: Yifei Guo, Jennifer M. Finan, Madeline D. Hedberg, Jonathan R. Brody, Robert Eil. The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A043.