bluuebunny/crossref_metadata_2025 huggingface dataset:
Proline‐directed yeast and human MAP kinases phosphorylate the Dot1p/DOT1L histone H3K79 methyltransferase
Authors: Separovich Ryan J. , Karakatsanis Nicola M. , Gao Kelley , Fuh David , Hamey Joshua J. , Wilkins Marc R.
Published: January 2024

Disruptor of telomeric silencing 1 (Dot1p) is an exquisitely conserved histone methyltransferase and is the sole enzyme responsible for H3K79 methylation in the budding yeast Saccharomyces cerevisiae. It has been shown to be highly phosphorylated in vivo; however, the upstream kinases that act on Dot1p are almost entirely unknown in yeast and all other eukaryotes. Here, we used in vitro and in vivo kinase discovery approaches to show that mitogen‐activated protein kinase HOG1 (Hog1p) is a bona fide kinase of the Dot1p methyltransferase. In vitro kinase assays showed that Hog1p phosphorylates Dot1p at multiple sites, including at several proline‐adjacent sites that are consistent with known Hog1p substrate preferences. The activity of Hog1p was specifically enhanced at these proline‐adjacent sites on Dot1p upon Hog1p activation by the osmostress‐responsive MAP kinase kinase PBS2 (Pbs2p). Genomic deletion of HOG1 reduced phosphorylation at specific sites on Dot1p in vivo, providing further evidence for Hog1p kinase activity on Dot1p in budding yeast cells. Phenotypic analysis of knockout and phosphosite mutant yeast strains revealed the importance of Hog1p‐catalysed phosphorylation of Dot1p for cellular responses to ultraviolet‐induced DNA damage. In mammalian systems, this kinase–substrate relationship was found to be conserved: human DOT1L (the ortholog of yeast Dot1p) can be phosphorylated by the proline‐directed kinase p38β (also known as MAPK11; the ortholog of yeast Hog1p) at multiple sites in vitro. Taken together, our findings establish Hog1p and p38β as newly identified upstream kinases of the Dot1p/DOT1L H3K79 methyltransferase enzymes in eukaryotes.
Influence of Geometric Characteristics on Water Flow and Solute Transport at Fracture Intersections
Authors: Qian Jiazhong , Liang Xueqi , Liu Yong , Ma Lei , Li Xiangquan , Zhang Chunchao
Published: January 2024

Laboratory experiments and numerical simulations were performed to explore the influence of intersection geometry on fluid flow and solute transport in fractures. Fractures were engraved and sealed into an acrylic plate and two orthogonal intersections with different geometry were constructed. The effects of curvature and relative shear displacement at intersections on preferential flow and solute transport were investigated. By solving the Navier–Stokes (NS) equation, the fluid mixing and solute distribution were predicted. The results showed that the geometric characteristics at the intersection have a significant effect on the preferential flow and solute distribution. The results agreed well with the experimental results, in terms of flow direction, preferential flow rate, and heterogeneous solute distribution. With an increase in curvature, the flow difference between the two outlets increases gradually. Increasing curvature can reduce the preferential flow and weaken the inhomogeneity of solute distribution. An increase of relative shear displacement decreases the pressure gradient and flow rate at the entrance of the two branch fractures, and thereby increases preferential flow and inhomogeneity of solute distribution. The results provide a basis and reference for further exploring the relationship between the geometric characteristics of fracture intersections and flow behaviors.
Creating Healthy Environments for Schools: A Comprehensive Approach to Improving Nutrition in Arkansas Public Schools
Authors: Langner Jonathan , Langston Krista , Mrachek Ally , Faitak Bonnie , Martin Pamela , Cueto Alexa , Clampitt Jennifer L. , Long Christopher R. , Bartow Amy , Bodey Susan , McElfish Pearl A.
Published: January 2024

BACKGROUND

Nutrition plays a vital role in children's physical and emotional health. More than half of school age children's calories are provided in the school food environment, making school interventions an opportunity to address child nutrition.

METHODS

The Creating Health Environments for Schools (CHEFS) program is designed to leverage local resources to create customized solutions that improve the nutritional content of school food and encourage children to choose healthier food. There are 8 components: (1) customizing nutrition plans, (2) modifying/replacing menu items, (3) helping procure healthier food, (4) providing equipment grants, (5) training cafeteria staff, (6) implementing environmental changes and nudges, (7) engaging students and parents, and (8) supporting sustainability. Supporting child nutrition directors is key to facilitating cooperation with schools.

IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY

Menu modifications and procurement are interrelated and depend on successfully collaborating with corporate, independent, and local food services organizations. Limited school budgets require low or no‐cost solutions and staff training. Student and parent engagement are critical to facilitate culturally‐appropriate solutions that increase awareness of healthy food.

CONCLUSIONS

Every school district has particular resources and constraints. CHEFs engaged stakeholders to design customized solutions and encourage healthier nutrition for school children.
Methane emissions from tree stems – current knowledge and challenges: an introduction to a Virtual Issue
Authors: Barba Josep , Brewer Paul E. , Pangala Sunitha R. , Machacova Katerina
Published: January 2024

This article is a Commentary on the Virtual Issue ‘Methane emissions from tree stems – current knowledge and challenges’ that includes the following papers: Barba et al. (2019), Bréchet et al. (2021), Covey & Megonigal (2019), Feng et al. (2022), Flanagan et al. (2021), Jeffrey et al. (2019, 2021, 2023), Kohl et al. (2019), Machacova et al. (2021a,b, 2023), Megonigal et al. (2020), Pangala et al. (2013, 2014), Pitz & Megonigal (2017), Plain et al. (2019), Putkinen et al. (2021), Sjögersten et al. (2020), Takahashi et al. (2022), Tenhovirta et al. (2022), Wang et al. (2016), and Yip et al. (2018). Access the Virtual Issue at www.newphytologist.com/virtualissues.
An Active Phantom Cooling Concept for Turbine Endwall Cooling From Pressure-Surface Film Coolant Injection
Authors: Yang Xing , Zhao Qiang , Wu Hang , Feng Zhenping
Published: January 2024

Cooling of the endwall of a nozzle guide vane should receive special attention due to its uniqueness of near-wall complex secondary flows and concomitant challenge of offering film-coverage for cooling the endwall pressure-side corner regions. The use of internal enhanced cooling at the endwall backside could be an option, but it increases manufacturing cost, adds weight to the component, causing excessive pressure losses in the secondary air system. Novel film cooling concepts are, therefore, required to provide effective cooling for these difficult-to-cool regions. This study proposes an active cooling concept effected by placing a row of film cooling holes on the vane pressure surface near the endwall with the intention of utilizing second-order cooling (or phantom cooling) from pressure-surface film-coolant injection to provide increased cooling effectiveness and enlarge the area of coverage on the endwall. The effects of hole diameter, injection angle, and compound angle, as well as coolant injection rate are investigated. Detailed phantom cooling effectiveness over the endwall is documented using pressure-sensitive paint (PSP). To provide a description of the flow physics driving the cooling process, computational modeling is carried out to qualitatively document mixing of coolant with the freestream flows and further to qualitatively evaluate heat transfer changes caused by the pressure-surface film injection. Experiments show that significant cooling occurs in the endwall pressure-side corner and extends beyond the passage throat. Higher coolant injection rates and an optimized pressure-surface injection geometry maximize endwall phantom cooling. An effectiveness correlation for the active cooling is developed to provide a straightforward tool for designers to apply in turbine design.
Super-tetragonal Sr
4
Al
2
O
7
as a sacrificial layer for high-integrity freestanding oxide membranes
Authors: Zhang Jinfeng , Lin Ting , Wang Ao , Wang Xiaochao , He Qingyu , Ye Huan , Lu Jingdi , Wang Qing , Liang Zhengguo , Jin Feng , Chen Shengru , Fan Minghui , Guo Er-Jia , Zhang Qinghua , Gu Lin , Luo Zhenlin , Si Liang , Wu Wenbin , Wang Lingfei
Published: January 2024

Identifying a suitable water-soluble sacrificial layer is crucial to fabricating large-scale freestanding oxide membranes, which offer attractive functionalities and integrations with advanced semiconductor technologies. Here, we introduce a water-soluble sacrificial layer, “super-tetragonal” Sr
4
Al
2
O
7
(SAO
T
). The low-symmetric crystal structure enables a superior capability to sustain epitaxial strain, allowing for broad tunability in lattice constants. The resultant structural coherency and defect-free interface in perovskite ABO
3
/SAO
T
heterostructures effectively restrain crack formation during the water release of freestanding oxide membranes. For a variety of nonferroelectric oxide membranes, the crack-free areas can span up to a millimeter in scale. This compelling feature, combined with the inherent high water solubility, makes SAO
T
a versatile and feasible sacrificial layer for producing high-quality freestanding oxide membranes, thereby boosting their potential for innovative device applications.
Catalytic enantioselective reductive Eschenmoser-Claisen rearrangements
Authors: Zhang Guoting , Wodrich Matthew D. , Cramer Nicolai
Published: January 2024

An important challenge in enantioselective catalysis is developing strategies for the precise synthesis of neighboring congested all-carbon quaternary stereocenters. The well-defined transition states of [3,3]-sigmatropic rearrangements and their underlying stereospecificity render them powerful tools for the synthesis of such arrays. However, this type of pericyclic reaction remains notoriously difficult to catalyze, especially in an enantioselective fashion. Herein, we describe an enantioselective reductive Eschenmoser-Claisen rearrangement catalyzed by chiral 1,3,2-diazaphospholene-hydrides. This developed transformation enables full control of the two newly formed acyclic stereogenic centers, leading to amides with vicinal all-carbon quaternary-tertiary or quaternary-quaternary carbon atoms.
Water batteries
Authors: Kunzig Robert
Published: January 2024

Pumped storage hydropower plants can bank energy for times when wind and solar power fall short
TcZC3HTTP, a regulatory element that contributes to
Trypanosoma cruzi
cell proliferation
Authors: Romagnoli Bruno Accioly Alves , Lucena Aline Castro Rodrigues , Freire Eden Ribeiro , Munhoz da Rocha Isadora Filipaki , Alves Lysangela Ronalte. , Goldenberg Samuel
Published: January 2024

Post-transcriptional regulation of gene expression is a critical process for adapting to and surviving
Trypanosoma cruzi
, a parasite with a complex life cycle. RNA-binding proteins (RBPs) are key players in this regulation, forming ribonucleoprotein complexes (messenger ribonucleoproteins) and RNA granules that control transcript stability, localization, degradation, and translation modulation. Understanding the specific roles of individual RBPs is crucial for unraveling the details of this regulatory network. In this study, we generated null mutants of the TcZC3HTTP gene, a specific RBP in the
Trypanosoma
family characterized by a C3H zinc finger and a DNAJ domain associated with RNA and protein binding, respectively. Through cell growth assays, we demonstrated that the absence of TcZC3HTTP or the expression of an additional tagged version impacted epimastigote growth, indicating its contribution to cell proliferation. TcZC3HTTP was found to associate with mRNAs involved in cell cycle and division in epimastigotes, while in nutritionally stressed parasites it exhibited associations with mRNAs coding for other RBPs and rRNA. Furthermore, our analysis identified that TcZC3HTTP protein partners were different during normal growth conditions compared to starvation conditions, with the latter showing enrichment of ribosomal proteins and other RBPs. Therefore, this study provides insights into TcZC3HTTP’s role in the post-transcriptional regulation of gene expression during normal growth and nutritional stress in
T. cruzi
, uncovering its versatile functions in different cellular contexts.

IMPORTANCE

Understanding how
Trypanosoma cruzi
, the causative agent of Chagas disease, regulates gene expression is crucial for developing targeted interventions. In this study, we investigated the role of TcZC3HTTP, an RNA-binding protein, in post-transcriptional regulation. Our findings demonstrate that TcZC3HTTP is relevant for the growth and proliferation of epimastigotes, a stage of the parasite’s life cycle. We identified its associations with specific mRNAs involved in cell cycle and division and its interactions with enzymes and other RNA-binding proteins (RBPs) under normal and starvation conditions. These insights shed light on the regulatory network underlying gene expression in
T. cruzi
and reveal the multifaceted functions of RBPs in this parasite. Such knowledge enhances our understanding of the parasite’s biology and opens avenues for developing novel therapeutic strategies targeting post-transcriptional gene regulation in
T. cruzi
.
Mental Health Admissions to Paediatric Wards Study (MAPS): protocol of a prospective study of mental health admissions to paediatric wards in England using surveillance and qualitative methods
Authors: Hudson Lee Duncan , Vázquez-Vázquez Adriana , Gibson Faith , Phillips Kirsty , Mathews Gabrielle , Roberts Helen , Cornaglia Francesca , Roland Damian , Ward Joseph , Nicholls Dasha E , Elphinstone Holly , Viner Russell
Published: January 2024

Introduction

Children and young people (CYP) presenting with a mental health (MH) crisis are frequently admitted to general acute paediatric wards as a place of safety. Prior to the pandemic, a survey in England showed that CYP occupied 6% of general paediatric inpatient beds due to an MH crisis, and there have been longstanding concerns about the quality of care to support these patients in this setting. MAPS aims to generate a Theory of Change (ToC) model to improve the quality of care for CYP admitted to acute paediatric services after presenting with an MH crisis. Here, we describe work packages (WPs) 2 and 3 of the study, which have been granted ethics approval.

Methods and analysis

We will undertake a national (England), sequential, mixed-methods study to inform a ToC framework alongside a stakeholder group consisting of patients, families/carers and healthcare professionals (HCPs). Our study consists of four WPs undertaken over 30 months. WP2 is limited to working with stakeholders to develop a data collection instrument and then use this in a prospective study of MH admissions over 6 months in 15 purposively recruited acute paediatric wards across England. WP3 consists of gathering the views of CYP, their families/carers and HCPs during admissions using semistructured interviews.

Ethics and dissemination

WP2 and WP3 received ethical approval (ref: 23/LO/0349). We will publish the overall synthesis of data and the final ToC to improve care of CYP with MH crisis admitted to general acute paediatric settings. As co-producers of the ToC, we will work with our stakeholder group to ensure wide dissemination of findings. Potential impacts will be upon service development, new models of care, training and workforce planning.

PROSPERO registration number

CRD42022350655.
De novo heterozygous missense variants inCELSR1as cause of fetal pleural effusions and progressive fetal hydrops
Authors: de Koning Maayke A , Pimienta Ramirez Paula A , Haak Monique C , Han Xiao , Ruiterkamp-Versteeg Martina HA , de Leeuw Nicole , Schatz Ulrich A , Shoukier Moneef , Rieger-Fackeldey Esther , Ortiz Javier U , van Duinen Sjoerd G , Klein Willemijn M , Witlox Ruben S G M , Finnell Richard H , Santen Gijs W E , Lei Yunping , Suerink Manon
Published: January 2024

Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whomde novoheterozygous missense variants in the planar cell polarity geneCELSR1were detected using exome sequencing. Using several in vitro assays, we show that theCELSR1p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rareCELSR1variants could be a possible cause of fetal hydrops.
Reinforcement Learning for Solving Multiple Vehicle Routing Problem with Time Window
Authors: Zong Zefang , Tong Xia , Zheng Meng , Li Yong
Published: January 2024

Vehicle routing problem with time window (VRPTW) is of great importance for a wide spectrum of services and real-life applications, such as online take-out and car-hailing platforms. A promising method should generate high-qualified solutions within limited inference time, and there are three major challenges: (a) directly optimizing the goal with several practical constraints; (b) efficiently handling individual time-window limits; and (c) modeling the cooperation among the vehicle fleet. In this article, we present an end-to-end reinforcement learning framework to solve VRPTW. First, we propose an agent model that encodes constraints into features as the input and conducts harsh policy on the output when generating deterministic results. Second, we design a time penalty augmented reward to model the time-window limits during gradient propagation. Third, we design a task handler to enable the cooperation among different vehicles. We perform extensive experiments on two real-world datasets and one public benchmark dataset. Results demonstrate that our solution improves the performance by up to 11.7% compared to other RL baselines and could generate solutions for instances within seconds, while existing heuristic baselines take for minutes as well as maintain the quality of solutions. Moreover, our solution is thoroughly analyzed with meaningful implications due to the real-time response ability.
Can Perturbations Help Reduce Investment Risks? Risk-aware Stock Recommendation via Split Variational Adversarial Training
Authors: Cheng Jiezhu , Huang Kaizhu , Zheng Zibin
Published: January 2024

In the stock market, a successful investment requires a good balance between profits and risks. Based on the
learning to rank
paradigm, stock recommendation has been widely studied in quantitative finance to recommend stocks with higher return ratios for investors. Despite the efforts to make profits, many existing recommendation approaches still have some limitations in risk control, which may lead to intolerable paper losses in practical stock investing. To effectively reduce risks, we draw inspiration from adversarial learning and propose a novel
Split Variational Adversarial Training
(SVAT) method for risk-aware stock recommendation. Essentially, SVAT encourages the stock model to be sensitive to adversarial perturbations of risky stock examples and enhances the model’s risk awareness by learning from perturbations. To generate representative adversarial examples as risk indicators, we devise a variational perturbation generator to model diverse risk factors. Particularly, the variational architecture enables our method to provide a rough risk quantification for investors, showing an additional advantage of interpretability. Experiments on several real-world stock market datasets demonstrate the superiority of our SVAT method. By lowering the volatility of the stock-recommendation model, SVAT effectively reduces investment risks and outperforms state-of-the-art baselines by more than 30% in terms of risk-adjusted profits. All the experimental data and source code are available at
https://drive.google.com/drive/folders/14AdM7WENEvIp5x5bV3zV_i4Aev21C9g6?usp=sharing
.
Pelvic Abscess Caused by Ureteral Calculus and Abscess Treatment through Aspiration by Transperineal Puncture
Authors: An Bo-Ran , Gao Chao , An Di
Published: January 2024

Pelvic abscess is mostly caused by gynecological inflammation or digestive system diseases such as appendicitis or Crohn’s disease. This case of pelvic abscess originates from ureteral calculus and is not commonly seen in clinical practice. This is mainly due to the patient’s ureteral stones not being actively treated. After local puncture and pus extraction, as well as the application of effective antibiotics, the patient recovered. Therefore, this case provides clinical doctors with experience that ureteral stones may cause serious complications and should be actively treated after detection.
Multiple Abscess Collections: Antibiotics or Steroids?
Authors: Dias Philippe Raphael , Bolt Levin , Iking-Konert Christof , Arrigo Mattia , Huber Lars C.
Published: January 2024

Aseptic abscess syndrome (AAS) is a medical rarity. The combination of multiple abscess collections in different organs, negative microbiological studies, and the association with an inflammatory bowel disease is highly suggestive for an AAS. The AAS is an acute neutrophilic dermatosis, so “generalized pyoderma gangraenosum” or “generalized bullous sweet syndrome” might be used synonymously. It is important to note that the diagnosis of an AAS can be made only after careful exclusion of an infectious disease. Of interest, despite the severity of the inflammation, patients with AAS are commonly hemodynamically stable. To date, no studies have investigated the optimal regimen, dose, and duration of therapy. Corticosteroids are the cornerstone of immunosuppression during the acute phase. After the induction phase, therapy might be switched to anakinra or infliximab.
Light and Shadow of Na-Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Points for Improvement Based on Our Clinical Experience
Authors: Sonoda Akihiro , Shimada Toshio , Saito Kohei , Kosugi Rieko , Taguchi Yoshitaka , Inoue Tatsuhide
Published: January 2024

We analyzed the effect of Na-glucose cotransporter 2 inhibitors (SGLT2-I) in diabetic patients visiting our hospital. The study included 236 patients treated with SGLT2-I alone or with codiabetic drugs for at least two years. We analyzed overtime changes in glycosylated hemoglobin A1c (HbA1c) in the patients by repeated analyses of variance (ANOVA) and evaluated the therapeutic effect. HbA1c levels decreased significantly in the first six months after treatment. Afterward, they leveled off and increased slightly over the next two years. Six months after treatment, the mean (SD) of HbA1c was 8.19 (1.46) %; the mean difference dropped by 0.91%, and HbA1c in mild DM2 did not drop by below 8.0%. Overall, there was only a slight improvement. We performed multivariate logistic regression analysis using a model with or without improvement as the objective variable and several explanatory variables. Na and Hct were significant factors. They increased considerably over six months and then leveled off. eGFR significantly reduced in the hyperfiltration group six months after treatment. The annual decline rate in eGFR was also faster, even in the nonhyperfiltration group than in the healthy subjects, which may be a characteristic of renal clearance in SGLT2-I treatment. In conclusion, SGLT2-I is an excellent antidiabetic, nephroprotective agent to eliminate hyperfiltration, but unfortunately, SGLT2-I alone does not have enough power to reduce blood glucose levels. SGLT2-I, with insulin or insulin secretagogues, enhances insulin resistance, induces hyperinsulinemia, and exacerbates type 2 DM. In contrast, SGLT2-I, with noninsulin antidiabetic agents and a low-carbohydrate diet, may bring better results.
Data from Mechanistic Dissection of PARP1 Trapping and the Impact on In Vivo Tolerability and Efficacy of PARP Inhibitors
Authors: Hopkins Todd A. , Shi Yan , Rodriguez Luis E. , Solomon Larry R. , Donawho Cherrie K. , DiGiammarino Enrico L. , Panchal Sanjay C. , Wilsbacher Julie L. , Gao Wenqing , Olson Amanda M. , Stolarik DeAnne F. , Osterling Donald J. , Johnson Eric F. , Maag David
Published: January 2024

Abstract
Poly(ADP-ribose) polymerases (PARP1, -2, and -3) play important roles in DNA damage repair. As such, a number of PARP inhibitors are undergoing clinical development as anticancer therapies, particularly in tumors with DNA repair deficits and in combination with DNA-damaging agents. Preclinical evidence indicates that PARP inhibitors potentiate the cytotoxicity of DNA alkylating agents. It has been proposed that a major mechanism underlying this activity is the allosteric trapping of PARP1 at DNA single-strand breaks during base excision repair; however, direct evidence of allostery has not been reported. Here the data reveal that veliparib, olaparib, niraparib, and talazoparib (BMN-673) potentiate the cytotoxicity of alkylating agents. Consistent with this, all four drugs possess PARP1 trapping activity. Using biochemical and cellular approaches, we directly probe the trapping mechanism for an allosteric component. These studies indicate that trapping is due to catalytic inhibition and not allostery. The potency of PARP inhibitors with respect to trapping and catalytic inhibition is linearly correlated in biochemical systems but is nonlinear in cells. High-content imaging of γH2Ax levels suggests that this is attributable to differential potentiation of DNA damage in cells. Trapping potency is inversely correlated with tolerability when PARP inhibitors are combined with temozolomide in mouse xenograft studies. As a result, PARP inhibitors with dramatically different trapping potencies elicit comparable in vivo efficacy at maximum tolerated doses. Finally, the impact of trapping on tolerability and efficacy is likely to be context specific.

Implications: Understanding the context-specific relationships of trapping and catalytic inhibition with both tolerability and efficacy will aid in determining the suitability of a PARP inhibitor for inclusion in a particular clinical regimen. Mol Cancer Res; 13(11); 1465–77. ©2015 AACR.
Table S1 from Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel
Authors: Paiva Bruno , Manrique Irene , Rytlewski Julie , Campbell Timothy , Kazanecki Christian C. , Martin Nathan , Anderson Larry D. , Berdeja Jesús G. , Lonial Sagar , Raje Noopur S. , Lin Yi , Moreau Philippe , San-Miguel Jesús F. , Munshi Nikhil C. , Kaiser Shari M.
Published: January 2024

Patient distribution of paired results
Supplementary Table S1 from ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma
Authors: Neri Paola , Barwick Benjamin G. , Jung David , Patton Jonathan C. , Maity Ranjan , Tagoug Ines , Stein Caleb K. , Tilmont Remi , Leblay Noemie , Ahn Sungwoo , Lee Holly , Welsh Seth J. , Riggs Daniel L. , Stong Nicholas , Flynt Erin , Thakurta Anjan , Keats Jonathan J. , Lonial Sagar , Bergsagel P. Leif , Boise Lawrence H. , Bahlis Nizar J.
Published: January 2024

Univariate and multi-variate analysis of ETV4 expression in the CoMMpass NDMM patients treated with IMiD as part of front-line therapy (N=567).
Supplementary Data 6 from ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma
Authors: Neri Paola , Barwick Benjamin G. , Jung David , Patton Jonathan C. , Maity Ranjan , Tagoug Ines , Stein Caleb K. , Tilmont Remi , Leblay Noemie , Ahn Sungwoo , Lee Holly , Welsh Seth J. , Riggs Daniel L. , Stong Nicholas , Flynt Erin , Thakurta Anjan , Keats Jonathan J. , Lonial Sagar , Bergsagel P. Leif , Boise Lawrence H. , Bahlis Nizar J.
Published: January 2024

ETV4 mRNA data and outcome from the POLLUX and MM-010 trials.
Supplementary Table 2 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma
Authors: Welsh Seth J. , Barwick Benjamin G. , Meermeier Erin W. , Riggs Daniel L. , Shi Chang-Xin , Zhu Yuan Xiao , Sharik Meaghen E. , Du Megan T. , Abrego Rocha Leslie D. , Garbitt Victoria M. , Stein Caleb K. , Petit Joachim L. , Meurice Nathalie , Tafoya Alvarado Yuliza , Fonseca Rodrigo , Todd Kennedi T. , Brown Sochilt , Hammond Zachery J. , Cuc Nicklus H. , Wittenberg Courtney , Herzog Camille , Roschke Anna V. , Demchenko Yulia N. , Chen Wei-dong D. , Li Peng , Liao Wei , Leonard Warren J. , Lonial Sagar , Bahlis Nizar J. , Neri Paola , Boise Lawrence H. , Chesi Marta , Bergsagel P. Leif
Published: January 2024

Primers
Supplementary Table 1 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma
Authors: Welsh Seth J. , Barwick Benjamin G. , Meermeier Erin W. , Riggs Daniel L. , Shi Chang-Xin , Zhu Yuan Xiao , Sharik Meaghen E. , Du Megan T. , Abrego Rocha Leslie D. , Garbitt Victoria M. , Stein Caleb K. , Petit Joachim L. , Meurice Nathalie , Tafoya Alvarado Yuliza , Fonseca Rodrigo , Todd Kennedi T. , Brown Sochilt , Hammond Zachery J. , Cuc Nicklus H. , Wittenberg Courtney , Herzog Camille , Roschke Anna V. , Demchenko Yulia N. , Chen Wei-dong D. , Li Peng , Liao Wei , Leonard Warren J. , Lonial Sagar , Bahlis Nizar J. , Neri Paola , Boise Lawrence H. , Chesi Marta , Bergsagel P. Leif
Published: January 2024

Multi-variate analysis of BATF, BATF2, and BATF3 expression
Supplementary Figures S1-S11 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma
Authors: Welsh Seth J. , Barwick Benjamin G. , Meermeier Erin W. , Riggs Daniel L. , Shi Chang-Xin , Zhu Yuan Xiao , Sharik Meaghen E. , Du Megan T. , Abrego Rocha Leslie D. , Garbitt Victoria M. , Stein Caleb K. , Petit Joachim L. , Meurice Nathalie , Tafoya Alvarado Yuliza , Fonseca Rodrigo , Todd Kennedi T. , Brown Sochilt , Hammond Zachery J. , Cuc Nicklus H. , Wittenberg Courtney , Herzog Camille , Roschke Anna V. , Demchenko Yulia N. , Chen Wei-dong D. , Li Peng , Liao Wei , Leonard Warren J. , Lonial Sagar , Bahlis Nizar J. , Neri Paola , Boise Lawrence H. , Chesi Marta , Bergsagel P. Leif
Published: January 2024

Supplementary Figures 1-11, which support data and conclusions provided in the main figures
Supplementary Data 4 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma
Authors: Welsh Seth J. , Barwick Benjamin G. , Meermeier Erin W. , Riggs Daniel L. , Shi Chang-Xin , Zhu Yuan Xiao , Sharik Meaghen E. , Du Megan T. , Abrego Rocha Leslie D. , Garbitt Victoria M. , Stein Caleb K. , Petit Joachim L. , Meurice Nathalie , Tafoya Alvarado Yuliza , Fonseca Rodrigo , Todd Kennedi T. , Brown Sochilt , Hammond Zachery J. , Cuc Nicklus H. , Wittenberg Courtney , Herzog Camille , Roschke Anna V. , Demchenko Yulia N. , Chen Wei-dong D. , Li Peng , Liao Wei , Leonard Warren J. , Lonial Sagar , Bahlis Nizar J. , Neri Paola , Boise Lawrence H. , Chesi Marta , Bergsagel P. Leif
Published: January 2024

Gene expression associated with BATF in NDMM bone marrow CoMMpass samples
Supplementary Data 2 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma
Authors: Welsh Seth J. , Barwick Benjamin G. , Meermeier Erin W. , Riggs Daniel L. , Shi Chang-Xin , Zhu Yuan Xiao , Sharik Meaghen E. , Du Megan T. , Abrego Rocha Leslie D. , Garbitt Victoria M. , Stein Caleb K. , Petit Joachim L. , Meurice Nathalie , Tafoya Alvarado Yuliza , Fonseca Rodrigo , Todd Kennedi T. , Brown Sochilt , Hammond Zachery J. , Cuc Nicklus H. , Wittenberg Courtney , Herzog Camille , Roschke Anna V. , Demchenko Yulia N. , Chen Wei-dong D. , Li Peng , Liao Wei , Leonard Warren J. , Lonial Sagar , Bahlis Nizar J. , Neri Paola , Boise Lawrence H. , Chesi Marta , Bergsagel P. Leif
Published: January 2024

GSEA Hallmark Gene Sets
Table S3 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Shichijo Takafumi , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Salah Tarig , Zhang Wenyi , Hussein Osama , Sonoda Miyu , Watanabe Miho , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: January 2024

Oligonucleotides used in this study.
Table S1 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Shichijo Takafumi , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Salah Tarig , Zhang Wenyi , Hussein Osama , Sonoda Miyu , Watanabe Miho , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: January 2024

Human cluster 2 genes whose H3K27me3 in TSS's was decreased.
Figure S6 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Shichijo Takafumi , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Salah Tarig , Zhang Wenyi , Hussein Osama , Sonoda Miyu , Watanabe Miho , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: January 2024

Efficacy of the MCT1/4 inhibitor syrosingopine on ATL cells.
Figure S5 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Shichijo Takafumi , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Salah Tarig , Zhang Wenyi , Hussein Osama , Sonoda Miyu , Watanabe Miho , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: January 2024

Transcriptional regulation of SLC16A1 and SLC16A3 by TAp73, and mRNA expression levels of MCT-coding genes among various cancers.
Figure S3 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Shichijo Takafumi , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Salah Tarig , Zhang Wenyi , Hussein Osama , Sonoda Miyu , Watanabe Miho , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: January 2024

Regulation of TP73 by BATF3 and IRF4.
Supplementary Tables S1 to S15 from Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells
Authors: Nelde Annika , Schuster Heiko , Heitmann Jonas S. , Bauer Jens , Maringer Yacine , Zwick Melissa , Volkmer Jens-Peter , Chen James Y. , Stanger Anna M. Paczulla , Lehmann Ariane , Appiah Bismark , Märklin Melanie , Rücker-Braun Elke , Salih Helmut R. , Roerden Malte , Schroeder Sarah M. , Häring Max-Felix , Schlosser Andreas , Schetelig Johannes , Schmitz Marc , Boerries Melanie , Köhler Natalie , Lengerke Claudia , Majeti Ravindra , Weissman Irving L. , Rammensee Hans-Georg , Walz Juliane S.
Published: January 2024

The Supplementary Tables file includes Tables S1 to S15.
Table S1: Frequencies of CD34+CD38- LSCs within primary AML patient samples.
Table S2: Immunopeptidomics cohort overview.
Table S3: Patient characteristics of AML immunopeptidomics cohort.
Table S4: AML- and AML/LSC-associated HLA class I targets.
Table S5: AML/LSC shared HLA class I-presented antigens.
Table S6: AML- and AML/LSC-associated HLA class II peptide, protein, and hotspot targets.
Table S7: AML/LSC shared HLA class II-presented peptide targets.
Table S8: Recurrent AML mutations included in neoepitope screening.
Table S9: Characteristics of AML patient samples used for T cell-based assays.
Table S10: Characteristics of HV samples used for T cell-based assays.
Table S11: Immunopeptidome diversity according to demographics and disease characteristics.
Table S12: Impact of demographics and disease characteristics on patient outcome in the immunopeptidome survival analysis group.
Table S13: Patient characteristics of immunopeptidome survival analysis group.
Table S14: Patient characteristics of immune response survival analysis group.
Table S15: Impact of demographics and hematopoietic stem cell transplantation on patient outcome in the immune response survival group.
Table S6 from A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML
Authors: Chen Lanpeng , Pronk Eline , van Dijk Claire , Bian Yujie , Feyen Jacqueline , van Tienhoven Tim , Yildirim Meltem , Pisterzi Paola , de Jong Madelon M.E. , Bastidas Alejandro , Hoogenboezem Remco M. , Wevers Chiel , Bindels Eric M. , Löwenberg Bob , Cupedo Tom , Sanders Mathijs A. , Raaijmakers Marc H.G.P.
Published: January 2024

Supplementary Table 6. Differentially expressed genes in BMSCs from AML vs. BMSCs from NBM (purified BMSC RNAseq)
Supplementary Figures S1-S13 from Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells
Authors: Nelde Annika , Schuster Heiko , Heitmann Jonas S. , Bauer Jens , Maringer Yacine , Zwick Melissa , Volkmer Jens-Peter , Chen James Y. , Stanger Anna M. Paczulla , Lehmann Ariane , Appiah Bismark , Märklin Melanie , Rücker-Braun Elke , Salih Helmut R. , Roerden Malte , Schroeder Sarah M. , Häring Max-Felix , Schlosser Andreas , Schetelig Johannes , Schmitz Marc , Boerries Melanie , Köhler Natalie , Lengerke Claudia , Majeti Ravindra , Weissman Irving L. , Rammensee Hans-Georg , Walz Juliane S.
Published: January 2024

The Supplementary Figures file includes Figures S1 to S13.
Figure S1: Gating strategy for the evaluation of LSC frequencies pre and post enrichment.
Figure S2: Amino acid distribution within LSC and AML bulk immunopeptidomes.
Figure S3: HLA class I immunopeptidomics.
Figure S4: Abundance of AML- and AML/LSC-associated HLA class I ligands within the immunopeptidome.
Figure S5: Identification of AML- and AML/LSC-associated HLA class II antigen targets by comparative immunopeptidome profiling.
Figure S6: Abundance of AML- and AML/LSC-associated HLA class II peptides within the immunopeptidome.
Figure S7: Spectral validation of HLA class I-restricted AML- and AML/LSC-associated peptides.
Figure S8: Spectral validation of HLA class II-restricted AML- and AML/LSC-associated peptides.
Figure S9: Magnitude and functionality of in vitro primed CD8+ T cells.
Figure S10: Characterization of memory T cell responses detected in ELISpot assays.
Figure S11: Further characterization of HLA class II-restricted antigens.
Figure S12: In-depth characterization and phenotyping of HLA class II AML/LSC-specific CD4+ T cells by single-cell RNA sequencing and multi-color flow cytometry.
Figure S13: Impact of immunopeptidome diversity and peptide-specific immune responses on patient survival.
Table S5 from A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML
Authors: Chen Lanpeng , Pronk Eline , van Dijk Claire , Bian Yujie , Feyen Jacqueline , van Tienhoven Tim , Yildirim Meltem , Pisterzi Paola , de Jong Madelon M.E. , Bastidas Alejandro , Hoogenboezem Remco M. , Wevers Chiel , Bindels Eric M. , Löwenberg Bob , Cupedo Tom , Sanders Mathijs A. , Raaijmakers Marc H.G.P.
Published: January 2024

Table S5 Differentially expressed genes in residual normal/pre-leukemic HSCs in AML vs. HSCs from NBM (scRNAseq)
Table S2 from A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML
Authors: Chen Lanpeng , Pronk Eline , van Dijk Claire , Bian Yujie , Feyen Jacqueline , van Tienhoven Tim , Yildirim Meltem , Pisterzi Paola , de Jong Madelon M.E. , Bastidas Alejandro , Hoogenboezem Remco M. , Wevers Chiel , Bindels Eric M. , Löwenberg Bob , Cupedo Tom , Sanders Mathijs A. , Raaijmakers Marc H.G.P.
Published: January 2024

Table S2 Differentially expressed genes in the HSC (low-output) cluster 0 vs. (high-output) HSC/MPP clusters 1-4
Data from ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma
Authors: Neri Paola , Barwick Benjamin G. , Jung David , Patton Jonathan C. , Maity Ranjan , Tagoug Ines , Stein Caleb K. , Tilmont Remi , Leblay Noemie , Ahn Sungwoo , Lee Holly , Welsh Seth J. , Riggs Daniel L. , Stong Nicholas , Flynt Erin , Thakurta Anjan , Keats Jonathan J. , Lonial Sagar , Bergsagel P. Leif , Boise Lawrence H. , Bahlis Nizar J.
Published: January 2024

Abstract
Immunomodulatory drugs (IMiD) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance, and the mechanisms are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 coactivators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor binding motifs, including ETV4. Chromatin immunoprecipitation sequencing showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and is upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance.
Significance:
We show that IKZF1-bound enhancers are critical for IMiD efficacy and that the factor ETV4 can bind the same enhancers and substitute for IKZF1 and mediate IMiD resistance by maintaining MYC and other oncogenes. These data implicate transcription factor redundancy as a previously unrecognized mode of IMiD resistance in MM.

See related article by Welsh, Barwick, et al., p. 34.

See related commentary by Yun and Cleveland, p. 5.

This article is featured in Selected Articles from This Issue, p. 4
Supplementary Table 1 from Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer
Authors: Soto Maira , Filbert Erin L. , Yang Hai , Starzinski Stephanie , Starzinski Alec , Gin Marissa , Chen Brandon , Le Phi , Li Tony , Bol Brandon , Cheung Alexander , Zhang Li , Hsu Frank J. , Ko Andrew , Fong Lawrence , Keenan Bridget P.
Published: January 2024

Patient clinical characteristics and sample availability.
Supplementary Figure 5 from Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer
Authors: Soto Maira , Filbert Erin L. , Yang Hai , Starzinski Stephanie , Starzinski Alec , Gin Marissa , Chen Brandon , Le Phi , Li Tony , Bol Brandon , Cheung Alexander , Zhang Li , Hsu Frank J. , Ko Andrew , Fong Lawrence , Keenan Bridget P.
Published: January 2024

Supplementary Figure 5
FIGURE 4 from Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer
Authors: Soto Maira , Filbert Erin L. , Yang Hai , Starzinski Stephanie , Starzinski Alec , Gin Marissa , Chen Brandon , Le Phi , Li Tony , Bol Brandon , Cheung Alexander , Zhang Li , Hsu Frank J. , Ko Andrew , Fong Lawrence , Keenan Bridget P.
Published: January 2024

Sotigalimab induces activation and trafficking of immune cells within the blood. A and B, Heat maps of cell frequency and cell surface marker expression as analyzed by CyTOF for T and NK cells (A) and antigen-presenting cells (B; pre n = 6, post n = 6). The count column shows the number of cells in each cluster. The “frequency signif” columns indicates statistical significance for differences in cell frequency of which there were none. Red and blue in the protein columns indicate significant up- or down-regulation of expression for the indicated cell cluster. C, UMAP plots of PBMCs analyzed by CITEseq showing cell annotation (top) and abundance of cells by timepoint (bottom; pre n = 6, post n = 6). D, Quantification of cell frequency as percentage of all immune cells by timepoint from the CITEseq data (pre n = 6, post n = 6). *, P < 0.05; **, P < 0.01, unmarked comparisons are not significant. E, Expression of cell surface proteins indicative of cell trafficking and activation via CITEseq for CD8+ and CD4+ T cells, and adhesion molecules in CD14+ monocytes, for pre- and post-sotigalimab (pre n = 6, post n = 6). For scRNAseq data in E, all comparisons are significant with an adjusted P < 0.05.
Data from Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer
Authors: Soto Maira , Filbert Erin L. , Yang Hai , Starzinski Stephanie , Starzinski Alec , Gin Marissa , Chen Brandon , Le Phi , Li Tony , Bol Brandon , Cheung Alexander , Zhang Li , Hsu Frank J. , Ko Andrew , Fong Lawrence , Keenan Bridget P.
Published: January 2024

Abstract
Sotigalimab is an agonistic anti-CD40 mAb that can modulate antitumor immune responses. In a phase II clinical trial of sotigalimab combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction (E/GEJ) cancer with the primary outcome of efficacy as measured by pathologic complete response (pCR) rate, the combination induced pCR in 38% of treated patients. We investigated the mechanism of action of sotigalimab in samples obtained from this clinical trial. Tumor biopsies and peripheral blood samples were collected at baseline, following an initial dose of sotigalimab, and at the time of surgery after CRT completion from six patients. High dimensional single-cell techniques were used, including combined single-cell RNA-sequencing and proteomics (CITEseq) and multiplexed ion beam imaging, to analyze immune responses. Sotigalimab dramatically remodeled the immune compartment in the periphery and within the tumor microenvironment (TME), increasing expression of molecules related to antigen processing and presentation and altering metabolic pathways in myeloid cells. Concomitant with these changes in myeloid cells, sotigalimab treatment primed new T cell clonotypes and increased the density and activation of T cells with enhanced cytotoxic function. Sotigalimab treatment also induced a decrease in the frequency of Tregs in the TME. These findings indicate that a single dose of sotigalimab leads to enhanced antigen presentation that can activate T cells and induce new T cell clones. This restructuring of the TME provides elements which are critical to the development of effective antitumor immune responses and improved clinical outcomes.