Intrinsic Roles Research Articles

Single-atom Barium Promoter Enormously Enhanced Non-noble Metal Catalyst for Ammonia Decomposition.

As a well-established topic, single-atom catalyst has drawn growing interest for its high utilization of metal. However, researchers prefer to develop various active metals with single-atom form, the intrinsic roles of single-atom promoters are usually underrated, which are significant in boosting reaction activity. In this work, Ba single atoms were in situ prepared in the Co-Ba/Y2O3 catalyst with crystallized BaCO3 as the precursor under the ammonia decomposition reaction condition. The optimized Co-Ba/Y2O3 catalyst achieves extremely high H2 production rate of 138.3 mmolH2·gcat-1·min-1 at very low temperature (500 °C, GHSV = 840,000 mL·g-1·h-1) and Co-Ba/Y2O3 exhibits excellent durability during the 350 h test, which realizes the highest activity among all non-noble catalysts, and reaches or even exceeds numerous reported Ru-based catalysts. Both Y2O3 and Co demonstrate positive interactions with Ba, which significantly facilitates the dispersion of Ba species at high temperatures (≥ 600 °C). Ba single atoms significantly enhance the charge density of Co and form additionally active Co-O-Ba-Y2O3 interfacial sites, which alleviates hydrogen poisoning and decreases the reaction barrier of the N-H bond activation of *NH. The exploration of atomically dispersed promoters is groundbreaking in heterogeneous catalysis, which opens up a whole new domain of catalytic material.

Single‐atom Barium Promoter Enormously Enhanced Non‐noble Metal Catalyst for Ammonia Decomposition

As a well‐established topic, single‐atom catalyst has drawn growing interest for its high utilization of metal. However, researchers prefer to develop various active metals with single‐atom form, the intrinsic roles of single‐atom promoters are usually underrated, which are significant in boosting reaction activity. In this work, Ba single atoms were in situ prepared in the Co‐Ba/Y2O3 catalyst with crystallized BaCO3 as the precursor under the ammonia decomposition reaction condition. The optimized Co‐Ba/Y2O3 catalyst achieves extremely high H2 production rate of 138.3 mmolH2·gcat−1·min−1 at very low temperature (500 °C, GHSV = 840,000 mL·g−1·h−1) and Co‐Ba/Y2O3 exhibits excellent durability during the 350 h test, which realizes the highest activity among all non‐noble catalysts, and reaches or even exceeds numerous reported Ru‐based catalysts. Both Y2O3 and Co demonstrate positive interactions with Ba, which significantly facilitates the dispersion of Ba species at high temperatures (≥ 600 °C). Ba single atoms significantly enhance the charge density of Co and form additionally active Co‐O‐Ba‐Y2O3 interfacial sites, which alleviates hydrogen poisoning and decreases the reaction barrier of the N‐H bond activation of *NH. The exploration of atomically dispersed promoters is groundbreaking in heterogeneous catalysis, which opens up a whole new domain of catalytic material.

Comparative proteomic analysis of regenerative mechanisms in mouse retina to identify markers for neuro-regeneration in glaucoma

The retina is part of the central nervous system (CNS). Neurons in the CNS and retinal ganglion cells lack the ability to regenerate axons spontaneously after injury. The intrinsic axonal growth regulators, their interaction and roles that enable or inhibit axon growth are still largely unknown. This study endeavored to characterize the molecular characteristics under neurodegenerative and regenerative conditions. Data-Independent Acquisition Mass Spectrometry was used to map the comprehensive proteome of the regenerative retina from 14-day-old mice (Reg-P14) and adult mice after lens injury (Reg-LI) both showing regrowing axons in vitro, untreated adult mice, and retina from adult mice subjected to two weeks of elevated intraocular pressure showing degeneration. A total of 5750 proteins were identified (false discovery rate < 1%). Proteins identified in both Reg-P14 and Reg-LI groups were correlated to thyroid hormone, Notch, Wnt, and VEGF signaling pathways. Common interactors comprising E1A binding protein P300 (EP300), CREB binding protein (CBP), calcium/calmodulin dependent protein kinase II alpha (CaMKIIα) and sirtuin 1 (SIRT1) were found in both Reg-P14 and Reg-LI retinas. Proteins identified in both regenerating and degenerative groups were correlated to thyroid hormone, Notch, mRNA surveillance and measles signaling pathways, along with PD-L1 expression and the PD-1 checkpoint pathway. Common interactors across regenerative and degenerative retinas comprising NF-kappa-B p65 subunit (RELA), RNA-binding protein with serine-rich domain 1 (RNPS1), EP300 and SIN3 transcription regulator family member A (SIN3A). The findings from our study provide the first mapping of regenerative mechanisms across postnatal, mature and degenerative mouse retinas, revealing potential biomarkers that could facilitate neuro-regeneration in glaucoma.

KRAS-Driven Tumorigenesis and KRAS-Driven Therapy in Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality and is projected to be the second leading cause of cancer-related deaths by 2030. Mutations in KRAS are found in the vast majority of PDAC cases and plays an important role in the development of the disease. KRAS drives tumor cell proliferation and survival through activating the MAPK pathway to drive cell cycle progression and to lead to MYC-driven cellular programs. Moreover, activated KRAS promotes a protumorigenic microenvironment through forming a desmoplastic stroma and by impairing antitumor immunity. Secretion of granulocyte-macrophage colony-stimulating factor and recruitment of myeloid-derived suppressor cells and protumorigenic macrophages results in an immunosuppressive environment while secretion of secrete sonic hedgehog and TGFβ drive fibroblastic features characteristic of PDAC. Recent development of several small molecules to directly target KRAS marks an important milestone in precision medicine. Many molecules show promise in preclinical models of PDAC and in early phase clinical trials. In this review, we discuss the underlying cell intrinsic and extrinsic roles of KRAS in PDAC tumorigenesis, the pharmacologic development of KRAS inhibition, and therapeutic strategies to target KRAS in PDAC.

The Many Faces of Hypusinated eIF5A: Cell Context-Specific Effects of the Hypusine Circuit and Implications for Human Health.

The unique amino acid hypusine [Nε-(4-amino-2-hydroxybutyl)lysine] is exclusively formed on the translational regulator eukaryotic initiation factor 5A (eIF5A) via a process coined hypusination. Hypusination is mediated by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), and hypusinated eIF5A (eIF5AHyp) promotes translation elongation by alleviating ribosome pauses at amino acid motifs that cause structural constraints, and it also facilitates translation initiation and termination. Accordingly, eIF5AHyp has diverse biological functions that rely on translational control of its targets. Homozygous deletion of Eif5a, Dhps, or Dohh in mice leads to embryonic lethality, and heterozygous germline variants in EIF5A and biallelic variants in DHPS and DOHH are associated with rare inherited neurodevelopmental disorders, underscoring the importance of the hypusine circuit for embryonic and neuronal development. Given the pleiotropic effects of eIF5AHyp, a detailed understanding of the cell context-specific intrinsic roles of eIF5AHyp and of the chronic versus acute effects of eIF5AHyp inhibition is necessary to develop future strategies for eIF5AHyp-targeted therapy to treat various human health problems. Here, we review the most recent studies documenting the intrinsic roles of eIF5AHyp in different tissues/cell types under normal or pathophysiological conditions and discuss these unique aspects of eIF5AHyp-dependent translational control.

Memory inflation: Beyond the acute phase of viral infection.

Memory inflation is confirmed as the most commonly dysregulation of host immunity with antigen-independent manner in mammals after viral infection. By generating large numbers of effector/memory and terminal differentiated effector memory CD8+ T cells with diminished naïve subsets, memory inflation is believed to play critical roles in connecting the viral infection and the onset of multiple diseases. Here, we reviewed the current understanding of memory inflated CD8+ T cells in their distinct phenotypic features that different from exhausted subsets; the intrinsic and extrinsic roles in regulating the formation of memory inflation; and the key proteins in maintaining the expansion and proliferation of inflationary populations. More importantly, based on the evidences from both clinic and animal models, we summarized the potential mechanisms of memory inflation to trigger autoimmune neuropathies, such as Guillain-Barré syndrome and multiple sclerosis; the correlations of memory inflation between tumorigenesis and resistance of tumour immunotherapies; as well as the effects of memory inflation to facilitate vascular disease progression. To sum up, better understanding of memory inflation could provide us an opportunity to beyond the acute phase of viral infection, and shed a light on the long-term influences of CD8+ T cell heterogeneity in dampen host immune homeostasis.

Using Attention-UNet Models to Predict Protein Contact Maps.

Proteins are essential to life, and understanding their intrinsic roles requires determining their structure. The field of proteomics has opened up new opportunities by applying deep learning algorithms to large databases of solved protein structures. With the availability of large data sets and advanced machine learning methods, the prediction of protein residue interactions has greatly improved. Protein contact maps provide empirical evidence of the interacting residue pairs within a protein sequence. Template-free protein structure prediction systems rely heavily on this information. This article proposes UNet-CON, an attention-integrated UNet architecture, trained to predict residue-residue contacts in protein sequences. With the predicted contacts being more accurate than state-of-the-art methods on the PDB25 test set, the model paves the way for the development of more powerful deep learning algorithms for predicting protein residue interactions.

Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC

Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine–glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8+ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.

255 Anchor Talk: Consider intrinsic factors that regulate homeostasis to optimize sustainability of mineral supplements for swine

Abstract Decades of research has focused on methodologies to improve the efficiency of mineral use while assuring sufficient intake to meet animal well-being and production needs. A primary focus of these efforts is P, as P is the third most expensive category of nutrients supplemented in swine diets. Bioavailability of P is more variable than other nutrients in feed ingredients commonly fed to swine. Due to complexities involved in assessments of P bioavailability efforts shifted to defining P digestibilities for each ingredient. Efforts to refine P digestibilities, based on intake and fecal excretion, even with corrections for endogenous losses, have failed to provide a constant coefficient for feed ingredients that can be included in diet formulations, as the digestibility estimates vary with animal age, production phases and inclusion of enzymes such as phytase. An under-appreciated contribution to inaccuracies of digestible P relates to intrinsic regulation of Ca and P homeostasis by the animal. Regulation of Ca and P homeostasis by PTH and 1,25(OH)2D3, must now include a third mineralotropic hormone, FGF23. Applying insights for intrinsic roles of FGF23 will allow more efficient use of nutrients, especially P and vitamin D. FGF23 regulates activation of vitamin D and controls renal P excretion. Over-supplementation of P signals osteocytes (bone cells embedded in a mineralized matrix) to release intact FGF23 which targets the kidney to block reabsorption of P for maintenance of soft tissue homeostasis, resulting in an inefficient use of dietary P. Intact FGF23 also inhibits hydroxylation of 25-OH D3 to form 1,25(OH)2D3. These endocrine pathways illustrate major roles provided by kidneys and bone to allow adaptation to variable Ca and P inputs, thus maintaining homeostasis. Recent efforts to assess P requirements of sows during gestation and lactation illustrate the sensitivity of using renal excretion of Ca and P to assess requirements. Based on 24-h collections, urine Ca:P ratios &amp;gt; 1.5 were consistent with deficient P intake, ratios from 0.5 to 1.5 reflected P adequacy, and ratios &amp;lt; 0.5 indicated excessive P intake. As a practical method, spot urine samples collected at variable times throughout the day reliably predicted Ca:P ratios in 24-h urine collections. Thus, a simplified approach using Ca to P ratio in spot urine samples can be used to assess P intake adequacy. This practical approach can be applied in commercial sow herd to allow herd-based assessment of P status. In conclusion, within herd assessments, based on urine Ca:P ratios, can be used to determine if P supplements are deficient, adequate, and excessive. As such, significant progress can be made to provide a balance between the need to adequately meet animal need with efforts to minimize negative environmental impacts from over-supplementation of P.

In EPAs we trust, is quality and safety a must? A cross-specialty analysis of entrustable professional activity guides

Purpose The inclusion of quality improvement (QI) and patient safety (PS) into CanMEDS reflects an expectation that graduating physicians are competent in these areas upon training completion. To ensure that Canadian postgraduate specialty training achieves this, the translation of QI/PS competencies into training standards as part of the implementation of competency-based medical education requires special attention. Methods We conducted a cross-specialty, multi-method analysis to examine how QI/PS was incorporated into the EPA Guides across 11 postgraduate specialties in Canada. Results We identify cross-specialty variability in how QI/PS is incorporated, positioned, and emphasized in EPAs and milestones. QI/PS was primarily referenced alongside clinical activities rather than as a sole competency or discrete activity. Patterns were characterized in how QI/PS became incorporated into milestones through repetition and customization. QI/PS was also decoupled, conceptualized, and emphasized differently across specialties. Conclusions Variability in the inclusion of QI/PS in EPAs and milestones has important implications considering the visibility and influence of EPA Guides in practice. As specialties revisit and revise EPA Guides, there is a need to balance the standardization of foundational QI/PS concepts to foster shared understanding while simultaneously ensuring context-sensitive applications across specialties. Beyond QI/PS, this study illuminates the challenges and opportunities that lie in bridging theoretical frameworks with practical implementation in medical education, prompting broader consideration of how intrinsic roles and emergent areas are effectively incorporated into competency-based medical education.

Dual purposes by design: exploring alignment between residents' and academic advisors' documents in a longitudinal program.

Longitudinal academic advising (AA) and coaching programs are increasingly implemented in competency based medical education (CBME) to help residents reflect and act on the voluminous assessment data they receive. Documents created by residents for purposes of reflection are often used for a second, summative purpose-to help competence committees make decisions-which may be problematic. Using inductive, thematic analysis we analyzed written comments generated by 21 resident-AA dyads in one large internal medicine program who met over a 2year period to determine what residents write when asked to reflect, how this aligns with what the AAs report, and what changes occur over time (total 109 resident self-reflections and 105 AA reports). Residents commented more on their developing autonomy, progress and improvement than AAs, who commented far more on performance measures. Over time, residents' writing shifted away from intrinsic roles, patient care and improvement towards what AAs focused on, including getting EPAs (entrustable professional activities), studying and exams. For EPAs, the emphasis was on getting sufficient numbers rather than reflecting on what residents were learning. Our findings challenge the practice of dual-purposing documents, by questioning the blurring of formative and summative intent, the structure of forms and their multiple conflicting purposes, and assumptions about the advising relationship over time. Our study suggests a need to re-evaluate how reflective documents are used in CBME programs. Further research should explore whether and how documentation can best be used to support resident growth and development.

Abstract B015: CCDC80 as a novel cell intrinsic tumor suppressor protein in high grade serous ovarian cancer

Abstract B015: CCDC80 as a novel cell intrinsic tumor suppressor protein in high grade serous ovarian cancer

A double inducible cell ablation system for eliminating senescent astrocytes via apoptosis.

Cell senescence stands as a principal risk factor for various neurodegenerative diseases, with astrocytic senescence emerging as a potentially pivotal player in the pathogenesis of aging and neurodegenerative disorders. Clearing senescent astrocytes holds promise as a potential therapeutic approach for senescence-related diseases. In this study, we designed and constructed two plasmids aimed at inducing apoptosis in senescent astrocytes. This was achieved through the ligation of FKBP (FK506-binding protein) and FRB (FKBP and FKBP rapamycin binding domain) and the formation of caspase8 dimers, thereby achieving the purpose of eliminating senescent astrocytes. The developed vector system demonstrates a specifically capability to induce apoptosis in aging astrocytes, offering a targeted approach to eliminate these cells. The utilization of the double -inducible suicide gene system provides a versatile tool forstimulating cell apoptosis and inhibiting cellular senescence. This system proves valuable in exploring the intrinsic roles and molecular mechanisms of senescent cells in the occurrence and development of aging-related diseases. Ultimately, it offers a potential avenue for developing an efficient treatment system for such conditions.

Making assessment a team sport: a qualitative study of facilitated group feedback in internal medicine residency.

Competency-based medical education relies on feedback from workplace-based assessment (WBA) to direct learning. Unfortunately, WBAs often lack rich narrative feedback and show bias towards Medical Expert aspects of care. Building on research examining interactive assessment approaches, the Queen's University Internal Medicine residency program introduced a facilitated, team-based assessment initiative ("Feedback Fridays") in July 2017, aimed at improving holistic assessment of resident performance on the inpatient medicine teaching units. In this study, we aim to explore how Feedback Fridays contributed to formative assessment of Internal Medicine residents within our current model of competency-based training. A total of 53 residents participated in facilitated, biweekly group assessment sessions during the 2017 and 2018 academic year. Each session was a 30-minute facilitated assessment discussion done with one inpatient team, which included medical students, residents, and their supervising attending. Feedback from the discussion was collected, summarized, and documented in narrative form in electronic WBA forms by the program's assessment officer for the residents. For research purposes, verbatim transcripts of feedback sessions were analyzed thematically. The researchers identified four major themes for feedback: communication, intra- and inter-personal awareness, leadership and teamwork, and learning opportunities. Although feedback related to a broad range of activities, it showed strong emphasis on competencies within the intrinsic CanMEDS roles. Additionally, a clear formative focus in the feedback was another important finding. The introduction of facilitated team-based assessment in the Queen's Internal Medicine program filled an important gap in WBA by providing learners with detailed feedback across all CanMEDS roles and by providing constructive recommendations for identified areas for improvement.

Intermittent proton bursts of single lactic acid bacteria.

Lactic acid bacteria are a kind of probiotic microorganisms that efficiently convert carbohydrates to lactic acids, thus playing essential roles in fermentation and food industry. While conventional wisdom often suggests continuous release of protons from bacteria during acidification, here we developed a methodology to measure the dynamics of proton release at the single bacteria level, and report on the discovery of a proton burst phenomenon, i.e., the intermittent efflux of protons, of single Lactobacillus plantarum bacteria. When placing an individual bacterium in an oil-sealed microwell, efflux and accumulation of protons consequently reduced the pH in the confined extracellular medium, which was monitored with fluorescent pH indicators in a high-throughput and real-time manner. In addition to the slow and continuous proton release behavior (as expected), stochastic and intermittent proton burst events were surprisingly observed with a typical timescale of several seconds. It was attributed to the regulatory response of bacteria by activating H+-ATPase to compensate the stochastic and transient depolarizations of membrane potential. These findings not only revealed an unprecedented proton burst phenomenon in lactic acid bacteria, but also shed new lights on the intrinsic roles of H+-ATPase in membrane potential homeostasis, with implications for both fermentation industry and bacterial electrophysiology.

Amorphization of Inorganic Solid Electrolyte Interphase Components and Its Impact on Enhancing Their Transport and Mechanical Properties.

The safety and cycle life of lithium-ion batteries (LIBs) are largely determined by the solid electrolyte interphase (SEI) formed on the surface of the anode. However, there is still a lack of understanding regarding the structure and properties of the individual SEI components. Among others, lithium oxide (Li2O), lithium carbonate (Li2CO3), and lithium fluoride (LiF) are known to be the main components of the inorganic SEI layer in conventional LIBs, but their intrinsic protective roles remain controversial. Herein, we present the transformational effects of their amorphous phase on the mechanical and transport characteristics, based on first-principles calculations. Our studies clearly demonstrate that their amorphous phases exhibit significantly improved Li-ion conductivity when compared to the crystalline structures. Additionally, among them, amorphous LiF emerges as a frontrunner for fast Li+ ion transportation, reversing the conventionally understood hierarchy. Under ambient conditions, the amorphous phases of LiF, Li2O, and Li2CO3 are thermodynamically unstable and tend to undergo recrystallization. However, this work highlights that exceptionally ductile and resilient amorphous phases can form if SEI formation and growth would involve some admixing of lithiophilic impurities like nitrogen (N) within the host matrices.

Branched Latent Neural Maps

We introduce Branched Latent Neural Maps (BLNMs) to learn finite dimensional input–output maps encoding complex physical processes. A BLNM is defined by a simple and compact feedforward partially-connected neural network that structurally disentangles inputs with different intrinsic roles, such as the time variable from model parameters of a differential equation, while transferring them into a generic field of interest. BLNMs leverage latent outputs to enhance the learned dynamics and break the curse of dimensionality by showing excellent in-distribution generalization properties with small training datasets and short training times on a single processor. Indeed, their in-distribution generalization error remains comparable regardless of the adopted discretization during the testing phase. Moreover, the partial connections, in place of a fully-connected structure, significantly reduce the number of tunable parameters. We show the capabilities of BLNMs in a challenging test case involving biophysically detailed electrophysiology simulations in a biventricular cardiac model of a pediatric patient with hypoplastic left heart syndrome. The model includes a 1D Purkinje network for fast conduction and a 3D heart-torso geometry. Specifically, we trained BLNMs on 150 in silico generated 12-lead electrocardiograms (ECGs) while spanning 7 model parameters, covering cell-scale, organ-level and electrical dyssynchrony. Although the 12-lead ECGs manifest very fast dynamics with sharp gradients, after automatic hyperparameter tuning the optimal BLNM, trained in less than 3 h on a single CPU, retains just 7 hidden layers and 19 neurons per layer. The resulting mean square error is on the order of 10−4 on an independent test dataset comprised of 50 additional electrophysiology simulations. In the online phase, the BLNM allows for 5000x faster real-time simulations of cardiac electrophysiology on a single core standard computer and can be employed to solve inverse problems via global optimization in a few seconds of computational time. This paper provides a novel computational tool to build reliable and efficient reduced-order models for digital twinning in engineering applications. The Julia implementation is publicly available under MIT License at https://github.com/StanfordCBCL/BLNM.jl.

TIMELESS upregulates PD-L1 expression and exerts an immunosuppressive role in breast cancer

BackgroundUpregulation of the PD-L1 (CD274) immune checkpoint ligand on the tumor surface facilitates tumor immune escape and limits the application of immunotherapy in various cancers, including breast cancer. However, the mechanisms underlying high PD-L1 levels in cancers are still poorly understood.MethodsBioinformatics analyses and in vivo and in vitro experiments were carried out to assess the association between CD8+ T lymphocytes and TIMELESS (TIM) expression, and to discover the mechanisms of TIM, the transcription factor c-Myc, and PD-L1 in breast cancer cell lines.ResultsThe circadian gene TIM enhanced PD-L1 transcription and facilitated the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Bioinformatic analyses of our RNA sequencing data in TIM-knockdown breast cancer cells and public transcriptomic datasets showed that TIM might play an immunosuppressive role in breast cancer. We found that TIM expression was inversely associated with CD8+ T lymphocyte infiltration in human breast cancer samples and subcutaneous tumor tissues. In vivo and in vitro experiments demonstrated that TIM knockdown increased CD8+ T lymphocyte antitumor activity. Furthermore, our results showed that TIM interacts with c-Myc to enhance the transcriptional capability of PD-L1 and facilitates the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Moreover, public database analysis suggested that high TIM levels were positively related to PD-L1 inhibitor therapeutic response.ConclusionsMechanistically, we first found that TIM could upregulate PD-L1 by interacting with c-Myc to enhance the transcriptional capability of c-Myc to PD-L1. Altogether, our findings not only provide a novel therapeutic strategy to treat breast cancer by targeting the oncogenic effect of TIM but also indicate that TIM is a promising biomarker for predicting the benefit of anti-PD-L1 immunotherapy.

Modulating Oxygen Vacancies in Lead Chromate forPhotoelectrocatalytic Water Splitting.

Although modulating oxygen vacancies in semiconductors has attracted broad interest in photocatalysis and photoelectrocatalysis, identifying the intrinsic roles of oxygen vacancies on photoelectrocatalytic properties is often elusive. In this work, the oxygen vacancies in a typical semiconductor lead chromate (PbCrO4 ) are regulated via controlling the oxygen chemical potentials of O-poor and O-rich post-annealing atmospheres. Oxygen vacancies identified in PbCrO4 can introduce electronically shallow energy levels and deep energy levels owing to the symmetry difference of oxygen atoms in the structure. A higher population of deep energy levels created under O-poor atmosphere induces the formation of more surface trapped states, resulting in a higher photovoltage for charge separation. Meanwhile, the existence of surface trapped states can significantly improve the charge injection efficiency of the PbCrO4 photoanode and enhance the water oxidation activity. By modulating oxygen vacancies in the PbCrO4 photoanode, a photocurrent density of 3.43mA cm-2 at 1.23V vs reversible hydrogen electrode (RHE) under simulated AM1.5G is acheived. Further passivation of surface trapped states and introducing the water oxidation cocatalyst CoPi lead to a record applied bias photon-to-current efficiency (ABPE) of 1.12%. This work provides a guide to understand the mechanism of oxygen vacancies in oxide-based semiconductor photocatalysis and photoelectrocatalysis.

Abstract 3731: The polyamine-hypusine circuit controls an oncogenic translational program essential for malignant transformation in MYC-driven lymphoma

Abstract The MYC oncoprotein is activated in a broad spectrum of human malignancies and transcriptionally reprograms the genome to drive cancer cell growth. Given these functions, it is unclear if targeting a single effector of MYC will have therapeutic benefit. MYC activates the polyamine-hypusine circuit, which post-translationally modifies a single lysine residue (Lys-50) of eukaryotic translation initiation factor eIF5A in a process coined hypusination via two enzymes,deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). The roles of this circuit in cancer are unclear. Here we report essential intrinsic roles for hypusinated eIF5A in the development and maintenance of MYC-driven lymphoma, where loss of eIF5A hypusination completely abolishes malignant transformation of MYC-overexpressing B cells in transgenic mice predestined to develop lymphoma. Mechanistically, integrating RNA-seq, Ribo-seq and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including regulators of G1-to-S phase cell cycle progression and DNA replication. Thus, this circuit controls MYC’s proliferative response at several levels and is activated in many tumor types. These findings suggest the hypusine circuit as a therapeutic target for a broad spectrum of malignancies. Citation Format: Shima Nakanishi, Jiannong Li, Anders E. Berglund, Youngchul Kim, Yonghong Zhang, Ling Zhang, Chunying Yang, Raghavendra G. Mirmira, John L. Cleveland. The polyamine-hypusine circuit controls an oncogenic translational program essential for malignant transformation in MYC-driven lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3731.