bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endocrine persistence in ER+ breast cancer is accompanied by metabolic vulnerability in oxidative phosphorylation
Authors: Tau Steven , Chamberlin Mary D. , Yang Huijuan , Marotti Jonathan D. , Roberts Alyssa M. , Carmichael Melissa M. , Cressey Lauren , Dragnev Christo , Demidenko Eugene , Hampsch Riley A. , Soucy Shannon M. , Kolling Fred , Samkoe Kimberley S. , Alvarez James V. , Kettenbach Arminja N. , Miller Todd W. 
Published: September 2024

AbstractDespite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2-breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Mice bearing cell line- and patient-derived xenografts were used to measure the anti-tumor effects of mitochondrial complex I inhibition in the context of endocrine therapy. Pharmacological inhibition of complex I suppressed the tumor-forming potential of persisters and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability in the context of endocrine-sensitive disease.Statement of SignificanceEndocrine-tolerant persister cancer cells that survive endocrine therapy can cause recurrent disease. Persister cells exhibit increased energetic dependence upon mitochondria for survival and tumor re-growth potential.
Rationalize the Functional Roles of Protein-Protein Interactions in Targeted Protein Degradation by Kinetic Monte-Carlo Simulations
Authors: Su Zhaoqian , Yin Shanye , Wu Yinghao 
Published: September 2024

ABSTRACTTargeted protein degradation is a promising therapeutic strategy to tackle disease-causing proteins that lack binding pockets for traditional small-molecule inhibitors. Its first step is to trigger the proximity between a ubiquitin ligase complex and a target protein through a heterobifunctional molecule, such as proteolysis targeting chimeras (PROTACs), leading to the formation of a ternary complex. The properties of protein-protein interactions play an important regulatory role during this process, which can be reflected by binding cooperativity. Unfortunately, although computer-aided drug design has become a cornerstone of modern drug development, the endeavor to model targeted protein degradation is still in its infancy. The development of computational tools to understand the impacts of protein-protein interactions on targeted protein degradation, therefore, is highly demanded. To reach this goal, we constructed a non-redundant structural benchmark of the most updated ternary complexes and applied a kinetic Monte-Carlo method to simulate the association between ligases and PROTAC-targeted proteins in the benchmark. Our results show that proteins in most complexes with positive cooperativity tend to associate into native-like configurations more often. In contrast, proteins very likely failed to associate into native-like configurations in complexes with negative cooperativity. Moreover, we compared the protein-protein association through different interfaces generated from molecular docking. The native-like binding interface shows a higher association probability than all the other alternative interfaces only in the complex with positive cooperativity. These observations support the idea that the formation of ternary complexes is closely regulated by the binary interactions between proteins. Finally, we applied our method to cyclin-dependent kinases 4 and 6 (CDK4/6). We found that their interactions with the ligase are not as similar as their structures. Altogether, our study paves the way for understanding the role of protein-protein interactions in PROTACE-induced ternary complex formation. It can potentially help in searching for degraders that selectively target specific proteins.
Detection of bacteria through taste receptors primes the cellular immune response
Authors: Mazariegos Alix Najera , Manière Gérard , Camp Darius , Kaul Rhea , Duval Carla Jane , Milleville Romane , Berthelot-Grosjean Martine , Alves George , Royet Julien , Grosjean Yaël , Musso Pierre-Yves , Tanentzapf Guy 
Published: September 2024

AbstractAnimals use their sensory system to detect cues in their external environment, then communicate, process, and integrate these cues through the nervous system in order to elicit a specific response. Taste is an important cue used by animals to explore their external environment and can modulate various aspects of animal behavior and physiology. A major ongoing challenge for animals is to detect and respond to the presence of a variety of pathogens in their environment. However, to date, the links between the sensory system and the response to pathogenic threats remain poorly understood. Here we show thatDrosophilalarvae use their taste system to detect bacterial peptidoglycans in their environment and respond by modulating the activity of their cellular immune system. We show that specific PeptidoGlycan Receptor Proteins (PGRPs) act in bitter taste neurons, via the IMmune Deficiency (IMD) pathway. These PGRPs mediate signaling in taste neurons and control immune cells production in the larval hematopoietic organ, the lymph gland. The taste-mediated sensing of bacteria in larvae primes the immune system, and improves survival after infection in adult flies. These results demonstrate that sensory inputs such as taste play an important role in protecting animals from bacterial infection by providing a powerful adaptive response to potential pathogens. Overall, our findings add to the growing list of examples of crosstalk between the nervous and immune systems and provide novel and important mechanisms for linking them.
Identification of genetic variants and their causal association underlying autism spectrum disorder
Authors: Yadav Prashasti , Srivastava Mona , Das Parimal 
Published: September 2024

AbstractBackgroundAutism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with a complex genetic architecture characterized by persistent deficits in social communication and social interaction along with restricted and repetitive behavior patterns, interests and activities. Over the years its prevalence has increased and affects 1% children globally. Etiology of ASD is remained unclear, but it is well recognized as a complex disorder involving interactions of several genes and environmental risk factors. Studies signify the role of whole exome sequencing in identifying rare genetic variation related to neurodevelopmental disorders and have greatly improved the chance of identifying known as well as novel responsible genes. This study aimed to identify genetic variant in a patient affected with autism spectrum disorder.MethodsA male patient of age range 0-5 years was investigated and identified according to DSM-5 criteria for autism spectrum disorder. Peripheral blood sample was collected followed by genomic DNA extraction and whole exome sequencing. The functional impact of variant, gene interaction network and pathway enrichment analysis were done usingin silicotools and databases.ResultsTwo heterozygous missense variants one inSHANK2(c.401C>G) another inCSNK2A1 (c.572G>A) were identified. Both of these variants were predicted to be deleterious by pathogenicity prediction tool. Gene interaction network and pathway enrichment analysis revealed the involvement ofSHANK2andCSNK2A1in various biological pathways such as protein binging, synaptogenesis, chromosome condensation and cell cycle regulation.ConclusionThis study revealed a novelSHANK2variant along with a knownCSNK2A1variant that expands the spectrum of genetic variants related to autism spectrum disorder and further enhances the understanding of the molecular mechanism underlyingSHANK2andCSNK2A1pathophysiology.
Cognitively healthy young adults withAPOEe4gene show disrupted functional connectivity of graph properties in multiple resting-state networks
Authors: Kucikova Ludmila , Zeng Jianmin , Brass Adam J. , Muñoz-Neira Carlos , Ritchie Craig W. , Muniz-Terrera Graciela , O’Brien John , Su Li 
Published: September 2024

AbstractTheapolipoprotein (APOE) e4allele is associated with brain changes in healthy carriers that are similar to changes observed in patients with Alzheimer’s Disease, including abnormalities in functional connectivity. The trajectory of these changes across the lifespan, specifically in early adulthood is still not clear. This study explores the link between theAPOEgenotype and functional connectivity in 129 cognitively healthy Chinese Han college students (aged 17-22 years). By using graph theory, we assessed the connectivity in seven resting-state networks of interest using three different thresholding methods and three different forms of network parcellation. Average Path Length and Closeness Centrality were disrupted ine4carriers in the sensorimotor, visual, salience, and Default Mode salience networks; with effects replicated using different thresholding but not different parcellation methods. This study demonstrated the genetics-related vulnerability in the brain of youngAPOEe4carriers across multiple resting-state networks.
Measuring aversion to health inequality in Canada: an equity-efficiency trade-off experiment
Authors: Iragorri Nicolas , Ali Shehzad , Mishra Sharmistha , Sander Beate 
Published: September 2024

AbstractOBJECTIVESTo estimate the extent to which Canadians are averse to health inequalities, a critical component for equity-informative economic evaluations but lacking in the Canadian context.METHODSWe conducted three experiments among a representative sample of adults living in Canada to elicit value judgements about reducing income-related health inequality vs. improving population health. Each experiment compared two programs: (Experiment 1) universal and tailored vaccination; (Experiment 2) non-specific prevention programs; (Experiment 3) generic health care programs. The programs varied in terms of efficiency (additional life years), and income-related health inequality. Preferences were elicited using benefit-trade off analysis and were classified as: pro-rich (maximizing the health of individuals with the highest income); health maximizer (maximizing total health); weighted prioritarian (willing to trade some health to reduce inequalities); maximin (only improving the health of the individuals with the lowest income); and egalitarian (minimizing health inequalities).RESULTSWe recruited 1,000 participants per experiment. Preferences for the vaccination, prevention, and generic experiments were distributed as follows: pro-rich (Atkinson Index<0): 31%, 22%, and 16% respectively; health maximizers (Atkinson Index=0): 2%, 3%, and 2%, respectively; weighted prioritarians (Atkinson Index>0): 13%, 19%, and 22% respectively; maximins (Atkinson Index=∞): 0%, 1%, and 3%, respectively; egalitarian (Atkinson Index undefined): 54%, 55%, and 57%, respectively. The median responses reflected a preference for minimizing health inequalities across the three experiments.CONCLUSIONSOur findings suggest a strong aversion to health inequality among people living in Canada with over half of respondents willing to minimize health inequalities regardless of the impact on efficiency.
Ancestrally diverse genome-wide association analysis highlights ancestry-specific differences in genetic regulation of plasma protein levels
Authors: Sarnowski Chloé , Ma Jianzhong , Nguyen Ngoc Quynh H. , Hoogeveen Ron C , Ballantyne Christie M , Coresh Josef , Morrison Alanna C , Chatterjee Nilanjan , Boerwinkle Eric , Yu Bing 
Published: September 2024

AbstractFully characterizing the genetic architecture of circulating proteins in multi-ancestry populations provides an unprecedented opportunity to gain insights into the etiology of complex diseases. We characterized and contrasted the genetic associations of plasma proteomes in 9,455 participants of European and African (19.8%) ancestry from the Atherosclerosis Risk in Communities Study. Of 4,651 proteins, 1,408 and 2,565 proteins had protein-quantitative trait loci (pQTLs) identified in African and European ancestry respectively, and twelve unreported potentially causal protein-disease relationships were identified. Shared pQTLs across the two ancestries were detected in 1,113 aptamer-region pairs pQTLs, where 53 of them were not previously reported (alltranspQTLs). Sixteen unique protein-cardiovascular trait pairs were colocalized in both European and African ancestry with the same candidate causal variants. Our systematic cross-ancestry comparison provided a reliable set of pQTLs, highlighted the shared and distinct genetic architecture of proteome in two ancestries, and demonstrated possible biological mechanisms underlying complex diseases.
Synthetic Data Distillation Enables the Extraction of Clinical Information at Scale
Authors: Woo Elizabeth Geena , Burkhart Michael C. , Alsentzer Emily , Beaulieu-Jones Brett K 
Published: September 2024

AbstractLarge-language models (LLMs) have shown promising potential for extracting information from clinical notes. Deploying these models at scale can be challenging due to high computational costs, regulatory constraints, and privacy concerns. To address these challenges, we used synthetic data distillation to fine-tune smaller, open-source LLMs that achieve performance similar to that of larger models, including the teacher model. These smaller models can be run on less expensive local hardware or at a vastly reduced cost in cloud deployments. In this study, we used Llama-3.1-70B-Instruct to generate synthetic training examples in the form of question-answer pairs along with supporting information and model-assigned difficulty scores. These synthetic examples were used to fine-tune the smaller Llama-3.1-8B-Instruct model. We evaluated the performance of these models on an annotated synthetic dataset resembling clinical trial criteria, the i2b2 2018 Clinical Trial Eligibility Challenge, and clinical notes reflecting the clinical trial for apixaban. The fine-tuned models outperformed the 8B-Instruct model on all tasks and in some cases even exceeded the performance of the larger 70B-Instruct model. This work demonstrates the potential of synthetic data distillation to enable more scalable and efficient clinical information extraction, which could be applied toward improving accuracy and efficiency of patient phenotyping and clinical-trial matching.
Outcome of Graves’ Disease and Associated Genetic Predisposition: A Systematic Review of Literature
Authors: Mokoagow Md. Ikhsan , Manthovani Ahmad Zufar , Epriliawati Marina 
Published: September 2024

AbstractBackgroundGraves’ disease (GD) is an autoimmune hyperthyroidism that primarily affects the thyroid gland. The susceptibility, activity, and risk of recurrence of GD may be influenced by various genetic factors, which can interact with environmental triggers to precipitate disease relapse. This review examines the literature on the genetic predisposition to GD recurrence.MethodsLiterature from PubMed, EBSCOhost, and SCOPUS were searched. Three reviewers performed study selection and critical appraisal.ResultFive studies were selected. The literature indicates a risk of relapse in PTPN22, CTLA-4, TSH-R, IL-21, KREC, and HLA gene abnormalities.ConclusionSeveral genes are associated with GD relapse. However, predicting relapse risk requires consideration of multiple factors beyond genetic predisposition.
Inhibition of FOXM1 synergizes with BCL2 inhibitor Venetoclax in killing non-t(11;14) multiple myeloma cells via repressing MYC pathway
Authors: Wen Zhi , Janz Siegfried , Wang Yidan , Katzenellenbogen Benita S. , Katzenellenbogen John A. , Kim Sung Hoon , Onitilo Adedayo 
Published: September 2024

AbstractDespite significant improvements in the prognosis of Multiple Myeloma (MM), relapsed/refractory MM remains a major challenge. BCL2 inhibitor Venetoclax induced complete or very good partial responses in 6% of non-t(11;14) MM cases, compared to 27% in t(11;14) cases, when used as monotherapy in relapsed/refractory MM. Though Venetoclax was proposed to treat t(11;14) cases, the resistance became a concern. Furthermore, non-t(11;14) cases account for 80-85% of MM cases, which underscores the value of Venetoclax in non-t(11;14) MM. Here, we report a recently-invented small molecule inhibitor of FOXM1 NB73 synergizing with Venetoclax in killing MM cells. FOXM1, a critical forkhead box transcription factor in high-risk and relapsed/refractory MM, represents a promising therapeutic target of MM. We examined the mechanisms underlying the synergies of Venetoclax and NB73 using multi-omics and molecular and cellular biology tools in non-t(11;14) myeloma cell lines with high FOXM1 expression. NB73 induces immediate loss of FOXM1, decreases BCL2 expression, and increases Puma expression in myeloma cells. Venetoclax enhances NB73-induced FOXM1 ubiquitination and degradation. The NB73-Venetoclax combination abrogates the binding of FOXM1 to the promoters of genes in the MYC pathway, such as PLK1, MYC, CDC20, and CCNA2, leading to the repression of the transcription of these MYC pathway genes. The PLK1-specific inhibitor GSK461364 synergies with NB73 in suppressing myeloma cell growth. Therefore, NB73 synergizes with Venetoclax in killing myeloma cells. Conclusively, the NB73-Venetoclax combination abolishes FOXM1-mediated transcriptional activation of the MYC pathway, resulting in intensive apoptosis of myeloma cells without t(11;14) but with high FOXM1 expression.Statement of significanceThis study implicates that targeting FOXM1 will alleviate resistance to BCL2 inhibitor Venetoclax in non-t(11;14) myeloma cells expressing high FOXM1.
Abundance measurements reveal the balance between lysis and lysogeny in the human gut microbiome
Authors: Lopez Jamie A. , McKeithen-Mead Saria , Shi Handuo , Nguyen Taylor H. , Huang Kerwyn Casey , Good Benjamin H. 
Published: September 2024

AbstractThe human gut contains diverse communities of bacteriophage, whose interactions with the broader microbiome and potential roles in human health are only beginning to be uncovered. Here, we combine multiple types of data to quantitatively estimate gut phage population dynamics and lifestyle characteristics in human subjects. Unifying results from previous studies, we show that an average human gut contains a low ratio of phage particles to bacterial cells (∼1:100), but a much larger ratio of phage genomes to bacterial genomes (∼4:1), implying that most gut phage are effectively temperate (e.g., integrated prophage, phage-plasmids, etc.). By integrating imaging and sequencing data with a generalized model of temperate phage dynamics, we estimate that phage induction and lysis occurs at a low average rate (∼0.001-0.01 per bacterium per day), imposing only a modest fitness burden on their bacterial hosts. Consistent with these estimates, we find that the phage composition of a diverse synthetic community in gnotobiotic mice can be quantitatively predicted from bacterial abundances alone, while still exhibiting phage diversity comparable to native human microbiomes. These results provide a foundation for interpreting existing and future studies on links between the gut virome and human health.
A Novel Mouse Model Demonstrates In Vivo Replenishment of Central Nervous System Pericytes After Successful Acute Ablation
Authors: Atak Dila , Yıldız Erdost , Özkan Esra , Yousefi Mohammadreza , Özkan Ayşe , Yılmaz Aysu Bilge , Kızılırmak Ali Burak , Alnajjar Iman Asaad , Kanar Çiçek , Caan Zeynep Lal , Zeybek Şakir Ümit , Küçükali Cem İsmail , Tüzün Erdem , Gürsoy-Özdemir Yasemin , Vural Atay 
Published: September 2024

AbstractCentral nervous system (CNS) pericytes play crucial roles in vascular development and blood-brain barrier maturation during prenatal development, as well as in regulating cerebral blood flow in adults. They have also been implicated in the pathogenesis of numerous neurological disorders. However, the behavior of pericytes in the adult brain after injury remains poorly understood, partly due to limitations in existing pericyte ablation models. To investigate pericyte responses following acute ablation, we developed a tamoxifen-inducible pericyte ablation model by crossingPDGFRβ-P2A-CreERT2andRosa26-DTA176transgenic mouse lines. Using this model, we studied the effects of different tamoxifen doses and conducted histological examinations 15 and 60 days post-injection to assess both short- and long-term impacts of pericyte ablation. Our results demonstrate that a low dose of tamoxifen effectively ablates CNS pericytes in mice without reducing survival or causing significant systemic side effects, such as weight loss. Additionally, we found that the extent of pericyte depletion varies between the cortex and the spinal cord’s gray and white matter regions. Importantly, both pericyte coverage and numbers increased in the weeks following acute ablation, indicating the regenerative capacity of CNS pericytes in vivo. This model offers a valuable tool for future studies on the role of pericytes in neurological disorders, overcoming the limitations of constitutive pericyte ablation models.
Integral-Omics: serial extraction and profiling of metabolome, lipidome, genome, transcriptome, whole proteome and phosphoproteome using biopsy tissue
Authors: Li Wei , Sun Jing , Sun Rui , Wei Yujuan , Zheng Junke , Zhu Yi , Guo Tiannan 
Published: September 2024

AbstractThe integrative multi-omics characterization of minute amount of clinical tissue specimens has become increasingly important. Here, we present an approach called Integral-Omics, which enables sequential extraction of metabolites, lipids, genomic DNA, total RNA, proteins, and phosphopeptides from a single biopsy-level tissue specimen. We benchmarked this method with various samples and applied the workflow to perform multi-omics profiling of tissues from six patients with colorectal cancer and found that tumor tissues exhibited suppressed ferroptosis pathway at multi-omics levels. Together, this study presents a methodology that enables sequential extraction and profiling of metabolomics, lipidomics, genomics, transcriptomics, proteomics and phosphoproteomics using biopsy tissue specimens.