bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor microenvironment governs the prognostic landscape of immunotherapy for head and neck squamous cell carcinoma: A computational model-guided analysis
Authors: Bhattacharya Priyan , Linnenbach Alban , South Andrew P. , Martinez-Outschoorn Ubaldo , Curry Joseph M. , Johnson Jennifer M. , Harshyne Larry A. , Mahoney Mỹ G. , Luginbuhl Adam J. , Vadigepalli Rajanikanth 
Published: September 2024

AbstractImmune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. An exhaustive simulation of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8+ killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.
From tumor microenvironment to immuno-therapeutic outcomes for solid tumors: A systems theoretic approach
Authors: Bhattacharya Priyan , Vadigepalli Rajanikanth 
Published: September 2024

AbstractIncreasing evidence suggests the tumor microenvironment (TME) governs solid tumor response to immune checkpoint inhibition (ICI). Decoding the relationship between the cell compositional diversity of the tumor microenvironment (TME) and the therapeutic outcomes has been a longstanding problem in solid tumor research. In this work, we develop a systems-theoretic formalism to decipher the key mechanisms of growth, proliferation, immune evasion, and drug resistance that run common across solid tumors in the context of Immune Checkpoint Inhibitors (ICI). We reconstructed a core TME network in common across most solid tumors, containing multiple tumor and non-tumor cell types in distinct functional states, and molecular agents mediating cellular signaling and cell-cell interactions. Our analysis shows that the core TME network is sufficient to yield a multiplicity of attractors corresponding to clinically observed TME subtypes namely, immune or fibro dominated, immune or fibro desert, and immune and fibro deficient. Importantly, the reachability around the pre-ICI attractors governs the response to ICI explaining the TME subtype-specific therapy outcomes. We analyzed the attractor transition network to identify subtype-specific combination therapies that can drive unresponsive TME to a responsive subtype. We derived mathematical conditions relating TME balances to determine the limits of the efficacy of combination therapies. Our results hold for a large class of smooth biochemical kinetics with monotone and bounded interactions and (semi-)concave proliferation rules. The analytical findings have been verified with extensive simulation of different TME sub-types. Overall, we propose a generalized systems formalism that accounts for the TME properties governing ICI response and can aid in designing intervention strategies for improved tumor prognosis.Significance StatementNon-responsive therapy outcomes have been a persistent problem in cancer treatment. Predicting the possibility of non-responsiveness to a particular therapy from the pre-treatment composition of the tumor microenvironment (TME) aids in designing appropriate combination treatment strategies toward an improved prognosis. The present work develops a systems-theoretic formalism that aims to unfold the mechanisms behind solid tumors’ growth, non-responsiveness, and recurrence. Unlike a single model, the proposed formalism does not assume any particular kinetics, barring some minimal assumptions. This enables us to explain some of the relevant observations made by the recent experimental studies. Finally, the closed-form conditions obtained for responsivity and recurrence can also guide novel therapeutic strategies that may be able to restore responsiveness to immunotherapy.
Genomic insights into the successful invasion of the avian vampire fly (Philornis downsi) in the Galápagos Islands
Authors: Basnet Aarati , Palacios Catalina , Meng Hao , Nakhwa Dhruv , Farmer Thomas , Dahal Nishma , Anchundia David , Heimpel George E. , Causton Charlotte , Koop Jennifer A.H. , Lamichhaney Sangeet 
Published: September 2024

AbstractInvasive species disrupt island ecosystems, posing significant threats to native species. The avian vampire fly(Philornis downsi), introduced into the Galápagos Islands, has become a major threat to endemic birds including Darwin’s finches, yet the genetic mechanisms of its invasion remain unclear. This study used whole-genome sequencing ofP. downsipopulations from Galápagos and its native range in mainland Ecuador, revealing reduced genetic diversity in Galápagos, indicative of a recent bottleneck. We found evidence of ongoing gene flow among island populations and identified regions under positive selection near genes related to neural signaling, muscle development, and metabolic processes, which may have contributed to the fly’s invasion success in Galápagos. These findings highlight the importance of genomic research for mitigating the impact ofP. downsion Galápagos biodiversity.
Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling
Authors: Nakagawa Rachel , Beardsley Andrew , Durney Sophia , Hayward Mary-Kate , Subramanyam Vishvak , Meyer Nathaniel P. , Wismer Harrison , Goodarzi Hani , Weaver Valerie M , Van de Mark Daniel , Goga Andrei 
Published: September 2024

AbstractNon-small cell lung cancers (NSCLC) harboring common mutations in EGFR and KRAS characteristically respond transiently to targeted therapies against those mutations, but invariably, tumors recur and progress. Resistance often emerges through mutations in the therapeutic target or activation of alternative signaling pathways. Mechanisms of acute tumor cell resistance to initial EGFR (EGFRi) or KRASG12C(G12Ci) pathway inhibition remain poorly understood. Our study reveals that acute response to EGFR/RAS/RAF-pathway inhibition is spatial and culture context specific. In vivo, EGFR mutant tumor xenografts shrink by > 90% following acute EGFRi therapy, and residual tumor cells are associated with dense stroma and have increased nuclear YAP. Interestingly, in vitro EGFRi induced cell cycle arrest in NSCLC cells grown in monolayer, while 3D spheroids preferentially die upon inhibitor treatment. We find differential YAP nuclear localization and activity, driven by the distinct culture conditions, as a common resistance mechanism for selective EGFR/KRAS/BRAF pathway therapies. Forced expression of the YAPS127Amutant partially protects cells from EGFR-mediated cell death in spheroid culture. These studies identify YAP activation in monolayer culture as a non-genetic mechanism of acute EGFR/KRAS/BRAF therapy resistance, highlighting that monolayer vs spheroid cell culture systems can model distinct stages of patient cancer progression.Graphical Abstract
Molecular Evolution and Functional Divergence of Heterodisulfide Reductase A (HdrA)
Authors: Banerjee Mousumi 
Published: September 2024

AbstractHeterodisulfide reductase is a key enzyme in methanogenesis pathway in archaea, which helps to recycle the coenzymes after methane is formed from C1 carbon sources. Homologous enzymes are observed in non-methanogenic archaea and prokaryotes but their functional and evolutionary details are not fully explored. This report aims at understanding the distribution of one such homologous enzyme, heterodisulfide reductase A (HdrA); it’s domain architecture, overall structural contribution in biological function and evolutionary details in organisms other than methanogen. Exhaustive sequence analysis from both archaea and prokaryotic lineages reveals the presence of highly conserved homologues which probably have an altered oxido-reductase function. Phylogenetic analysis and co-clustering showed the differential diversity of the homologues enzyme in metabolically diverse groups. The distribution of Heterodisulfide homologues in both archaea and prokaryotes shows differential expansion of this protein by multiple horizontal gene transfer events. Conserved domain analysis and structural modelling of different phylogenetic clades shows sequence and structural diversity at the C-terminal domain. Bimolecular network analysis highlights the functional association and interactions of the heterodisulfide homologues with diverse protein partners which participate in different metabolic function. HdrA involved in species specific metabolic function while the functional conservation is evident between close related species. Analysis of structural domain within HdrA’s reveals that clade specific sequence which helps to differentiate structural domain arrangement and contributes to functional constrains. The presence of HdrA protein in methanogenic archaea and non-methanogens suggests that the protein function involving redox reaction and electron transfer shared a common history.
Dynamic cognitive differences between internal and external attention are associated with depressive and anxiety disorders
Authors: Oka Taiki , Koyama Yutaro , Sasaki Akihiro , Murakami Misa , Kobayashi Nao , Cortese Aurelio 
Published: September 2024

AbstractThe internal/external attention framework characterises attention focused on internal representations, such as emotions, versus external representations, such as perceptual stimuli. The inability to focus one’s attention is considered a critical factor in psychiatric disorders. While these different attentional foci are likely generated by the dynamic interplay of multiple cognitive processes, previous studies have generally examined single cognitive dimensions. We developed a new method, cognitive dynamic similarity analysis (C-DSA), to clarify how cognitive processes differ between experimental conditions. In an MR scanner, participants performed a word-processing task in which they focused on either their own emotions or the number of letters associated with a stimulus. To extract cognitive dynamics at the single-trial level, we applied cognitive dynamics estimation, a recently developed method that generates whole-brain activation maps for four cognitive dimensions (emotion processing, selective attention, self-referential thought, and working memory) using a meta-analytic platform. We then performed C-DSA to calculate the difference between internal and external attention for each cognitive dimension. C-DSA revealed significant differences between internal/external attention in all cognitive dimensions, but especially in emotion processing. Moreover, the difference between attention conditions of selective attention was negatively associated with the severity of depression and state-anxiety, but positively associated with trait-anxiety. Our findings suggest that C-DSA applies to both naturalistic and controlled dynamic processes and may be valuable in clinical settings by linking dynamic cognitive mechanisms with issues like ageing and psychiatric disorders.Graphical abstract
Vibrio choleraeCsrA controls ToxR levels by increasing the stability and translation oftoxRmRNA
Authors: Mey Alexandra R. , Midgett Charles R. , Kull F. Jon , Payne Shelley M. 
Published: September 2024

ABSTRACTRegulation of colonization and virulence factor production in response to environmental cues is mediated through several regulatory factors inVibrio cholerae, including the highly conserved RNA-binding global regulatory protein CsrA. We have shown previously that CsrA increases synthesis of the virulence-associated transcription factor ToxR in response to specific amino acids (NRES) and is required for the virulence ofV. choleraein the infant mouse model of cholera. In this study, we mapped the 5’ untranslated region (5’ UTR) oftoxRand showed that CsrA can bind directly to an RNA sequence encompassing the 5’ UTR, indicating that the regulation of ToxR levels by CsrA is direct. Consistent with this observation, the 5’ UTR oftoxRcontains multiple putative CsrA binding sequences (GGA motifs), and mutating these motifs disrupted the CsrA-mediated increase in ToxR. Optimal binding of CsrA to a defined RNA oligonucleotide required the bridging of two GGA motifs within a single RNA strand. To determine the mechanism of CsrA regulation, we assayedtoxRtranscript levels, stability, and efficiency of translation. Both the amount oftoxRmRNA in NRES and the stability of thetoxRtranscript were increased by CsrA. Using an in vitro translation assay, we further showed that synthesis of ToxR was greatly enhanced in the presence of purified CsrA, suggesting a direct role for CsrA in the translation oftoxRmRNA. We propose a model in which CsrA binding to the 5’ UTR of thetoxRtranscript promotes ribosomal access while precluding interactions with RNA-degrading enzymes.IMPORTANCEVibrio choleraeis uniquely adapted to life in marine environments as well as in the human intestinal tract. Global regulators such as CsrA, which help translate environmental cues into an appropriate cellular response, are critical for switching between these distinct environments. Understanding the pathways involved in relaying environmental signals is essential for understanding both the environmental persistence and the intestinal pathogenesis of this devastating human pathogen. In this study, we demonstrate that CsrA directly regulates synthesis of ToxR, a key virulence factor ofV. cholerae. Under conditions favoring high levels of active CsrA in the cell, such as in the presence of particular amino acids, CsrA increases ToxR protein levels by binding to thetoxRtranscript and enhancing both its stability and translation. By responding to nutrient availability, CsrA is perfectly poised to activate the virulence gene regulatory cascade at the preferred site of colonization, the nutrient-rich small intestinal mucosa.
The Harvard-Emory ECG Database
Authors: Koscova Zuzana , Li Qiao , Robichaux Chad , Moura Junior Valdery , Ghanta Manohar , Gupta Aditya , Rosand Jonathan , Aguirre Aaron , Hong Shenda , Albert David E. , Xue Joel , Parekh Aarya , Sameni Reza , Reyna Matthew A. , Westover M. Brandon , Cliford Gari D. 
Published: October 2024

ABSTRACTThe Harvard-Emory ECG Database (HEEDB) is a large collection of 12-lead electrocardiogram (ECG) recordings, developed through a collaboration between Harvard University and Emory University. The database consists of 10,608,417 unique ECG recordings from 1,818,247 patients from Massachusetts General Hospital (MGH) and 1,452,964 recordings from 552,481 patients from Emory University Hospital (EUH) collected in clinical settings as part of routine patient care since the early 1990s. Continuously updated with new data, the recordings consist of 10-second, 12-lead ECGs sampled at 250 and 500 Hz, and stored in WFDB format. Future updates will include demographic information such as age, sex, race, and ethnicity. Additionally, 12SL annotations–encompassing ECG diagnoses, morphology, and rhythms–are available for 10,471,531 recordings from MGH and 1,268,277 recordings from EUH. Shortly, ICD-9/10 codes, CPT codes, and medication history will also be made publicly available.
Somatostatin interneurons select dorsomedial striatal representations of the initial learning phase
Authors: Rotariu S , Zalcman G , Badreddine N , Appaix F , Sarno S , Bureau I , Fino E 
Published: September 2024

ABSTRACTThe dorsomedial striatum (DMS) is an associative node involved in the adaptation of ongoing actions to the environmental context and in the initial formation of motor sequences. In early associative or motor learning phases, DMS activity shows a global decrease in neuron firing, eventually giving rise to a select group of active cells, whose number is correlated with animal performance. Unveiling how those representation emerge from DMS circuits is crucial for understanding plasticity mechanisms of early adjustments to learning a task. Here, we hypothesized that inhibitory microcircuits formed by local interneurons are responsible for the genesis of early DMS representation and associated task performance. Despite the low density of somatostatin (SOM)-positive cells, we observed that selective manipulation of SOM cells disrupted reorganization of DMS activity and modulated initial phases of learning in two behavioral contexts. This effect was cell-specific as manipulation of parvalbumin-positive interneurons had no significant effect. Finally, we identified the high plasticity of SOM innervation in the DMS as a key modulator of the SPN excitability and firing activity. Hence, SOM interneurons set the pace of early learning by actively controlling the remapping of DMS network activity.
In situquantification of ribosome number by electron tomography
Authors: El Hankouri Mounir , Nousch Marco , Müller-Reichert Thomas , Fabig Gunar 
Published: September 2024

AbstractRibosomes, discovered in 1955 by George Palade, were originally described as small cytoplasmic particles preferentially associated with the endoplasmic reticulum (ER). Over the years, numerous studies were conducted on both ribosome structure and function. The basic question, however, how many ribosomes are contained within whole cells has not been addressed so far. Here we developed a microscopic method to determine the total number of ribosomes in human hTRET-RPE-1 and in nematode cells from different tissues inCaenorhabditis eleganshermaphrodites. Electron tomography of high-pressure frozen, freeze substituted and resin-embedded samples revealed that the number of ribosomes as determined by this electron tomographic approach closely matches the biochemical estimates for the hTRET-RPE-1 cells. In addition, RPOA-1-depleted worms compared to control worms showed an expected decrease in the number of ribosomes in two out of three different tissue types investigated. The application of our imaging-based approach to directly count the number of ribosomes in given samples will significantly enhance our basic understanding of ribosome localization and distribution within cells and tissues.
Microbial Metagenomes Across a Complete Phytoplankton Bloom Cycle: High-Resolution Sampling Every 4 Hours Over 22 Days
Authors: Nunn Brook L. , Timmins-Schiffman Emma , Mudge Miranda C. , Plubell Deanna , Chebli Gabriella , Kubanek Julia , Riffle Michael , Noble William S. , Harvey Elizabeth , Nunn Tasman A. , Huntemann Marcel , Clum Alicia , Foster Brian , Foster Bryce , Roux Simon , Palaniappan Krishnaveni , Mukherjee Supratim , Reddy T.B.K. , Daum Chris , Copeland Alex , Chen I-Min A. , Ivanova Natalia N. , Kyrpides Nikos C. , del Rio Tijana Glavina , Eloe-Fadrosh Emiley A. 
Published: September 2024

AbstractIn May and June of 2021, marine microbial samples were collected for DNA sequencing in East Sound, WA, USA every 4 hours for 22 days. This high temporal resolution sampling effort captured the last 3 days of aRhizosoleniasp. bloom, the initiation and complete bloom cycle of Chaetoceros socialis (8 days), and the following bacterial bloom (2 days). Metagenomes were completed on the time series, and the dataset includes 128 size-fractionated microbial samples (0.22-1.2µm), providing gene abundances for the dominant members of bacteria, archaea, and viruses. This dataset also has time-matched nutrient analyses, flow cytometry data, and physical parameters of the environment at a single point of sampling within a coastal ecosystem that experiences regular bloom events, facilitating a range of modeling efforts that can be leveraged to understand microbial community structure and their influences on the growth, maintenance, and senescence of phytoplankton blooms.
Meta-analytic Review of Bacteria and Parasites in Elasmobranchs Provides Insight into Research Gaps
Authors: Modzelesky Alexis 
Published: September 2024

AbstractElasmobranchs have conservational and commercial importance. There is a need for a more complete understanding of their health, due to their ability to shape trophic webs and their money-making potential with fishers and ecotourists. Sharks have been known to influence the strength of food webs, including reef ecosystems where many fish species are harvested for food. The investigation of pathogenic agents and diseases in elasmobranchs has been biased to favor those natural enemies that inhabit the digestive system and epidermal surfaces. Certain groups of parasites such as cestodes, copepods, and monogeneans, were most often recorded in this review. The bacterial microbiota of elasmobranchs is currently being researched, but much information is lacking in the field, with the exception of certain well-known strains, such as members of the genus Vibrio. In addition, information on the 22 species of sharks included in this study is more in depth than that which can be found for the 11 ray species and three skates. A quantitative study was undertaken to investigate relationships between taxonomic Order and Family, as well as the relationship between diet and number of natural enemies with the use of the statistical software R. It was found that number of natural enemies present in an elasmobranch species correlates with the number of sources available. This first attempt at an exhaustive review of elasmobranch natural enemies from Florida waters includes over 400 pathogens as well as indicates the 14 most under-studied elasmobranch species.