Scholarly Works, Biological Sciences

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Advancements in Machine Learning for Precision Diagnostics and Surgical Interventions in Interconnected Musculoskeletal and Visual Systems
Kumar, Rahul; Gowda, Chirag; Sekhar, Tejas C.; Vaja, Swapna; Hage, Tami; Sporn, Kyle; Waisberg, Ethan; Ong, Joshua; Zaman, Nasif; Tavakkoli, Alireza (MDPI, 2025-05-23)
Artificial intelligence (AI) is reshaping precision medicine by revealing diagnostic links between ocular biomarkers and systemic musculoskeletal disorders. This review synthesizes clinical evidence on the associations between optical coherence tomography (OCT)-derived parameters, such as retinal nerve fiber layer (RNFL) thinning and choroidal thickness, and conditions including osteoporosis, cervical spine instability, and inflammatory arthritis. The findings, based on an analysis of studies that integrate AI with ocular and musculoskeletal imaging, highlight consistent correlations between ocular microstructural changes and systemic degenerative pathologies. These results suggest that the eye may serve as a non-invasive window into biomechanical dysfunction. This review also discusses the emerging role of AI-assisted surgical systems informed by ocular metrics. Overall, AI-driven ocular analysis offers a promising avenue for early detection and management of musculoskeletal disease, supporting its clinical relevance and interdisciplinary potential.
The swimming defect caused by the absence of the transcriptional regulator LdtR in Sinorhizobium meliloti is restored by mutations in the motility genes motA and motS
Sobe, Richard C.; Scharf, Birgit E. (Wiley, 2024-05)
The flagellar motor is a powerful macromolecular machine used to propel bacteria through various environments. We determined that flagellar motility of the alpha-proteobacterium Sinorhizobium meliloti is nearly abolished in the absence of the transcriptional regulator LdtR, known to influence peptidoglycan remodeling and stress response. LdtR does not regulate motility gene transcription. Remarkably, the motility defects of the ΔldtR mutant can be restored by secondary mutations in the motility gene motA or a previously uncharacterized gene in the flagellar regulon, which we named motS. MotS is not essential for S. meliloti motility and may serve an accessory role in flagellar motor function. Structural modeling predicts that MotS comprised an N-terminal transmembrane segment, a long-disordered region, and a conserved β-sandwich domain. The C terminus of MotS is localized in the periplasm. Genetics based substitution of MotA with MotAG12S also restored the ΔldtR motility defect. The MotAG12S variant protein features a local polarity shift at the periphery of the MotAB stator units. We propose that MotS may be required for optimal alignment of stators in wild-type flagellar motors but becomes detrimental in cells with altered peptidoglycan. Similarly, the polarity shift in stator units composed of MotB/MotAG12S might stabilize its interaction with altered peptidoglycan.
Chemoreceptors in Sinorhizobium meliloti require minimal pentapeptide tethers to provide adaptational assistance
Agbekudzi, Alfred; Scharf, Birgit E. (Wiley, 2024-07)
Sensory adaptation in bacterial chemotaxis is mediated by posttranslational modifications of methyl-accepting chemotaxis proteins (MCPs). In Escherichia coli, the adaptation proteins CheR and CheB tether to a conserved C-terminal receptor pentapeptide. Here,we investigated the function of the pentapeptide motif (N/D)WE(E/N)F in Sinorhizobium meliloti chemotaxis. Isothermal titration calorimetry revealed stronger affinity of the pentapeptides to CheR and activated CheB relative to unmodified CheB. Strains with mutations of the conserved tryptophan in one or all four MCP pentapeptides resulted in a significant decrease or loss of chemotaxis to glycine betaine, lysine, and acetate, chemoattractants sensed by pentapeptide-bearing McpX and pentapeptide-lacking McpU and McpV, respectively. Importantly, we discovered that the pentapeptide mediates chemotaxis when fused to the C-terminus of pentapeptide-lacking chemoreceptors via a flexible linker. We propose that adaptational assistance and a threshold number of available sites enable the efficient docking of adaptation proteins to the chemosensory array. Altogether, these results demonstrate that S. meliloti effectively utilizes a pentapeptide-dependent adaptation system with a minimal number of tethering units to assist pentapeptide-lacking chemoreceptors and hypothesize that the higher abundance of CheR and CheB in S. meliloti compared to E. coli allows for ample recruitment of adaptation proteins to the chemosensory array.
Cryo-EM structure of flagellotropic bacteriophage Chi
Sonani, Ravi R.; Esteves, Nathaniel C.; Scharf, Birgit E.; Egelman, Edward H. (Cell Press, 2024-07-11)
The flagellotropic bacteriophage χ (Chi) infects bacteria via the flagellar filament. Despite years of study, its structural architecture remains partly characterized. Through cryo-EM, we unveil χ′s nearly complete structure, encompassing capsid, neck, tail, and tail tip. While the capsid and tail resemble phage YSD1, the neck and tail tip reveal new proteins and their arrangement. The neck shows a unique conformation of the tail tube protein, forming a socket-like structure for attachment to the neck. The tail tip comprises four proteins, including distal tail protein (DTP), two baseplate hub proteins (BH1P and BH2P), and tail tip assembly protein (TAP) exhibiting minimal organization compared to other siphophages. Deviating from the consensus in other siphophages, DTP in χ forms a trimeric assembly, reducing tail symmetry from 6-fold to 3-fold at the tip. These findings illuminate the previously unexplored structural organization of χ’s neck and tail tip.
Serratia marcescens ATCC 274 increases production of the red pigment prodigiosin in response to Chi phage infection
Esteves, Nathaniel C.; Scharf, Birgit E. (Nature Portfolio, 2024-07-31)
Serratia marcescens is an opportunistic human pathogen that produces a vibrant red pigment called prodigiosin. Prodigiosin has implications in virulence of S. marcescens and promising clinical applications. We discovered that addition of the virulent flagellotropic bacteriophage χ (Chi) to a culture of S. marcescens stimulates a greater than fivefold overproduction of prodigiosin. Active phage infection is required for the effect, as a χ-resistant strain lacking flagella does not respond to phage presence. Via a reporter fusion assay, we have determined that the addition of a χ-induced S. marcescens cell lysate to an uninfected culture causes a threefold increase in transcription of the pig operon, containing genes essential for pigment biosynthesis. Replacement of the pig promoter with a constitutive promoter abolished the pigmentation increase, indicating that regulatory elements present in the pig promoter likely mediate the phenomenon. We hypothesize that S. marcescens detects the threat of phage-mediated cell death and reacts by producing prodigiosin as a stress response. Our findings are of clinical significance for two main reasons: (i) elucidating complex phage-host interactions is crucial for development of therapeutic phage treatments, and (ii) overproduction of prodigiosin in response to phage could be exploited for its biosynthesis and use as a pharmaceutical.
The dual role of a novel Sinorhizobium meliloti chemotaxis protein CheT in signal termination and adaptation
Agbekudzi, Alfred; Arapov, Timofey D.; Stock, Ann M.; Scharf, Birgit E. (Wiley, 2024-10)
Sinorhizobium meliloti senses nutrients and compounds exuded from alfalfa host roots and coordinates an excitation, termination, and adaptation pathway during chemotaxis. We investigated the role of the novel S. meliloti chemotaxis protein CheT. While CheT and the Escherichia coli phosphatase CheZ share little sequence homology, CheT is predicted to possess an α-helix with a DXXXQ phosphatase motif. Phosphorylation assays demonstrated that CheT dephosphorylates the phosphate-sink response regulator, CheY1~P by enhancing its decay two-fold but does not affect the motor response regulator CheY2~P. Isothermal Titration Calorimetry (ITC) experiments revealed that CheT binds to a phosphomimic of CheY1~P with a KD of 2.9 μM, which is 25-fold stronger than its binding to CheY1. Dissimilar chemotaxis phenotypes of the ΔcheT mutant and cheT DXXXQ phosphatase mutants led to the hypothesis that CheT exerts additional function(s). A screen for potential binding partners of CheT revealed that it forms a complex with the methyltransferase CheR. ITC experiments confirmed CheT/CheR binding with a KD of 19 μM, and a SEC-MALS analysis determined a 1:1 and 2:1 CheT/CheR complex formation. Although they did not affect each other's enzymatic activity, CheT binding to CheY1~P and CheR may serve as a link between signal termination and sensory adaptation.
Insights into the in-situ degradation and fragmentation of macroplastics in a low-order riverine system
Gray, Austin D.; Gore, Beija; Gaesser, Megan; Sequeira, Luisana Rodriguez; Thibodeau, Tessa; Montgomery, Allison; Purvis, Sam; Ouimet, Kathryn; Dura, Tina; Mayer, Kathleen (Oxford University Press, 2025-05)
Inland riverine systems are major conduits of microplastics to coastal environments. Plastic materials that pass through riverine systems are subjected to various degradation processes that facilitate their fragmentation into microplastics (MPs). Low-order streams, a critical yet understudied part of river networks, significantly influence the fate and transport of MPs. Here, we investigate the in situ degradation of common macroplastic polymers (e.g., low-density polyethylene, polyethylene terephthalate, and polystyrene) and their fragmentation into MPs in urban and forested streams. We deployed macroplastic items and a natural biodegradable polymer (cellulose) into a stream habitat for 52 weeks. We found that regardless of stream type (forested or urban), macroplastic polymers produced MPs in two weeks, with polystyrene having the highest fragmentation rate (8 particles/week). We explored several degradation indices (carboxyl index, hydroxyl index, and vinyl index), which revealed that photooxidation played a role in macroplastic degradation over time. Another driver of degradation was biofilm formation observed on the surface of all items, mainly composed of diatoms. Lastly, we found that field-aged macroplastics can leach plastic-derived dissolved organic. Our study narrows the knowledge gap regarding MP degradation and fragmentation in freshwater by providing real-time in situ data on the rate of polymer fragmentation in a low-order riverine system.
Cytoplasmic connexin43-microtubule interactions promote glioblastoma stem-like cell maintenance and tumorigenicity
Smyth, James W.; Guo, Sujuan; Chaunsali, Lata; O’Rourke, Laurie; Dahlka, Jacob; Deaver, Stacie; Lunski, Michael; Nurmemmedov, Elmar; Sontheimer, Harald; Sheng, Zhi; Gourdie, Robert G.; Lamouille, Samy (Springer, 2025-05-16)
Glioblastoma (GBM) is the most common primary tumor of the central nervous system. One major challenge in GBM treatment is the resistance to chemotherapy and radiotherapy observed in subpopulations of cancer cells, including GBM stem-like cells (GSCs). These cells have the capacity to self-renew and differentiate and as such, GSCs participate in tumor recurrence following treatment. The gap junction protein connexin43 (Cx43) has complex roles in oncogenesis and we have previously demonstrated an association between Cx43 and GBM chemotherapy resistance. Here, we report, for the first time, increased direct interaction between non-junctional Cx43 and microtubules in the cytoplasm of GSCs. We hypothesize that non-junctional Cx43/microtubule complexing is critical for GSC maintenance and survival and sought to specifically disrupt this interaction while maintaining other Cx43 functions, such as gap junction formation. Using a Cx43 mimetic peptide of the carboxyl terminal tubulin-binding domain of Cx43 (JM2), we successfully disrupted Cx43 interaction with microtubules in GSCs. Importantly, administration of JM2 significantly decreased GSC survival in vitro, and limited GSC-derived and GBM patient-derived xenograft tumor growth in vivo. Together, these results identify JM2 as a novel peptide drug to ablate GSCs in GBM treatment.
Integrating Artificial Intelligence in Orthopedic Care: Advancements in Bone Care and Future Directions
Kumar, Rahul; Sporn, Kyle; Ong, Joshua; Waisberg, Ethan; Paladugu, Phani; Vaja, Swapna; Hage, Tamer; Sekhar, Tejas C.; Vadhera, Amar S.; Ngo, Alex; Zaman, Nasif; Tavakkoli, Alireza; Masalkhi, Mouayad (MDPI, 2025-05-13)
Artificial intelligence (AI) is revolutionizing the field of orthopedic bioengineering by increasing diagnostic accuracy and surgical precision and improving patient outcomes. This review highlights using AI for orthopedics in preoperative planning, intraoperative robotics, smart implants, and bone regeneration. AI-powered imaging, automated 3D anatomical modeling, and robotic-assisted surgery have dramatically changed orthopedic practices. AI has improved surgical planning by enhancing complex image interpretation and providing augmented reality guidance to create highly accurate surgical strategies. Intraoperatively, robotic-assisted surgeries enhance accuracy and reduce human error while minimizing invasiveness. AI-powered smart implant sensors allow for in vivo monitoring, early complication detection, and individualized rehabilitation. It has also advanced bone regeneration devices and neuroprosthetics, highlighting its innovation capabilities. While AI advancements in orthopedics are exciting, challenges remain, like the need for standardized surgical system validation protocols, assessing ethical consequences of AI-derived decision-making, and using AI with bioprinting for tissue engineering. Future research should focus on proving the reliability and predictability of the performance of AI-pivoted systems and their adoption within clinical practice. This review synthesizes recent developments and highlights the increasing impact of AI in orthopedic bioengineering and its potential future effectiveness in bone care and beyond.
Environmental bodies of water as reservoirs for Salmonella: A Scoping Review
Chowdhury, Bhaswati; Ehsan, Rakib; Weller, Daniel; Kummer, Amber; Nguyen, Han; Comer, C. Cozette; Hoch, Jackson; Cheng, Rachel (2025-05)
Salmonella enterica is a leading cause of foodborne illness in the United States. Emerging evidence suggests that surface water may act as an environmental reservoir, contributing to its persistence and transmission. However, no comprehensive synthesis of the available literature exists to evaluate the strength of this evidence or to identify patterns in Salmonella occurrence in surface water sources from different regions in the United States. To address this gap, this protocol describes the methodology for conducting a scoping review, developed in accordance with PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines by trained reviewers in collaboration with evidence synthesis librarians, to assess the prevalence of Salmonella contamination in surface water in the US and evaluate its potential role in transmission, including links to agricultural runoff and wildlife activity. In brief, the descriptor terms for the pathogen of interest, i.e., “Salmonella” and surface water bodies (e.g., river, stream, wetland) were identified. These terms were then tailored to the syntax requirements of nine selected databases, based on scope and topical fit, and used to develop search strategies incorporating Boolean and proximity operators to enhance the retrieval of relevant records. Controlled vocabularies, such as MeSH and CAB Thesaurus terms, were also incorporated, and the search was restricted to studies conducted within the United States. Inclusion and exclusion criteria were defined a priori to guide the screening of retrieved records through title, abstract, and full-text review. Finally, data extraction items were identified to (i) synthesize evidence on risks associated with surface water used for irrigation in small and large produce operations and (ii) identify key knowledge gaps to inform future research on surface water as an environmental reservoir for Salmonella.
Dynamics of RNA m⁵C modification during brain development
Johnson, Zachary; Xu, Xiguang; Lin, Yu; Xie, Hehuang (Elsevier, 2023-05)
Post-transcriptional RNA modifications have been recognized as key regulators of neuronal differentiation and synapse development in the mammalian brain. While distinct sets of 5-methylcytosine (m5C) modified mRNAs have been detected in neuronal cells and brain tissues, no study has been performed to characterize methylated mRNA profiles in the developing brain. Here, together with regular RNA-seq, we performed transcriptome-wide bisulfite sequencing to compare RNA cytosine methylation patterns in neural stem cells (NSCs), cortical neuronal cultures, and brain tissues at three postnatal stages. Among 501 m5C sites identified, approximately 6% are consistently methylated across all five conditions. Compared to m5C sites identified in NSCs, 96% of them were hypermethylated in neurons and enriched for genes involved in positive transcriptional regulation and axon extension. In addition, brains at the early postnatal stage demonstrated substantial changes in both RNA cytosine methylation and gene expression of RNA cytosine methylation readers, writers, and erasers. Furthermore, differentially methylated transcripts were significantly enriched for genes regulating synaptic plasticity. Altogether, this study provides a brain epitranscriptomic dataset as a new resource and lays the foundation for further investigations into the role of RNA cytosine methylation during brain development.
Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis
Caldwell, Blake A.; Ie, Susanti; Lucas, Amy; Li, Liwu (Nature Portfolio, 2025-01-15)
Sepsis is a leading cause of death worldwide, with most patient mortality stemming from lingering immunosuppression in sepsis survivors. This is due in part to immune dysfunction resulting from monocyte exhaustion, a phenotype of reduced antigen presentation, altered CD14/CD16 inflammatory subtypes, and disrupted cytokine production. Whereas previous research demonstrated improved sepsis survival in Ticam2-/- mice, the contribution of TICAM2 to long-term exhaustion memory remained unknown. Using a cecal slurry injection sepsis model, we monitored the establishment and recovery of monocyte exhaustion in Ticam2-/- mice. After one week of recovery, we profiled bone marrow and splenic reservoir monocytes in Ticam2-/- mice and found that, in contrast to the persistent exhaustion observed in wild-type monocytes, Ticam2-/- monocytes largely resembled healthy controls. To determine the impact of TICAM2 ablation on innate epigenetic memory in sepsis, we measured genome-wide DNA methylation in bone marrow monocytes and found that Ticam2-/- cells exhibit a unique profile of altered methylation at CEBPE binding sites and regulatory features for key immune genes such as Dmkn and Btg1. Bearing human translational relevance, a case study of time course blood samples collected from a sepsis patient presenting with SIRS and a positive qSOFA revealed a similar effect in human monocytes, which steadily transition into an exhausted memory characterized by a CD38high; CX3CR1low; HLA-DRlow state within four days of hospital admittance. Together, our data reveal the chronic preservation of monocyte exhaustion, partially controlled by TICAM2.
Oral dosage forms for drug delivery to the colon: an existing gap between research and commercial applications
Martínez, Estefanía; Gamboa, Jennifer; Finkielstein, Carla V.; Cañas, Ana I.; Osorio, Marlon A.; Vélez, Yesid; Llinas, Néstor; Castro, Cristina I. (2025-03-05)
Oral drug administration is the preferred route for pharmaceuticals, accounting for ~90% of the global pharmaceutical market due to its convenience and cost-effectiveness. This study provides a comprehensive scientific and technological analysis of the latest advances in oral dosage forms for colon-targeted drug delivery. Utilizing scientific and patent databases, along with a bibliometric analysis and bibliographical review, we compared the oral dosage forms (technology) with the specific application of the technology (colon delivery) using four search equations. Our findings reveal a gap in the publications and inventions associated with oral dosage forms for colon release compared to oral dosage forms for general applications. While tablets and capsules were found the most used dosage forms, other platforms such as nanoparticles, microparticles, and emulsions have been also explored. Enteric coatings are the most frequently applied excipient to prevent the early drug release in the stomach with pH-triggered systems being the predominant release mechanism. In summary, this review provides a comprehensive analysis of the last advancements and high-impact resources in the development of oral dosage forms for colon-targeted drug delivery, providing insights into the technological maturity of these approaches.
Toward a Universal Model of Hyporheic Exchange and Nutrient Cycling in Streams
Monofy, Ahmed; Grant, Stanley B.; Boano, Fulvio; Rippy, Megan A.; Gomez-Velez, Jesus D.; Kaushal, Sujay S.; Hotchkiss, Erin R.; Shelton, Sydney (American Geophysical Union, 2024-11-12)
In this paper we demonstrate that several ubiquitous hyporheic exchange mechanisms can be represented simply as a one-dimensional diffusion process, where the diffusivity decays exponentially with depth into the streambed. Based on a meta-analysis of 106 previously published laboratory measurements of hyporheic exchange (capturing a range of bed morphologies, hydraulic conditions, streambed properties, and experimental approaches) we find that the reference diffusivity and mixing length-scale are functions of the permeability Reynolds Number and Schmidt Number. These dimensionless numbers, in turn, can be estimated for a particular stream from the median grain size of the streambed and the stream's depth, slope, and temperature. Application of these results to a seminal study of nitrate removal in 72 headwater streams across the United States, reveals: (a) streams draining urban and agricultural landscapes have a diminished capacity for in-stream and in-bed mixing along with smaller subsurface storage zones compared to streams draining reference landscapes; (b) under steady-state conditions nitrate uptake in the streambed is primarily biologically controlled; and (c) median reaction timescales for nitrate removal in the hyporheic zone are (Formula presented.) 0.5 and 20 hr for uptake by assimilation and denitrification, respectively. While further research is needed, the simplicity and extensibility of the framework described here should facilitate cross-disciplinary discussions and inform reach-scale studies of pollutant fate and transport and their scale-up to watersheds and beyond.
A framework for developing a real-time lake phytoplankton forecasting system to support water quality management in the face of global change
Carey, Cayelan C.; Calder, Ryan S. D.; Figueiredo, Renato J.; Gramacy, Robert B.; Lofton, Mary E.; Schreiber, Madeline E.; Thomas, R. Quinn (Springer, 2024-09-20)
Phytoplankton blooms create harmful toxins, scums, and taste and odor compounds and thus pose a major risk to drinking water safety. Climate and land use change are increasing the frequency and severity of blooms, motivating the development of new approaches for preemptive, rather than reactive, water management. While several real-time phytoplankton forecasts have been developed to date, none are both automated and quantify uncertainty in their predictions, which is critical for manager use. In response to this need, we outline a framework for developing the first automated, real-time lake phytoplankton forecasting system that quantifies uncertainty, thereby enabling managers to adapt operations and mitigate blooms. Implementation of this system calls for new, integrated ecosystem and statistical models; automated cyberinfrastructure; effective decision support tools; and training for forecasters and decision makers. We provide a research agenda for the creation of this system, as well as recommendations for developing real-time phytoplankton forecasts to support management.
Atmospheric Deposition of Microplastics in South Central Appalachia in the United States
Elnahas, Adam; Gray, Austin; Lee, Jennie; AlAmiri, Noora; Pokhrel, Nishan; Allen, Steve; Foroutan, Hosein (American Chemical Society, 2024-12-26)
Due to the increased prevalence of plastic pollution globally, atmospheric deposition of microplastics (MPs) is a significant issue that needs to be better understood to identify potential consequences for human health. This study is the first to quantify and characterize atmospheric MP deposition in the Eastern United States. Passive sampling was conducted at two locations within the Eastern United States, specifically in remote South Central Appalachia, from March to September 2023. Each location had five sampling periods, with collections over a 21 day period. Samples were processed to remove biological material, and the presence of MPs was confirmed using Raman spectroscopy to match particles based on polymer similarity. The relative average atmospheric MP deposition in South Central Appalachia was determined to be 68 MPs m^-2 d^-1. Most verified MPs were fibers, and the most abundant polymer type identified was poly(ethylene terephthalate) PETE. This study's average MP deposition rate is qualitatively comparable to rates reported in other studies that employed a similar methodology in a similar landscape. Scaling up our measured deposition rate to all of South Central Appalachia, an area of over 94,000 km² and home to five million people, suggests a yearly MP deposition of approximately 321 metric tonnes. Our study highlights the prevalence of MP deposition in the Eastern United States, providing baseline data for future work to further assess routes of MP introduction.
Aquatic and Wetland Plants of Northeastern North America, Second Edition [Book review]
Metzgar, Jordan (Torrey Botanical Society, 2024-05-30)
Colder temperatures augment viability of an indirectly transmitted songbird pathogen on bird feeders
Teemer, Sara R.; Tulman, Edan R.; Arneson, Alicia G.; Geary, Steven J.; Hawley, Dana M. (Wiley, 2024-12)
Inanimate surfaces that are contaminated with infectious pathogens are common sources of spread for many communicable diseases. Understanding how ambient temperature alters the ability of pathogens to remain viable on these surfaces is critical for understanding how fomites can contribute to seasonal patterns of disease outbreaks. House finches (Haemorhous mexicanus) experience fall and winter outbreaks of mycoplasmal conjunctivitis, caused by the bacterial pathogen Mycoplasma gallisepticum (MG). Although bird feeder surfaces serve as an indirect route of MG transmission between sick and healthy individuals, the contributions of feeders to MG transmission in the wild will depend on how ambient temperature affects viability and pathogenicity of MG on feeder surfaces over time. Here, we used two experiments, with identical initial design, to assess such temperature effects. For both experiments, we pipetted equal amounts of MG onto replicate feeder ports held at night-day temperatures representing summer (22–27°C) or winter (4–9°C). We allowed MG to incubate on feeders at either temperature and swabbed remaining inocula from surfaces at 0, 1, 2, 4, or 7 days post-inoculation of the feeder, with each replicate feeder port only swabbed at a single time point. In the first study, we analyzed swabs using a culture-based assay and found that MG incubated at colder versus warmer temperatures maintained higher viability on feeder surfaces over time. In the second study, we replicated the same experimental design but used MG swabs from feeder surfaces to inoculate wild-caught, pathogen-naïve birds and measured resulting disease severity and pathogen loads to determine pathogenicity. We found that MG remained pathogenic on feeder surfaces at cold ambient temperatures for up to one week, much longer than previously documented. Further, MG was significantly more pathogenic when incubated on feeders in colder versus warmer temperatures, with the strongest effects of temperature present after at least four days of incubation on feeder surfaces. Overall, cold ambient temperatures appear to alter the role of fomites in the MG transmission process, and temperature likely contributes to seasonal disease dynamics in this system and many others.
Proteomic insights into breast cancer response to brain cell-secreted factors
Ahuja, Shreya; Lazar, Iuliana M. (Springer, 2024-08-21)
The most devastating feature of cancer cells is their ability to metastasize to distant sites in the body. HER2 + and TN breast cancers frequently metastasize to the brain and stay potentially dormant for years until favorable conditions support their proliferation. The sheltered and delicate nature of the brain prevents, however, early disease detection and effective delivery of therapeutic drugs. Moreover, the challenges associated with the acquisition of brain biopsies add compounding difficulties to exploring the mechanistic aspects of tumor development. To provide insights into the determinants of cancer cell behavior at the brain metastatic site, this study was aimed at exploring the early response of HER2 + breast cancer cells (SKBR3) to factors present in the brain perivascular niche. The neural microenvironment was simulated by using the secretome of a set of brain cells that come first in contact with the cancer cells upon crossing the blood brain barrier, i.e., endothelial cells, astrocytes, and microglia. Cytokine microarrays were used to investigate the secretome mediators of intercellular communication, and proteomic technologies for assessing the changes in the behavior of cancer cells upon exposure to the brain cell-secreted factors. The cytokines detected in the brain secretomes were supportive of inflammatory conditions, while the SKBR3 cells secreted numerous cancer-promoting growth factors that were either absent or present in lower abundance in the brain cell cultures, indicating that upon exposure the SKBR3 cells may have been deprived of favorable conditions for optimal growth. Altogether, the results suggest that the exposure of SKBR3 cells to the brain cell-secreted factors altered their growth potential and drove them toward a state of quiescence, with broader overall outcomes that affected cellular metabolism, adhesion and immune response processes. The findings of this study underscore the key role played by the neural niche in shaping the behavior of metastasized cancer cells, provide insights into the cellular cross-talk that may lead cancer cells into dormancy, and highlight novel opportunities for the development of metastatic breast cancer therapeutic strategies.
Proteomic assessment of SKBR3/HER2+ breast cancer cellular response to Lapatinib and investigational Ipatasertib kinase inhibitors
Karcini, Arba; Mercier, Nicole R.; Lazar, Iuliana M. (Frontiers, 2024-08-29)
Introduction: Modern cancer treatment strategies aim at achieving cancer remission by using targeted and personalized therapies, as well as harnessing the power of the immune system to recognize and eradicate the cancer cells. To overcome a relatively short-lived response due to resistance to the administered drugs, combination therapies have been pursued. Objective: The objective of this study was to use high-throughput data generation technologies such as mass spectrometry and proteomics to investigate the broader implications, and to expand the outlook, of such therapeutic approaches. Specifically, we investigated the systems-level response of a breast cancer cell line model to a mixture of kinase inhibitors that has not been adopted yet as a standard therapeutic regime. Methods: Two critical pathways that sustain the growth and survival of cancer cells, EGFR and PI3K/AKT, were inhibited in SKBR3/HER2+ breast cancer cells with Lapatinib (Tyr kinase inhibitor) and Ipatasertib (Ser/Thr kinase inhibitor), and the landscape of the affected biological processes was investigated with proteomic technologies. Results: Over 800 proteins matched by three unique peptide sequences were affected by exposing the cells to the drugs. The work corroborated the anti-proliferative activity of Lapatinib and Ipatasertib and uncovered a range of impacted cancer-supportive hallmark processes, among which immune response, adhesion, and migration emerged as particularly relevant to the ability of drugs to effectively suppress the proliferation and dissemination of cancer cells. Changes in the expression of key cancer drivers such as oncogenes, tumor suppressors, EMT and angiogenesis regulators underscored the inhibitory effectiveness of drugs on cancer proliferation. The supplementation of Lapatinib with Ipatasertib further affected additional transcription factors and proteins involved in gene expression, trafficking, DNA repair, and development of multidrug resistance. Furthermore, over fifty of the impacted proteins represent approved or investigational targets in the DrugBank database, which through their protein-protein interaction networks can inform the selection of effective therapeutic partners. Conclusion: Altogether, the exposure of SKBR3/HER2+ cells to Lapatinib and Ipatasertib kinase inhibitors uncovered a broad plethora of yet untapped opportunities that can be further explored for enhancing the anti-cancer effects of each drug as well as of many other multi-drug therapies that target the EGFR/ERBB2 and PI3K/AKT pathways.

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