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A TRAJECTORY-BASED DIFFERENTIAL EXPRESSION ANALYSIS FRAMEWORK WITH MULTIPLE SINGLE-CELL RNA-SEQ SAMPLES
No full textSingle-cell RNA-sequencing (scRNA-seq) provides profound insights into the dynamic gene expression shifts within cells, critical for understanding complex biological processes such as differentiation and disease progression. Traditional trajectory inference methods of pseudotemporal ordering have been crucial in mapping these dynamics but often fail to account for variability across multiple samples, a gap that is significant in disease studies. We introduce a novel model for differential multi-sample pseudotime analysis that not only captures gene expression changes along disease trajectories but also adjusts for batch effects and other sample-specific covariates such as age and sex. This comprehensive framework, implemented as an open-source R package, allows for the analysis of cells ordered along continuous pseudotemporal trajectories of patient samples, facilitating a deeper understanding of gene regulatory mechanisms involved in disease progression. We demonstrate the model's efficacy through the reapplication to integrated scRNA-seq datasets from various studies, confirming its robustness against batch effects. Our results indicate consistent gene expression rankings across datasets and suggest the model's applicability to other single-cell modalities like scATAC-seq, potentially expanding its application in translational and clinical research
Sox11 Function in Supporting Cell Proliferation and Hair Cell Regeneration in the Murine Cochlea
No full textUnlike birds which can regenerate auditory hair cells and recover their hearing after hair cells
are lost or damaged, we human do not regenerate auditory hair cells. My study examines the role of the
transcription factor SOX11 in auditory (cochlear) hair cell regeneration, using the mouse as a model
system to test whether hair cell regeneration can be achieved in humans. I manipulated Sox11
expression in cultured cochlear supporting cells using a lentiviral overexpression and knockdown
strategy to determine whether Sox11 is essential and/ or sufficient for supporting cell proliferation and
hair cell regeneration. My preliminary results indicate that Sox11 overexpression as well as Sox11
knockdown have no effect on cochlear supporting cell proliferation or cochlear hair cell
regeneration. However, a recent study provided evidence that Sox11 is sufficient for hair cell
regeneration in the inner ear utricle at postnatal stages, which indicates a similar role in cochlear hair
cell regeneration. More experiments are needed to conclusively rule out SOX11 as a potential target for
hair cell regenerative strategies
The hypothalamic ARC → PVN pathway is involved in mechanical loading-induced PGE2/EP4 skeletal interoception
No full textMechanical stress plays an integral role in the maintenance of both bone and overall systemic homeostasis. Despite its significance, the neural circuits mediating these effects remain poorly understood. This study explores the regulation of mechanical loading by Prostaglandin E2 (PGE2)/prostaglandin receptor 4 (EP4)-mediated skeletal interoception and uncovers the neural pathway involved. Through immunofluorescence, I observed an increase in phosphorylated cAMP response element-binding protein (pCREB) in the arcuate nucleus (ARC) during mechanical loading, alongside a decrease in tyrosine hydroxylase (TH) expression in the paraventricular nucleus (PVN). These changes were abrogated when PGE2/EP4 signaling was blocked. Utilizing anterograde tracing, retrograde tracing, and chemogenetics, I demonstrated the activation of an ARC PVN neural pathway in response to mechanical loading. Moreover, RT-PCR, western blot, and chromatin immunoprecipitation (ChIP) assays confirmed that mechanical loading-induced PGE2/EP4 skeletal interoception suppresses sympathetic activity by upregulating the transcriptional repressor CREM to inhibit TH expression. Our findings reveal a previously undiscovered neural pathway, originating from neurons in the ARC that project to TH+ neurons in the paraventricular nucleus. This pathway is activated in response to PGE2/EP4-mediated mechanical loading signals and possesses the potential to regulate bone homeostasis. This novel neural pathway offers novel perspectives and targets for future research and potential therapeutic approaches for bone-related disorders
Biochemical and molecular studies of BuGZ protein interactions
No full textBuGZ is an evolutionarily conserved protein with myriad characterized functions including gene transcription, RNA splicing, and mitotic spindle assembly. New physiological roles for these characteristics are being continuously discovered, particularly in the context of BuGZ’s role in cancer biology where loss of BuGZ specifically impacts the viability of human cancer cell lines. Here, we report two additional functions of BuGZ as a tubulin guanine nucleotide exchange factor and as a potential regulator of oxidative stress response in colorectal cancer cells. We characterize BuGZ as the first tubulin binding protein to preferentially bind GDP-tubulin (KD = 45 nM) over GTP-tubulin (KD = 477 nM), a 10-fold difference in affinity. Additionally, we show that BuGZ’s binding affinity for either GDP-tubulin or GTP-tubulin is 210- and 20-fold stronger than for microtubules (KD = 9.5 μM) respectively. Subsequently, we show that BuGZ promotes GTP incorporation into tubulin which results in an increase of GTP-bound tubulin by 64% as measured by radio-labeled GTP. This is the first report of a tubulin GEF, and this activity may be mediated by BuGZ’s preferential binding activity to GDP-tubulin, promoting the release of GDP to accelerate the rate of nucleotide exchange of tubulin with the surrounding environment. We also report that BuGZ is a resident of stress granules formed in response to oxidative stress and that loss of BuGZ inhibits stress granule disassembly in colorectal cancer cells. These results add to the repertoire of functions that BuGZ has been shown to perform and support the continued exploration of BuGZ as an important protein in a variety of biological contexts
APPLICATION OF THE CONSOLIDATED FRAMEWORK FOR IMPLEMENTATION RESEARCH TO DETERMINE VACCINATION PRACTICES AMONG HEALTHCARE PROVIDERS OF CHILDREN WITH CANCER IN LATIN AMERICA
Get PDFWhile large advances have been made in the survival for children with cancer, the majority of childhood cancer cases are estimated to occur in low- and middle-income settings where survival rates are much lower than they are in high-income settings. Concurrently, childhood immunizations are an essential infection prevention intervention that has improved morbidity and mortality for vaccine-preventable infections worldwide. However, children with cancer can have their childhood immunization schedules interrupted or vaccine protection reduced due to the immune-suppressing and extended treatments that they receive.
We developed and distributed a self-administered electronic cross-sectional survey to healthcare providers in Latin America and the Caribbean who care for children with cancer. We asked them to respond to questions that examined their knowledge, attitudes and practices towards vaccinating this special population as well as questions that sought to describe the implementation factors that influence the context in which they are attempting to vaccinate these pediatric patients with cancer.
We analyzed 378 participant responses representing experiences across clinical specialties and reflecting practices from 20 countries across the region. Most participants (321, 84.9%) reported recommending vaccines to their pediatric patients with cancer, regardless of work background, institutional factors, or geographical features. Knowledge about the safety of vaccines and the risks to patients who do not receive vaccines was well documented and attitudes were fairly positive towards vaccinating patients. Institutional culture, such as reviewing of patient vaccine record before starting cancer-directed treatment, reflected a significant relationship with whether providers reported recommending vaccines to their patients. Global agendas from agencies like the World Health Organization which focus on expanding and improving both childhood cancer care and childhood immunizations offer an opportunity for collaborative efforts and interventions that can create greater and more effective impact.
This study found that individual level factors are not impacting the decision to vaccinate and that providers are more inclined to be vaccinating this population than first thought. Interventions to improve vaccination coverage should focus beyond the individual level and focus efforts on factors at the institutional, governmental, and global levels
Integrated Photonics Utilizing Silicon Nitride and Sputtered Metal Oxides
No full textIn the ever-advancing world of technology, electronic circuits in this day and age play an important role in our everyday lives. In pursuit of faster speeds, efficiency, and miniaturization, the combination of photonics on a chip emerges as a solution. These photonic integrated circuits (PICs) use existing, mature fabrication processes for electronics, as well as embody the convergence of photonics and electronics. Unlike electronic circuits that utilize the flow of electronics, photonic integrated circuits use photons that travel at the speed of light through waveguides etched onto a common silicon wafer. Using the unique properties of light, photonic integrated circuits promise unparalleled performance, enabling faster communication, increased bandwidth, and lower power consumption in applications ranging from telecommunications and data centers to sensing and medical diagnostics.
Although photonic integrated circuits have a wide variety of films to utilize, the photonic palette is expanding to include new materials that can be useful. In my thesis, I further characterize and test upcoming materials for use in integrated photonics. These materials include silicon nitride (SiN), a non-commercial sputtered metal oxide film, and a set of new sputtered metal oxide films from a commercial partner. The non-commercial film is a sputtered metal oxide commonly known as germanium oxide (GeOx). The films from the commercial partner include sputtered tantalum pentoxide (Ta2O5), niobium-tantalum oxide (NbTaOx), and niobium-titanium oxide (NbTiOx) which can all be referred to as "sputtered metal oxide films" or the last two as "sputtered metal alloy oxide films".
More specifically, I explore the above mentioned materials in detail in the sequential chapters/sections: first, the use of silicon nitride as a spectrometer and splitter; then, a single and multi-layer platform utilizing germanium oxide as a release film; and finally, the visible losses, linear/nonlinear performance, and autofluorescence properties of sputtered metal oxide films. These alternative materials expand the field of integrated photonics and could potentially bring additional capabilities to existing foundries
PLASMODIUM FALCIPARUM ACYL CARRIER PROTEIN MODULATES IN VITRO ACTIVITY OF PYRUVATE KINASE II
No full textThere are more than 200 million malaria cases annually, with a global mortality rate of 15 per 100,000 population at risk. Plasmodium falciparum is the most lethal agent of malaria. Around 90% of cases are due to P. falciparum in some countries. The apicoplast, an important organelle, in malaria parasites has been a target for many antimalaria drugs. Two important proteins in the apicoplast are required for parasite survival. Pyruvate Kinase II (PfPyrKII) has been proven to be essential for organelle maintenance and NTP production in multiple pathways. Acyl Carrier Protein (PfACP) shuttles acyl groups between enzymes in type II fatty acid biosynthesis.
The goal of this study is to build upon preliminary data indicating that PfACP interacts with PfPyrKII. We hypothesize that PfACP can bind to PfPyrKII, and binding alters PfPyrKII activity. We performed a series of co-expression and pull-down studies to validate the binding interaction of these two proteins. To determine the effect of PfACP on PfPyrKII activity, we performed kinetic assays. We found that PfACP can form a complex with PfPyrKII, and upon binding, PfPyrKII activity was increased. The results suggest that PfACP may stabilize PfPyrKII in the apicoplast and may function as an enhancer of PfPyrKII activity
VIRION DISPLAY UNCOVERS MD-1 AS THE ENDOGENOUS AGONIST FOR THE ORPHAN RECEPTOR GPRC5B
Get PDFOver a third of all non-odorant GPCRs in humans are orphans with no known ligands. De-orphanization is hampered by the difficulty of producing purified GPCRs in their native conformation and the lack of a proteome-wide, high-throughput screening approach. Here, we validate a generalizable strategy to deorphanize multi-pass membrane receptors in the human genome. We leverage the Virion Display (VirD) technology to produce recombinant viruses that display the four orphan receptors in the GPRC5 family and used them as probes against the human proteome (HuProt) array to identify potential protein ligands. We discovered that a macrophage-secreted protein, MD-1, is a ligand that selectively activates GPRC5B, which couples to Gαs signaling. The binding of MD-1 to GPRC5B on adipocytes stimulates lipolysis, an effect markedly and maximally induced by cell-cell contact. Our discovery defines a novel signaling axis regulating lipolysis that depends on adipocyte-macrophage interaction. Disrupting this interaction may have therapeutic value in mitigating obesity-associated dyslipidemia
PSYCHOSOCIAL INTERVENTIONS FOR PATIENTS WITH GASTROINTESTINAL CANCER UNDERGOING ELECTIVE ONCOLOGIC RESECTION: A SYSTEMATIC REVIEW
Get PDFBackground: Psychosocial interventions aim to mitigate the psychosocial impact of a cancer diagnosis and treatment. Literature on the impact of psychosocial interventions for patients with gastrointestinal cancer undergoing surgery remains limited.
Objective: The objective of this systematic review is to identify and summarize the existing evidence on psychosocial interventions for patients with gastrointestinal cancer undergoing elective oncologic resection. This objective will be accomplished through two specific aims: (1) to characterize psychosocial interventions; and (2) to assess their impact on quality of life, anxiety, and depression.
Methods: We searched five electronic databases (PubMed, Embase, Cochrane Trials, CINAHL, and PsycInfo) on December 1, 2023, using a combination of controlled vocabulary and keyword terms. Two independent reviewers conducted title and abstract screening and full text review to identify randomized controlled trials including adult participants undergoing gastrointestinal cancer surgery, which evaluated the impact of a psychosocial intervention delivered before and/or after surgery, in which participants were randomly assigned to psychosocial intervention versus standard of care groups. Data abstraction was performed by one reviewer with a second reviewer checking for accuracy. We performed a qualitative synthesis of included studies to describe intervention characteristics and impact on quality of life, anxiety, and depression.
Results: Twenty-seven studies were included in our analysis. The included studies were published between 2005 and 2023 and were conducted in Asia (n=16, 59.3%), Europe (n=9, 33.3%), and South America (n=2, 7.4%). Psychosocial interventions were variable in terms of therapeutic modalities, which included education (n=5, 18.5%), behavioral training (n=3, 11.1%), psychotherapy (n=4, 14.8%), emotional support (n=2, 7.4%), multimodal (education and emotional support) (n=10, 37%), and other multimodal therapy (n=3; 11.1%). Eight studies demonstrated significant increases in quality of life, whereas nine and seven studies reported significant decreases in anxiety and depression scores, respectively.
Conclusion: There is significant heterogeneity in the therapeutic modalities and characteristics of psychosocial interventions for patients undergoing gastrointestinal cancer surgery. This systematic review offers preliminary evidence that psychosocial interventions may be beneficial to this patient population in terms of quality of life, anxiety, and depression. Additional primary research is required to further delineate which therapeutic modalities are most effective
A COMPARATIVE ASSESSMENT OF METAL UPTAKE AND BIOAVAILABILITY IN LUNG CELLS EXPOSED TO MILITARY-TYPE AIR POLLUTANTS: IMPLICATIONS FOR HEALTH RISK MITIGATION
Get PDFExposure to metal-containing particulate matter (MCPM) poses significant health risks, particularly in regions of military activity where metal-containing airborne pollutants are prevalent. This study investigates the uptake and bioavailability of soluble iron (SolFe), iron nanoparticles (FeNP(s)), and urban particulate matter (UPM) in lung epithelial cells and macrophages. Using in vitro models, we assessed the time and temperature dependency of Fe uptake, dose-response relationships, and cell type differences in uptake mechanisms.
The results demonstrate that Fe uptake is time-, temperature-, and dose-dependent, with differences observed between cell types. Macrophages exhibit higher and more sustained uptake of Fe compared to lung epithelial cells, likely due to their specialized phagocytic machinery. Additionally, Fe nanoparticles are preferentially internalized over soluble forms of Fe, potentially due to their larger surface area and interaction with specific cellular receptors.
These findings highlight the importance of understanding cellular responses to MCPM exposure in mitigating health risks, particularly for military personnel. By elucidating uptake mechanisms and dose-response relationships, this study provides valuable insights for setting exposure limits and developing strategies to minimize adverse health outcomes associated with MCPM inhalation