Alliance One Tobacco (Malawi)
Academic Research Repository at the Institute of Developing EconomiesNot a member yet
52305 research outputs found
Sort by
Large Scale, User-Defined Peptide and Peptide-Human Leukocyte Antigen Library for High Throughput Detection of Immunogenic Antigens
No full textTargeted immunotherapies—ranging from personalized cancer vaccines to adoptive T‐cell therapies—have revolutionized oncology by leveraging the specificity of T cells to recognize tumor‐associated peptide-bound Human Leukocyte Antigen complexes (pHLA), leading to a durable and robust T cell response against infected or tumor cells. While the process of profiling the pHLA repertoire through mass spectrometry (MS), also known as immunopeptidomics, excels at identifying abundant peptides, it routinely misses lower‐abundance antigens, noncanonical antigens, and neoantigens—antigens arising from tumor-specific somatic mutations. Conversely, existing computational models—though high‐throughput—are constrained by limited HLA allele coverage and poor incorporation of peptide stability or immunogenicity features. These gaps limit our ability to comprehensively elucidate the tumor immunopeptidome and to discover the most clinically effective targets for next‐generation, personalized immunotherapies.
To address the limitations in immunopeptidomics and the biases inherent in contemporary in silico predictors, we have devised two synergistic high-throughput platforms based on the recombinant protein expression system in Escherichia coli (E. coli): (1) Pepyrus: a method for rapid and scalable production of user-defined pure synthetic peptides and peptide spectral libraries, and (2) a method for production of recombinant pHLA from user-defined peptide libraries for targeted screening of HLA-bound peptide.
Using Pepyrus, we produced user-defined peptide libraries totalling over 100,000 patient-specific and off-the-shelf shared cancer-specific peptides and acquired extensive reference spectra through high-resolution MS. From the peptide spectral libraries, we demonstrated its ability to improve low-abundance peptide detection when used together with data-independent mass spectrometry (DIA-MS), an acquisition method which provides a comprehensive spectral map of a given sample but requires a reference spectral library for peptide identity deconvolution. Pepyrus significantly increased detection sensitivity for primary tumor samples and patient-derived cell lines, successfully recovering numerous low-abundance neoantigen, endogenous retroviral, and unannotated open-reading-frame peptides that were undetected by conventional MS methods.
Subsequently, we combined Pepyrus with recombinant HLA expression in E. coli and generated a recombinant pHLA library encompassing 10,000 peptides across 10 prevalent class I HLA alleles, systematically measuring binding at scale. All HLA alleles tested identified novel bound peptide motifs, thus potentially expanding the space of known allele-specific peptide sequences which could enhance the accuracy of prediction models to predict genuine binders. The design of the pHLA construct also allows for high-throughput screening and heat treatments, potentially allowing for systematic interrogation of features related to peptide stability, which could enhance the accuracy of predicting immunogenic epitopes within patient samples.
Collectively, these integrated pipelines amplify the scope and intricacy of immunopeptidome profiling in a user-defined and high throughput manner, facilitating the reliable identification of both shared antigens and patient-specific neoantigens for the development of personalized vaccines and adoptive T-cell therapies. Our approach establishes a robust foundation for next-generation antigen detectors and predictors and paves the way for more efficient and broadly applicable targeted immunotherapies.Biological and Biomedical Science
The Impact of Industrial Value Chain Characteristics on Firms’ Financial Performance: Insights from the US Stock Market
No full textapplication/pdfIDP000928_001This study explores the influence of industry-level value chain characteristics on firms’ financial performance, a subject that is frequently discussed yet rarely examined empirically. By correlating US input-output data across 405 sectors with financial information from listed companies in the US stock market, we discern a significant influence of value chain position, length, and complexity on firm financial performance, with a notable marginal effect at the industry level. Furthermore, we identify a U-shaped relation between value chain attributes and financial outcomes, aligning with the so-called “Smile Curve” phenomenon. This study offers new insights for investors aiming to make informed industry-specific investment decisions.technical repor
Evaluation of the Immunogenicity of Novel HIV-1 gp160 Env mRNA Vaccines in Pre-clinical Mouse and Guinea Pig Models
No full textHuman immunodeficiency virus (HIV) is one of the biggest healthcare challenges that humans have ever faced, with millions of people living with HIV and new cases of infections each year. Despite advances in HIV treatments, an example being antiretroviral therapies (ART), there is still no cure. Individuals with HIV are required to take lifelong treatment for virologic control. As a result, developing a safe and effective HIV vaccine is needed to reduce new infections and protect the public. In this study, we explored the immunogenicity of structure-based, epitope-targeted HIV-1 nanoparticle enclosed messenger RNA (mRNA) vaccines targeting V2 apex of HIV Envelope (Env) glycoprotein. The vaccine encodes three engineered Env glycoproteins as immunogens: Wildtype (WT), Optimized (OPT), and Alternative (ALT). All immunogens build on HIV clade C serotype 459C backbone and are informed with broadly neutralizing antibody (bNAb) signatures. Key modifications such as stabilizing mutations, glycan hole mutations, antigenic diversity set mutations, and cleavage site linkers were introduced to improve trimer stability, immunogenicity, and the breadth of antibody responses.
mRNA encoding these immunogens was formulated into lipid nanoparticles (LNPs) for delivery. Mice and Guinea pigs were immunized, and sera were collected at regular intervals. Binding antibody responses were monitored by endpoint ELISA, demonstrating that SOSIP-stabilized gp160 constructs induce significantly higher IgG titers than non-SOSIP gp160 or SOSIP gp140 constructs. Moreover, incorporating fusion peptide (FP) bNAb signatures into V2-SET designs might further improve immunogenicity in both models. These findings highlight that stabilizing full-length Env in a native-like conformation and targeting multiple vulnerable epitopes enhances vaccine-induced antibody responses.
For future studies, serum collected a month after the third boosting immunization would be tested with neutralizing antibody (NAb) assays against heterologous panels of select tier 2 V2-sensitive and/or FP-sensitive HIV-Env pseudoviruses. Additional boosts and longer-term follow-ups will be performed to evaluate durability and breadth of the antibody responses. After completion of these studies in mice and guinea pigs, select candidate vaccines would finally be tested in non-human primates in the future.
This study highlights the potential of mRNA-LNP vaccine platforms to elicit broad and robust immune responses against HIV. Our findings provide valuable insights into epitope-targeted immunogen design and could further inform the development of next-generation HIV vaccines capable of inducing broadly neutralizing antibodies.Graduate Educatio
How Culture Drove Us Into the Cognitive Niche
No full textHow have humans become such outliers in our behavioral flexibility and our rapid learning? How have our brains evolved to learn and reason in evolutionarily novel domains, such as mathematics and number systems, laws and mores, or science and medicine? In this dissertation, combining work in cognitive science and cultural evolution, I seek to answer such questions by building informational-ecological models that show how minds that perform different computational strategies fare under different conditions. In the first chapter, I show, using a simple and general model, that any species that is heavily dependent on social learning to acquire much of its adaptive behavior would evolve to make increasingly accurate generalizations. This in turn demands greater mental capacity to learn abstract concepts and world-models. This model ties the evolution of our brains directly to the fact that our babies can expect to be born into a world where they can learn from other skilled individuals. However, our nature as a cultural species has done more than just making available skilled models to learn from. Culture can shape our informational environments (i.e. informational niche construction) in other ways as well. In chapter two of my dissertation, I show how differences between cultural populations in communication styles, or in how knowledge flows across a population, can alter how information is sampled, in such a way as to explain computationally why different cultural groups develop Analytic or Holistic thought--a major distinction made by cross-cultural psychologists. In the third chapter, I extend this informational-ecological perspective to the physical world of tools and dwellings, and the social world of norms, institutions and organizations, to show how the phenomenon of standardization in cultural products is yet another form of informational-niche construction, with far-reaching consequences that explain a wide range of cross-cultural findings in cognitive psychology, sociology, anthropology and political science. One source of increasing standardization in a cultural system is increased population mobility, and on my final chapter, I present archaeogenetic work showing how an ancient episode of increased mobility has led to the development of just such a standardized suite of bronze weaponry that took on ritual, political and economic significance across Northern Eurasian societies in the Bronze Age.Human Evolutionary Biolog
Noradrenergic Modulation of an Amygdalo-thalamic Circuit
No full textEmotional and cognitive processing rely on communication between the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC). The BLA regulates mPFC both directly and indirectly via the medial sub-division of the medial dorsal thalamus (MDm). Although the BLA projection to MDm has been established anatomically, less is known about the functional properties of this synapse. Here, using patch-clamp electrophysiology and optogenetics in ex vivo mouse brain slices, we found that BLA neurons make potent synaptic connections onto MDm neurons capable of evoking action potentials. The site of this BLA input overlaps with strong innervation from locus coeruleus norepinephrine (NE) axons. We found that NE acts via α₂-adrenergic receptors to strongly reduce excitatory postsynaptic currents from BLA to MDm. NE also decreases the release probability of BLA axon terminals through a presynaptic mechanism. Postsynaptically, NE depolarizes MDm neurons and increases their tonic firing rates. These findings show that NE, whose levels are elevated during arousal and stress, can suppress transmission of affective information from BLA into MDm, thereby blunting this potent indirect pathway from BLA to mPFC.Neuroscienc
L.A Nocturne
No full textAbstract
It’s 1984, Los Angeles is on the brink of celebrating the Olympics, and Tony Coletta just got out of San Quentin. Ex Malibu surfer, ex-Vietnam Long Range Scout, ex-psychedelic enthusiast, Tony went inside after a very bad day in 1977. Now, he’s stepping out into a strange new world of neon, new wave, greed and “pro-active” policing. Gone are the easy beach days of the 70s. In these go-go 80s, everyone’s on the hustle, everyone’s making deals and the LAPD is hell bent on “cleaning up the streets”.
These are the opening chapters of LA Nocturne, the first novel in a series featuring Tony Coletta, “just a guy from Malibu” who finds himself pulling the threads on some of the most earth-shattering events in Los Angeles and American history. From the 80s Olympics to the 90s riots and the rise of a rogue element in the LAPD, Tony’s adventures capture the strange unreality of the city of the Angels and the striving energy that endures as the city morphs and grows, mimicking the evolution of America itself.Extension Studie
"Keeping It Real": Authenticity, Mediation, and the Dynamics of the Hiphop Game
No full textThis dissertation is an exploration of the slogan “Keep[ing] it Real” within the context of Hiphop culture and rap music. The slogan relates to social and cultural conceptions of authenticity, mediation, vitality, and their dynamic interconnectedness in discourse, interaction, and artistry. While committed to a semiotic anthropological analysis, I stretch the perspective to integrate, ideas, and frameworks drawn from several academic disciplines across the humanities, social, and natural sciences to argue for the centrality of games and play to elucidate the meanings of “keep[ing],” “it,” and “real.” The approach is meant to track, but also to speculate on the future of Hiphop cultural form, health, decline and death more broadly. My evidence comes, primarily, but not exclusively, from Hiphop and African American culture in the United States from the 1980’s to the present day.
The 3 general chapters follow an introductory argument for the relevance of Hiphop, and they precede a synthetic conclusion organized around my three key terms. Chapter 1 attends to the “real” and considers the intellectual history of authenticity and media(ti(zati)on) to propose a new theorization of Hiphop studies, and to recast cultural life in terms of finite and infinite games. Chapter 2 focuses on the “it” to give concrete examples of cultural games. At stake are interpretations of historical episodes and enduring epics of (ant)agonistic competition and critique (“beef”) between rappers and their crews. Of particular interest are the attributes and values that make up existential concerns for Hiphop cultural agents on the foreground of postmodernity. Chapter 3 asks what “keep[ing]” means by ethnographically interrogating the case of female Hiphop artists who have strived for their own immortality by way of battling for respect and power through their artistry.African and African American Studie
Contexts of Care: Supporting Immigrant-Origin Students and Families in a New Destination
No full textThis dissertation examines how educators, families, and youth collectively build caring contexts of reception in a growing, diversifying school district in the United States. Drawing on over 800 hours of embodied ethnographic research conducted during the 2023–2024 school year, the study explores the daily experiences of immigrant educators, students, and families. Merging critical qualitative ethnographic research with applied experience, the author worked as an Amharic- and Spanish-speaking family liaison across the district and as a college access mentor for immigrant-origin students in a college preparation program for immigrant-origin youth.
First, the study demonstrates that immigrant educators develop creative strategies to meet both individual and collective needs within institutional constraints. These educators actively work to interrupt systemic harm while navigating educational structures that often perpetuate inequities for immigrant-origin students. Second, the research illuminates how multiple actors—including students, families, and educators—interact within layered institutional contexts. An intersectional analysis reveals that these interactions are significantly shaped by factors beyond immigration status alone, including income, housing status, and national origin. Third, the findings show that caring educational practices emerge in complex and sometimes contradictory ways. While symbolic gestures of inclusion exist, the most effective practices address material needs and structural barriers facing immigrant communities. Fourth, the data indicates that student outcomes are closely tied to the availability of multilingual staff and resources that reflect the diverse backgrounds of the student population. Schools with more comprehensive linguistic support systems demonstrated more positive integration experiences. Finally, the research documents how immigrant youth themselves develop resilience strategies and peer support networks that function as protective mechanisms against exclusion and discrimination. These student-led initiatives often operate alongside formal institutional supports but fill critical gaps in the educational context of reception.
The dissertation concludes with policy recommendations that address structural barriers facing immigrant communities, including expanding higher education access for students with liminal immigration statuses, implementing staffing practices that reflect student diversity, providing attendance stipends for low-income students, and developing welcoming school cultures that address material needs beyond symbolic gestures. These recommendations are grounded in transformative care ethics and target multiple dimensions of contexts of reception, recognizing that meaningful immigrant integration requires coordinated interventions across educational and social domains.Educatio
Elucidating the mechanistic role of NDRG1 in DNA repair, replication, and chemoresistance through characterization of novel protein-protein interactions
No full textFaithful DNA replication is critical for maintaining genomic stability but is constantly challenged by endogenous and exogenous replication stress, a hallmark of cancer. While many chemotherapies used to treat cancer induce replication stress, cancer cells frequently develop resistance, underscoring the need to understand mechanisms by which tumor cells overcome this stress and enhance their DNA repair efficiency. We have identified a novel ECM-induced resistance pathway involving N-myc downstream regulated gene 1 (NDRG1) that results in NDRG1-dependent protection from chemotherapy-induced replication stress in pancreatic cancer cells.
To uncover the molecular basis of NDRG1-mediated DNA repair, we utilized a BioID proximity labeling screen and identified Transglutaminase 2 (TGM2) and Meiotic Recombination 11 (MRE11) as two novel NDRG1 binding partners. We characterized the physical protein-protein interactions and functional interactions of these complexes using biochemical, co-immunoprecipitation, and DNA fiber assays.
We found that the NDRG1-TGM2 interaction is enriched upon hydroxyurea and gemcitabine-induced replication stress and is regulated by ECM-induced signaling, and serum- and glucocorticoid-induced kinase 1 (SGK1)-mediated NDRG1 phosphorylation. Importantly, we discovered that TGM2 modulates DNA replication fork homeostasis, and this function was dependent on both the nuclear localization and transamidase catalytic activity of TGM2. Furthermore, we identified a putative NDRG1-TGM2 binding site and demonstrated that this physical interaction contributes to efficient DNA replication fork progression and stalled fork recovery. This work establishes TGM2, an enzyme traditionally regarded to function in the cytoplasm and extracellular space, as a novel regulator of nuclear DNA replication.
The NDRG1-MRE11 interaction was found to be enriched during late S/early G2 phases and upon treatment with fork stalling agents. The lack of binding between purified MRE11 and NDRG1 suggests the interaction is indirect, implying the existence of a regulatory scaffold or post translational modification necessary to mediate the interaction. Functionally, we demonstrated that NDRG1 and MRE11 cooperate to promote the degradation of nascent DNA at stalled forks.
Taken together, our work identified novel mechanistic functions of NDRG1 in DNA replication and repair, through its interactions with TGM2 and MRE11, and provided fundamental new insights into the functions and interplay between these proteins. Furthermore, our work positions NDRG1 as a promising therapeutic target to suppress PDAC chemoresistance.Biological and Biomedical Science