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The Nexus of Planetary and Human Health: Exploring the Effects of a Planetary Health Diet on Cardiometabolic Risk Outcomes in South Asians Living in America
No full textThe modern global food system, responsible for ~30% of the total global greenhouse gas emission, is a major contributor to climate change and is exerting significant influence on both human and environmental health. Recognizing the imperative to address the accelerated impacts of anthropogenic climate change while ensuring sustainable production and consumption practices, the EAT-Lancet Commission proposed a Planetary Health reference Diet in 2019. This dietary pattern is based on a diverse range of whole plant-based foods, including fruits, vegetables, legumes, nuts, and whole grains, and encourages reduced consumption of red and processed meats, added sugars, and refined grains. Poor diet is among the top risk factors for cardiometabolic disease (CMD), which disproportionately burdens South Asian populations. Studies indicate that South Asian Americans, comprising 4%-5% of the total US population, and while genetics and family history play roles in increased cardiometabolic risk factors among South Asians, the interplay of sociocultural factors and dietary shifts towards a more westernized diet in the context of South Asians living in America underscores their disproportionate vulnerability. Given this context, this dissertation endeavored to explore the effects of a Planetary Health Diet on cardiometabolic risk outcomes in South Asians Living in America. The reference diet proposed by the 2019 EAT-Lancet Commission is associated with significant health benefits, including a substantial decrease in overall mortality; however, there is a lack of evidence and a standardized metric to quantify the health outcomes, diet quality, and environmental advantages of adhering to a planetary-conscious diet. Thus, using data from the longitudinal Mediators of Atherosclerosis in South Asians Living in America (MASALA) study, Chapter One we developed and validated a Planetary Health Diet Index (PHDI) that measures adherence to the EAT-Lancet reference diet. In Chapter Two, we delve into the predictive criteria of this index by examining the associations of the PHDI with cardiometabolic risk markers and disease outcomes in the MASALA cohort.
Finally, in Chapter Three, we employ a systems epidemiology approach to identify and validate plasma metabolomic profiles associated with the Planetary Health diet and evaluate associations of the derived metabolomic profile with cardiometabolic risk in South Asian Americans
X-inactivation mosaicism and the effects of X-linked mutations in the human brain
No full textCells in every human female have inactivated one or the other X chromosome (X1 or X2). To enable analysis of this epigenetic mosaicism – and its biological effects – we developed a computational approach that uses single-cell RNA-seq data and transcribed SNPs to infer the X-inactivation choice of individual cells.
Within the dorsolateral prefrontal cortex of human female brain donors, active-X proportions varied by cell type, and, across 68 females, quantitative patterns in this variation reflected shared and distinct features of these cell types’ developmental histories.
In most females, differences in global gene expression between X1 and X2 cells of a given cell type were modest and largely involved X-chromosome genes. In contrast, we found profound gene-expression differences between X1 and X2 cells of the same cell type when we analyzed brain tissue from donors with two X-linked neurodevelopmental disorders – Rett syndrome (caused by mutations in MECP2) and CDKL5 Deficiency Disorder (CDD, caused by mutations in CDKL5) – reflecting the functional mosaicism resulting from heterozygous X-linked mutations of large effect. Though CDD has been considered a variant of Rett syndrome due to the similarity in the disorders’ clinical symptoms, our analyses revealed that the cell-autonomous transcriptional effects of MECP2 and CDKL5 mutations were largely distinct, suggesting that clinical overlap between these disorders arises primarily from convergent, cell non-autonomous effects.
We hypothesized that this same approach could also identify, among females not known to have X-linked mutations, individuals with unusual levels of X-inactivation-associated gene expression mosaicism. We discovered two such individuals, with distinct gene-expression-mosaicism signatures, among 38 females diagnosed with schizophrenia. One of these individuals had a gene-expression-mosaicism signature strongly resembling that of MECP2 mutations; genome sequencing revealed a previously unrecognized MECP2 missense mutation (R167W), which likely contributed to this individual’s lifelong struggles with learning disabilities preceding schizophrenia.
Our approach can be used to characterize X-inactivation mosaicism in any female (XX) tissue, offering insight into cell types’ developmental histories and the cell-autonomous effects of X-linked genetic variation
Preliminary Results in the Investigation of In Vivo Iliac and Coronary Flow Collision, Vortex Formation, and Disorganized Flow Degeneration: Insights from Invasive Cardiology Based on Fluid Mechanics Principles and Practices
No full textBackground: In the research of coronary artery disease, the precise initial injury that starts the atherosclerotic cascade remains unidentified. Moreover, the mechanisms governing the progression or regression of coronary plaque are not yet fully understood. Based on the concept that the cardiovascular system is a network of pumps and pipes, could fluid mechanics principles and practices elucidate the question of atherosclerosis using flow dynamics images from a novel angiographic technique, focusing on antegrade and retrograde flows and their collisions in iliac and coronary arteries?
Methods: From January 2023 to May 2024, coronary angiograms of all hemodynamically stable patients with stable or unstable angina were screened. The angiograms displaying either no lesions (normal) or mild-to-moderate lesions were selected. Each patient underwent an evaluation of flow dynamics and arterial phenomena in both iliac and right coronary arteries. For each artery, data were categorized based on the following parameters: laminar versus non-laminar flow, presence versus absence of collisions, and presence versus absence of retrograde flow. Additionally, in two sub-studies, we analyzed the relationship between retrograde flow and blood pressure, and artificial intelligence algorithms were used to detect the retrograde flow in the right coronary artery.
Results: A total of 95 patients were screened, and 51 were included in this study. The results comprised quantitative data (prevalence of laminar flows, collisions, and retrograde flows) and qualitative data (morphological characteristics of antegrade laminar flow, retrograde contrast flow, and instances of flow collision). The results showed that in the iliac artery, laminar flow was observed in 47.06% (24/51) of cases, with collisions noted in 23.53% (12/51). Retrograde flow was present in 47.06% (24/51) of cases, and notably, 75% (18/24) of these cases were associated with uncontrolled diastolic blood pressure (DBP) above 80 mmHg (p 0.05).
Conclusions: Based on the concept that the cardiovascular system is a network of pumps and pipes, this research methodology provides intriguing insights into arterial flow behaviors by integrating fluid mechanics practices with novel angiographic observations. The preliminary results of this study identified laminar flow as the predominant pattern, with retrograde flow and collisions occurring infrequently. The implications of vortex, collision, and disorganized flow highlight potential mechanisms for endothelial damage and atherosclerosis initiation. Moreover, the correlation with blood pressure underscores the critical role of hypertension management in preventing adverse hemodynamic events. Future directions include refining imaging techniques and further exploring the mechanistic links between flow dynamics and vascular pathophysiology to enhance diagnostic and therapeutic strategies for cardiovascular diseases.Version of Recor
Gene expression programs in the nose
No full textSensory processing in the nose filters the external olfactory world and supports a wide variety of olfactory behaviors that are fundamental to life. Natural odor stimuli are complex mixtures of volatile chemicals that interact with an array of chemical detectors in olfactory sensory neurons that, in rodents, is built from more than 1,000 unique odorant receptors. These odorant receptors are expressed in a one receptor per neuron fashion, leading to ~1,000 different olfactory sensory neuron subtypes in the rodent nose. Since each olfactory sensory neuron subtype can be identified across individuals based upon its expression of a single odorant receptor, the nose provides a model system to query transcriptional variation and functional differences in parallel across subtypes and contexts. In this work we use single-cell genomic approaches to identify nasal targets of pathogens and to comprehensively probe the normal physiology of the nose.
We first examined the expression patterns of genes required for coronavirus cell entry in the nasal epithelium and found that these genes were only expressed in non-neuronal supportive cells in mice and humans, suggesting that infection of these supportive cells rather than sensory neurons leads to the widespread impairment of smell observed in COVID-19 patients. Second, we developed approaches to decompose transcriptional variation across olfactory sensory neurons into gene expression programs that reflect differences in either cellular activity or identities. We discovered that each of the ~1,000 olfactory sensory neuron subtypes harbors a distinct transcriptome whose content is precisely shaped by interactions between its odorant receptor and the environment. Analog changes in activity deterministically yield proportional, bidirectional, and coordinated changes in the expression of ~100 genes that adaptively tune sensory responses. In contrast, dorsoventral identities also vary across olfactory sensory neuron subtypes, but they emerge prior to olfactory receptor expression and remain constant across environmental contexts. In combination with clonal lineage tracing experiments, we integrated single-cell gene expression patterns with spatial transcriptomics datasets and find that these identity programs map smoothly onto the nasal epithelium, yielding a precise and unique spatial position for each sensory neuron subtype. Taken together, our work identifies fixed and flexible gene expression programs that independently maintain constant aspects of neuronal identities while also supporting ongoing adaptation.Medical SciencesMedical Science
Drug Resistance Amplification in Tuberculosis: Integrating Drug Sensitivity Testing with Whole Genome Sequencing
No full textTuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), remains a global health threat, presenting significant challenges to effective treatment due to the emergence of drug-resistant strains. The prevalence and mechanisms of drug resistance amplification in TB remain areas of ongoing research and debate.
This study investigated the consequences of suboptimal treatment on the acquisition of drug resistance mutations in Mtb. We sought to assess the frequency of amplification while identifying potential risk factors; in particular, our goal was to understand the true prevalence of resistance amplification. Utilizing patient data collected during a comprehensive TB transmissibility and treatment study in Peru, we examined changes in drug susceptibility profiles through conventional drug sensitivity testing (phenotypic) and identifying genotypic changes via whole-genome sequencing. This dual examination provides a comprehensive understanding of drug resistance dynamics, going beyond conventional phenotypic assessments to explore the genomic landscape.
We investigated various factors that we hypothesized might contribute to suboptimal treatment outcomes, as suboptimal treatment has been associated with resistance amplification. Specifically, we examined variables such as HIV status, diabetes status, the presence of cavitary lesions, Mtb lineage, time to effective treatment, and adherence to treatment regimens.
While logistic regression analysis did not reveal statistically significant relationships between suboptimal treatment and resistance amplification, our study
provides valuable insight into the acquisition of drug-resistance amplification. It underscores the complexity of TB treatment outcomes and emphasizes the need for further investigation into the factors contributing to drug-resistance amplification. Our main finding was that drug-resistance amplification is rare. Thus, relying solely on phenotypic drug susceptibility testing (DST) data may lead to an overestimation of resistance amplification. This finding highlights the importance of considering the limitations of phenotypic DST data and the potential benefits of integrating advanced molecular techniques such as whole genome sequencing to gain a more accurate understanding of drug resistance dynamics in TB patients
Optimal Pitch Selection Policies Via Markov Decision Processes
No full textIn this thesis, we employ Markov Decision Processes to consider the challenge of optimizing
pitch selection in Major League Baseball. Using empirical transition frequencies from pitch-by-
pitch data, transition probabilities are estimated between states that consist of the count,
number of outs, and configuration of base runners. A Markov Decision Process determines
that MLB pitchers could have, on average, reduced their earned run average by around 0.54
by adopting a policy that throws many more breaking balls than MLB pitchers currently
tend to throw. Sensitivity analyses are conducted to confirm the robustness of these results
to uncertainty in the estimated transition probabilities. We then consider two extensions to
attempt to model more realistic pitcher behavior: a regularized setting where pitchers are
forced to mix the pitch types they throw, and a simplified game-theoretic setting where data
from the 2017 Houston Astros’ season models the behavior of the batter. In both cases, the
results also suggest that pitchers would benefit from relying less on fastballs
Unraveling Kinase-Substrate Relationships through Enzymology and Chemical Biology
No full textProtein post-translational modifications (PTMs) are important events that expand the complexity of the human proteome. Over 2/3 of all encoded proteins have been shown to be phosphorylated by a class of enzymes called protein kinases. Since phosphorylation affects aspects such as enzyme activity, protein-protein interactions, and cellular localization, aberrant phosphorylation is often implicated in abnormal cell growth and metabolism, giving rise to many diseases including cancer and cardiovascular disorders. Therefore, understanding how kinases recognize and phosphorylate their substrates can provide insights into novel therapeutic development.
This dissertation outlines my work on deciphering kinase-substrate relationships through enzymology and chemical biology methods. Starting with a project that focuses on a specific phosphorylation reaction of Akt by the mTORC2 complex, Chapter 2 summarizes our efforts in dissecting the kinetic parameters underlying Akt Ser473 phosphorylation. We prepared stoichiometric mTORC2 complex and semisynthetic Akt proteins to perform enzymatic characterizations using our newly developed quantitative western blot-based assay. In vitro and in cellulo data suggested that mTORC2 directly phosphorylates Akt at Ser473. Biochemical experiments and crosslinking mass spectrometry provided clues to a mechanism through which distal interactions drive mTORC2 substrate recognition.
In Chapter 3, I present the structural basis of a long-range recruitment mechanism for mTORC2 substrate recognition. Employing a bisubstrate inhibitor approach, we successfully obtained a first cryo-EM structure of the mTORC2-Akt co-complex. We identified two major interfaces between Akt and the mTORC2 complex that are critical for substrate recruitment: (1) between mSin1 CRIM domain and Akt kinase domain N-lobe, and (2) between mSin1 N-terminus and Akt kinase domain C-lobe. We validated these interfaces in biochemical and cellular assays and suggest this mechanism to be conserved across other canonical mTORC2 substrates.
In Chapter 4, I discuss a separate project in which we aim to devise a chemical rescue-based approach to study Ser/Thr kinases, their substrates and precise roles in signaling pathways. We introduced an inactivating mutation into a model kinase, CK2α, and identified small molecule rescue agents that could be supplemented to restore catalytic activity in vitro. This approach appears generalizable, as we have successfully applied chemical rescue to a number of kinases from different families in purified systems. We propose that, with further optimization, chemical rescue can be used in live cells to delineate the physiological functions of protein kinases.
In summary, my projects present a range of enzymology and chemical biology approaches that enhance our understanding of kinase-substrate relationships, which could be the key to uncovering disease biology and discovering novel therapeutics
Prenatal arsenic exposure, folic acid use and spina bifida in Bangladesh
No full textSpina bifida, a severe neural tube defect, constitutes a substantial population health burden globally. It increases the risk of stillbirth, infant and child mortality, and multiple neurological conditions, including lower limb paralysis and urinary and fecal incontinence. The etiology of spina bifida is multifactorial, and the prevalence varies greatly across different populations. Prenatal folic acid supplementation is an effective strategy for prevention of spina bifida; folic acid corrects folate deficiency and supports multiple essential reactions during neural tube development. However, folic acid alone does not lead to complete prevention of spina bifida, and the interactions of folic acid and naturally occurring folate with genetic and environmental factors are not fully understood.
Arsenic exposure is a risk factor for spina bifida, and arsenic toxicity is closely linked to folate metabolism. Animal studies have shown that arsenic exposure increases the risk of neural tube defects by influencing folate metabolism and reducing available methyl groups. The risk of neural tube defects was particularly high in animals with folate deficiencies and those with genetic mutations related to folate metabolism. Epidemiologic studies also showed varying risks of spina bifida by arsenic exposure and mothers’ folic acid use. The association between arsenic exposure and spina bifida and its interactions with folic acid is particularly important for the population in Bangladesh. The country experiences widespread groundwater arsenic pollution, prevalent folate deficiency, and a higher prevalence of spina bifida and other neural tube defects. Therefore, this dissertation aims to understand the interactions between prenatal arsenic exposure, folic acid, and genetic factors on spina bifida risk in Bangladesh.
Overview of Dissertation
The first two studies utilized data from a case-control study at the National Institute of Neurosciences & Hospital, Dhaka, Bangladesh. The first study examined the associations between mothers' arsenic exposure and spina bifida risk. This study showed evidence of effect modification—the association between mothers' folic acid use and spina bifida risk differed by mothers’ toenail arsenic concentrations. Folic acid use reduced the risk of spina bifida among mothers with lower arsenic exposure, but this association was not observed among mothers with higher arsenic exposure. The second study explored the potential interactions between mothers' toenail arsenic concentrations and polymorphisms in both mothers' and infants' arsenic and folate metabolism genes. In this paper, we found that infants' AS3MT, MTR, and mothers' CBS and DNMT1 variants interacted with mothers' arsenic exposure to alter the risk of spina bifida. In the third study, we reviewed existing literature to estimate spina bifida prevalence in Bangladesh. Additionally, we assessed the prevention of neural tube defects under different folic acid provisions and arsenic reduction strategies in a hypothetical cohort with high arsenic exposure in Bangladesh. This study quantified the reduction in the prevalence and number of cases with neural tube defects when combining folic acid provision and arsenic reduction strategies.
These studies expand the current understanding of the interaction between arsenic and folic acid, which influences the risk of spina bifida in Bangladesh. The dissertation advocates the approach of integrating environmental health interventions and nutritional strategies to optimize the prevention of spina bifida and neural tube defects. Specifically, the dissertation highlights the importance of addressing environmental arsenic exposure to enhance spina bifida prevention, especially in Bangladesh, where arsenic exposure remains prevalent
Julián Carrillo, Laws of Musical Metamorphosis, and the Landscape of Early Atonal Thought
No full textI offer a translation of, and commentary on, Julián Carrillo’s Leyes de metamorfosis musicales, Chapter 1 (self-published originally as Julián Carrillo, Leyes de metamorfosis musicales [Laws of Musical Metamorphosis], 1949). In my commentary, I show how Carrilo’s text brings together a unique constellation of theoretical interests, encompassing whole-tone collections, microtonality, and pitch multiplication. I also show how Carrillo positioned his theories in relation to those of his international peers, particularly Arnold Schoenberg. Alongside many composer-theorists of the early twentieth century, Carrillo developed a conception of the atonal that was both technically systematic and deeply mythological. Understanding his ideas today contributes to an expanded history of early atonal music theory, beyond its habitual geographical boundaries.MusicAccepted Manuscrip