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A Nonribosomal Peptide Pheromone Controls Male-Induced Female Sexual Development in Schistosoma mansoni
Full text linkSchistosomes are parasites causing one of most prevalent and serious neglected tropical diseases. Their immense egg output in the host is the main source of pathology, placing their reproductive biology of great importance for scientific researches. A bizarre, and physiologically meaningful phenomenon of their reproduction process is that a female schistosome requires constant physical pairing by the male worms to achieve sexual maturity for egg production. The stimulation of the pairing is even sufficient to induce parthenogenetic eggs from the females when insemination is artificially ablated. The molecular mechanism of the process is unknown despite the attention of 100 years. In this study, a master transcription regulator (GLI1), a nonribosomal peptide synthetase (SmNRPS) and a pheromone metabolite β-alanyl-tryptamine (BATT) were discovered to firstly demonstrate the way a male parasite might signal his paired female. Using RNA sequencing, biochemistry assays and metabolomic analysis, we believe a male parasite starts to secret SmNRPS synthesized BATT into his pairing groove, upon copulation, to stimulate the paired female. The process is activated through transcription upregulation of the enzyme by GLI1. Virgin female Schistosoma mansoni can sexually develop and eventually lay eggs by being soaked in BATT supplemented media. This result is pioneering in understanding the schistosome female-male interplay and provides novel therapeutic targets directly related to schistosomiasis pathology
A Cerebellar Role in the Development and Regulation of Autism-Relevant Behavior in Neurodevelopmental Disorders
Full text linkPages ix-x are misnumbered as pages x-xi.Cerebellar dysfunction is a consistent observation in autism spectrum disorders (ASD) and associated genetic disorders like Fragile X Syndrome (FXS). Growing evidence for cerebellar regulation of behaviors that characterize these disorders has provided a greater understanding of non-motor roles for the cerebellum. Consistent observations of cerebellar pathology in human and mouse models of FXS indicate a potential contribution of cerebellar activity to ASD-relevant behavior impairments that has yet to be fully described. Here, we define a role for cerebellar Fmr1 in ASD-relevant behaviors a model of cerebellar dysfunction and show normal social and sensory behaviors require cerebellar expression of Fmr1. We show that cerebellar Fmr1 is sufficient to rescue those deficits observed a model of translationally relevant global Fmr1 loss. We also demonstrate a modulatory role for cerebellar domain RCrus1 in the presentation of social behaviors in these Fmr1 models.
To further our understanding genetic mechanisms in ASD and how to leverage them in the development of therapeutics, we investigated critical periods of developmental vulnerability in another genetic model of ASD, tuberous sclerosis complex (TSC). Specifically addressing how the timing abnormal cerebellar development contributes to the onset of ASD-relevant behaviors. Through timed pharmacologic manipulation of the mTOR pathway, which is overactive in models of TSC, we identified independent critical periods for the development of cerebellar-mediated social and restrictive and repetitive behaviors. Together these studies highlight the translational impact for cerebellar modulation of ASD-relevant behaviors in multiple genetic models of ASD, in an effort to direct future study of the cerebellum as a therapeutic target
Investigating the Function of an Actin Nucleation-Promoting Factor N-WASP in Mammalian Myoblast Fusion
Full text linkPages 61-89 are misnumbered as pages 75-103, and pages 90-100 are misnumbered as pages 102-112.Skeletal muscle makes up ~ 40% of the total body weight. For mature, functioning muscle to develop from undifferentiated cells, several processes must be coordinated. During myogenesis, muscle progenitor cells activate a muscle-specific genetic program that restricts their cell fate to the myogenic lineage, exiting the cell cycle and differentiating into myocytes. Fusion between myocytes leads to the generation of multinucleated syncytial cells called myotubes which grow and form mature myofibers. Cell-cell fusion is the underlying process for skeletal muscle development and regeneration. While Drosophila has been used extensively to study myoblast fusion, little is known about the site of fusion in mammalian myoblast fusion. Through my work, I show that invasive finger-like protrusions are present during fusion in vitro and in vivo during development. I investigate the role of nucleation promoting factor, N-WASP, in C2C12 cells and in mouse models. N-WASP is present at the site of fusion prior to a fusion event and is involved in protrusion formation. Lastly, in vivo mouse models result in a mild muscle phenotype
Life's Swirls
No full textPrompt: "If you could write a letter to your younger self, what wisdom and encouragement would you share?"
The Transcription Factor TFEB Protects Against Cardiac Hypertrophy by Increasing Lysosomal Capacity and Activating AMPKα
Full text linkHeart failure is one of the leading causes of morbidity and mortality in the modern world. Stress-induced pathological hypertrophy is observed in most forms of heart disease. Pathological cardiac remodeling is a hallmark of impending heart failure. Lysosome-assisted processes such as autophagy and mitophagy play important roles in this remodeling, as do signaling pathways associated with the lysosome, such as AMPK and mTOR, a negative and positive regulator of hypertrophy, respectively. Yet, lysosomal biogenesis and function remain poorly studied in the heart, and the possible role of the lysosome as a signaling nexus for hypertrophic stress is as yet unknown. Recently, the transcription factor EB (TFEB) has emerged as a key regulator of lysosomal genes in multiple tissues, especially in response to external stress.
Here, we set out to test the hypothesis that TFEB-dependent control of lysosomal biogenesis is required in the setting of pathological hypertrophic stress. Our data demonstrate that TFEB is activated and translocates to the nucleus in cardiomyocytes under hypertrophic stress conditions and upregulates lysosomal genes. We engineered a novel cardiomyocyte-specific TFEB knockout mouse (CTKO). At baseline, contractile function measured by echocardiography appears normal in these mice compared to their Cre-negative littermates. However, in the setting of hypertrophic stress, the CTKO mice manifest an exacerbated hypertrophic response leading quickly to heart failure. As expected, we observe a failure in the up-regulation of key TFEB-mediated lysosomal genes after TAC (thoracic aortic constriction) in CTKO mice. In contrast, autophagosome-associated proteins such as LC3II and p62 are increased in the CTKO animals after TAC, as are levels of ubiquitinated proteins, suggesting a decrease in protein turnover. Surprisingly, AMPK signaling is significantly decreased in the CTKO hearts. To further elucidate the cardiomyocyte-specific effects and regulation of TFEB we employed a loss-of-function (knockdown) approach in neonatal rat ventricular myocytes (NRVMs) challenged with pro-hypertrophic stimuli. Our in vitro system phenocopies the exacerbated hypertrophic response seen in vivo. We confirmed a requirement for TFEB in the activation of AMPK signaling under hypertrophic conditions. This occurs in a manner dependent on Camkk2 activity. Based on these data, we conclude that TFEB antagonizes pathological, hypertrophic cardiac remodeling through up-regulation of lysosomal capacity and AMPK signaling. Ins light of recent effort in developing TFEB agonists, our study has potential translational importance
Characterization of Oral Cavity Lesions Within Betel Nut Users in Remote Pacific Islands
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.This thesis includes 2 separate documents: [Part One] Efficacy and safety of artemether-lumefantrine to treat uncomplicated Plasmodium falciparum after a decade of its use as first-line antimalarial treatment in Namibia and [Part Two] Characterization of oral cavity lesions within betel nut users in remote Pacific Islands.Pages 1-30 are misnumbered as pages 2-31.[Efficacy and Safety of Artemether-lumefantrine to Treat Uncomplicated Plasmodium falciparum After a Decade of its Use As First-Tine Antimalarial Treatment In Namibia]
BACKGROUND: Artemether-lumefantrine (AL) has been the first-line treatment against uncomplicated Plasmodium falciparum malaria in Namibia since 2005. The World Health Organization regularly monitors and recommends antimalarial drugs in order to contain the rapid spread of the disease and for the early detection of drug resistant strains of the parasite.
AIM: The objective of this study is to assess the efficacy of AL in a low-transmission setting in Namibia.
METHODS: The study is conducted in the Zambezi region of Namibia and is a secondary analysis of a prior longitudinal cohort study. Symptomatic patients reporting to health facilities that were tested positive on the rapid diagnostic test were included in the study. A total of 44 patients were observed and given a 3-day course of AL and single low dose of primaquine as recommended by the WHO.
RESULTS: At Day 7, 100% of the patients had successfully cleared the infection. 95% of the participants had an adequate clinical and parasitological response with 2 patients presenting febrile at a follow-up visit classifying them as having late clinical failure.
CONCLUSION: Overall there were no apparent signs of drug resistance and AL was shown to be safe as a first-line antimalarial drug choice in a low-transmission setting for the treatment of uncomplicated P. falciparum malaria.[Characterization of Oral Cavity Lesions Within Betel Nut Users in Remote Pacific Islands]
BACKGROUND: Betel nut is a commonly chewed substance by the residents of Saipan and many other islands in the Western Pacific Ocean. 43% of Asian Pacific Islander adults in Saipan chew betel nut and 13% of cancer-related mortality in this region is due to oral cavity lesions.
AIM: The purpose of this study is to further characterize the types of oral cavity cancers that occur due to chewing betel nut and better understand best methods of treatment and prevention.
METHODS: A single-institution retrospective review was undertaken for 81 patients who were treated for primary cancers of the head and neck region at the Commonwealth Healthcare Corporation (CHC) in Saipan, CNMI between 2005 and 2019. Biopsies of the oral cavity lesions were obtained from the patients in Saipan and analyzed for further workup.
RESULTS: A majority of head and neck cancer patients had oral cavity cancer (64/81, 79.0%). Preliminary biopsy results show a high incidence of squamous cell carcinoma with squamous hyperplasia. A particularly high incidence of rare verrucous carcinoma was found (8/55, 14.5%).
CONCLUSIONS: Patients with the uncommon verrucous carcinoma should be treated differently as surgical outcomes differ in comparison to oral squamous cell carcinoma. Surgical resection in comparison to radiation therapy has been shown to have a good prognosis in patients with oral verrucous carcinoma. Further studies should be conducted to best prevent and treat these oral lesions
Facing Fear: Image or Reality?
No full textI have been afraid of everything most of life. Even when I tried it seemed as though I kept hitting a brick wall. I felt others watched and got satisfaction of seeing me fail and even if they saw a misstep they did not step in to course correct. I found this cruelty worst than the fear itself. Then I found insight that my fear was energized by chasing an image of what might make happy. The branch is me and branch is anchored on tree of truth. Truth is the reality I seek and not the image of Truth
Development of a Novel MRI system for Preclinical Small Animal Radiation Experiments
No full textPreclinical small animal radiation research (SARR) is an integral component of RT research, as it serves as a critical counterpart for validating new therapeutic approaches, developing advanced techniques, or testing radiobiological hypotheses in a controllable manner at low costs and manageable timelines. Current SARR platforms (irradiators) use cone-beam CT for image guidance, which suffers from low soft-tissue contrast and additional radiation exposure. It is desired to use MR imaging for image guidance purposes. Yet, integrating an MR scanner to an irradiator is a challenging problem due to geometric and magnetic interferences between the scanner and the x-ray system. This thesis work proposes a novel low-field single-sided MR system that can potentially enable preclinical MR-guided radiation studies. We utilized an inhomogeneous single-sided ultra-low-field MR design to achieve geometric and magnetic compatibility with the irradiator. After a brief background introduction and system overview in Chapters 2 and 3, Chapter 4 details our work designing a main magnet that was constructed using an optimized arrangement of neodymium magnets in a modified Halbach cylinder to generate a magnetic field with a spatially decaying distribution for encoding along the axial direction. Chapter 5 discusses the work of designing gradient coils for encoding in the other two directions by constructing coils with a 4cm gap to allow the radiation beam to pass. A 4 cm diameter radiofrequency (RF) coil with a wide bandwidth of ~0.1 MHz was constructed and tuned to allow for an approximate 2 mm slice thickness, which is detailed in Chapter 6. Chapter 7 details our work finalizing the signal chain of the system and assembling the standalone MRI system in an RF shielded enclosure. Chapter 8 introduces the 3D CPMG single-point acquisition pulse sequence scheme that was implemented to overcome dephasing in the inhomogeneous magnetic field, while Chapter 9 presents 2D imaging results on the system. We also studied deep learning-based image reconstruction to incorporate prior information to enhance reconstructed image quality, which is detailed in Chapter 10, and may potentially overcome the challenge of low signal-to-noise ratio in the low-field MR context. Chapter 11 then extends beyond this work to present a potential generalization of the low-field MR technology to clinical settings for image guidance in radiation therapy. Finally, Chapter 12 concludes the dissertation and presents future directions of this work
Regulation of HMG CoA Reductase ER-Associated Degradation by the Vitamin K2 Synthetic Enzyme UBIAD1
Full text linkUbiA prenyltransferase domain containing protein-1 (UBIAD1) is a polytopic membrane-bound enzyme that synthesizes the vitamin K2 subtype menaquinone-4 (MK-4) by conjugating the prenyl group of geranylgeranyl pyrophosphate (GGpp) to the aromatic acceptor menadione. The enzyme moonlights as a regulator of Endoplasmic Reticulum (ER)-localized 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate limiting enzyme in the synthesis of sterol and nonsterol isoprenoids. When cells are replete with isoprenoids, UBIAD1 constitutively cycles between membranes of the medial-trans Golgi and the ER. When ER membranes become depleted of GGpp, UBIAD1 becomes trapped in the ER where it binds to and inhibits the ER-associated degradation (ERAD) of HMGCR. This inhibition permits continued synthesis of nonsterol isoprenoids, even when sterols are abundant. The resultant accumulation of GGpp in the ER causes dissociation of the HMGCR-UBIAD1 complex, which allows maximal ERAD of HMGCR and translocation of UBIAD1 to the Golgi. These findings disclose a novel GGpp sensing mechanism that allows for metabolically-regulated, intracellular trafficking of UBIAD1. This regulated trafficking enables UBIAD1 to modulate reductase ERAD such that synthesis of nonsterol isoprenoids is maintained in sterol-replete cells. These findings establish UBIAD1 as a central player in the HMGCR ERAD pathway and regulation of isoprenoid synthesis. However, the mechanism by which GGpp induces transport, as well as the importance of UBIAD1 in regulating HMGCR ERAD to maintain evolutionary fitness in eukaryotes, has yet to be determined. In this dissertation, I use cysteine derivatization, protease protection assays and statistical modeling to determine the membrane topology of UBIAD1 and to gain insight into the enzyme's role in maintaining the evolutionary fitness of eukaryotic cells. These findings are key to determining the mechanism through which UBIAD1 modulates the ERAD of HMGCR and ultimately, the metabolic flux between sterols and nonsterol isoprenoids
Pak Center for Mineral Metabolism: integrating patient care and discovery
No full textDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern’s Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin