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Getting to the heart of the matter: GLP-1 receptor agonists and CV disease
Full text linkDetailed 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
Experience Induced Shift in CA1 Firing Dynamics and Replay Content to the Slow Gamma Oscillation During Sharp Wave-Ripples
Full text linkThe hippocampus is required for the encoding and storage of spatial and episodic memory, however the neural mechanisms used by this region to facilitate these processes are not well understood. During "off-line" periods such as immobility and slow-wave sleep, the hippocampus replays sequences of neural activity that represent previous experience. This "replay" is often associated with high frequency oscillatory events that originate within the hippocampus known as sharp wave-ripples. Sharp wave-ripple encoded replay has emerged as an attractive mechanism for memory consolidation, as these events synchronize neural activity across the hippocampus and downstream memory storage sites while the neural activity patterns associated with an experience are repetitively played out. This is thought to support plasticity across these networks, effectively resulting in the storage of experience-associated ensemble activity through reorganization of synaptic weights.
However, sharp wave-ripple encoded replay appears to play multiple roles in hippocampal-dependent memory processing, as it seems to support memory retrieval during wakefulness. Currently, it is unclear how the hippocampus may use these events to facilitate multiple different memory processes across different behavioral states. One possibility is that these events, and/or their associated network activity change to support these different processes.
In my dissertation work, I investigated how hippocampal network activity during sharp wave-ripple encoded replay differs across experience, and how these differences may support the different mnemonic processes that occur across different behavioral states. By analyzing in vivo electrophysiology recordings, I found that experience induces the synchronization of deep and superficial neural sub-populations in area CA1 of the hippocampus during sharp wave-ripple encoded replay. This synchronization occurs within an underlying 25-55 Hz "slow gamma" oscillation and persists into the rest period experience. This synchronization is also associated with the linkage of CA1 replay content to slow gamma during experience, which also persists into subsequent rest. These data suggest that the hippocampus utilizes different network activity states during sharp wave-ripple encoded replay across experience, a process that may limit and support cross-regional communication during these events based on mnemonic demands
haiku
No full textI love writing poetry inspired by shows I enjoy. This one is about a woman who is a healer, and I thought her story would be relevant for us working in a medical field
Obstructive Sleep Apnea in Special Pediatric Populations: Down Syndrome and Sickle Cell Disease
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.Pediatric obstructive sleep apnea (OSA) is a sleep-related disorder of breathing caused by upper airway obstruction. Polysomnography is the gold standard for diagnosis, and the first-line treatment of tonsillectomy with or without adenoidectomy (T&A) typically resolves OSA in most of the general pediatric population. However, several special populations with significant comorbidities are at high risk of OSA, as well as surgical and anesthetic complications. The purpose of this work is to further investigate OSA in two specific groups: children with (1) Down syndrome and (2) sickle cell disease.
The first study involved children with Down syndrome, and its primary aim was to evaluate outcomes after T&A and predictors for persistent OSA. The second study focused on children with sickle cell disease, and the objective was to compare demographic, clinical, and polysomnographic characteristics of children with and without sickle disease prior to surgical intervention. Two separate retrospective chart review studies were conducted utilizing electronic medical records from UT Southwestern/Children's Medical Center in Dallas, TX. The final population included 81 children with Down syndrome who had both pre- and postoperative (within 12 months of T&A) polysomnography. The second study included 89 children with sickle cell disease and 192 children without sickle cell disease with preoperative polysomnography.
In the study of children with Down syndrome, most of the final population (nearly 75%) had severe OSA, based on an apnea-hypopnea index (AHI) ≥ 10. T&A improved, based on a decrease in AHI, but did not completely resolve OSA. Approximately 60% of children had persistent moderate or severe OSA; outcomes depended on the baseline severity and obesity rates. Notably, 20% of patients had worsening AHI after T&A. Asthma (odds ratio 4.77; 95% CI, 1.61-14.09; P = .005) and increasing age (odds ratio, 1.25; 95% CI, 1.09-1.43; P = .001) were identified as predictors for persistent OSA. These findings suggest close follow-up in children with Down syndrome after T&A due to the high risk of persistent OSA that may worsen with age.
In children with sickle cell disease, severe OSA was present in 43% of the study population versus 67% in the non-sickle cell group (P < .001). Children with sickle cell disease had a lower mean AHI compared to the non-sickle cell group but spent more percent sleep time below 90% oxygen saturation. Most children with sickle cell disease were of normal weight, particularly among the HbSS genotype, whereas most of the comparative group were either overweight or obese. Predicted probability for severe OSA in children with sickle cell disease decreased with increasing age (OR = .81, 95% CI: 0.70-0.93, P =.005). This study highlights the need to screen children with sickle cell disease as they are at high risk for severe OSA, despite being of normal weight, and suffer from longer periods of nocturnal hypoxemia compared to the general pediatric population
On the Structure and Function of Tau Assemblies in Neurodegenerative Diseases
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.Tauopathies, a group of neurodegenerative diseases characterized by aggregation of tau protein, are heterogeneous clinically and pathologically. Recent cryo-EM studies of tau filaments derived from diseased brains have confirmed that most tauopathies are associated with a unique fold, or strain, of misfolded and aggregated tau. It is unclear how tau strains form, or how they relate to the pathogenesis of disease. However, inoculation experiments into the brains of mice have shown that distinct strains of tau encode sufficient information to cause unique and transmissible neuropathology. We and others have proposed that this information transfer, in the form of templated aggregation, or seeding, is necessary for disease progression in tauopathies. This model predicts that identifying the conformations of seeding-competent tau in patients with tauopathies may aid in diagnosis and treatment.
Here, we address the need for quick and accurate tools that enable the discrimination of tau strains. We develop a method to classify samples containing aggregated tau based on their ability to seed new aggregates of mutated tau in cells. Our findings offer valuable implications for the development of targeted diagnostic and therapeutic approaches for tauopathies and other neurodegenerative disorders
The Woman's Fortitude
Full text linkPrompt: "What stories are held in the hands of a woman?"Her strength, tenderness, and resilience
Women Are Like the Clouds
Full text linkPrompt: "What stories are held in the hands of a woman?"This piece was written when I was younger and almost always underestimated, which limited my perception of my potential. It serves as a reminder of our power and importance
The Potential of Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) in Cancer Cachexia
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.BACKGROUND: Cachexia is an inflammatory and metabolic syndrome of unintentional weight loss through depletion of muscle and adipose tissue. Despite extensive involvement of prostaglandin signaling in central and peripheral signaling pathways implicated in the development of cachexia, there is limited clinical knowledge of how chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) might affect cachexia presentation.
OBJECTIVE: The purpose of this study was to investigate associations between prior long-term use of NSAIDs with cachexia incidence and post-diagnosis weight loss progression in a retrospective cancer patient cohort.
METHODS: Of 3,802 lung or gastrointestinal cancer patient records, 3,180 comprised our final cohort. Patient demographic information, tumor qualities, medication histories, and comorbidities were assessed. Cachexia was defined as having developed prior to oncologic treatment. Statistical evaluations included categorical, multivariate logistic regression, and log-rank survival analyses. Development of substantial post-diagnosis weight loss was calculated and interpreted for patients who did not meet criteria for cachectic weight loss at diagnosis.
RESULTS: Chronic prior use of any NSAID was associated with approximate absolute and relative reductions in cachexia incidence at diagnosis of 10 and 35 percent (P<0.0001). In multivariate analyses, patients with prior NSAID medication use demonstrated a 23 percent reduction in likelihood of cachexia incidence (odds ratio=0.750; 95% CI=0.580, 0.969; P=0.280). Patients without cachexia at diagnosis were significantly more likely to develop substantial post-diagnosis weight loss if they had chronic pre-diagnosis NSAID use (OR=1.411; 95% CI=1.082, 1.840; P=0.011).
CONCLUSIONS: The findings of this study suggest a protective effect of prior NSAID use against manifestations of the cachexia phenotype at cancer diagnosis. The clinical outcomes we observed are consistent with the biomolecular reasoning that cachexia progression would possess vulnerability to this medication type, which specifically mitigates inflammatory mechanisms of the syndrome not attributable to the body tissue wasting observed consequently to oncologic therapies. These observations support further exploration of potential therapeutic benefits from this medication class early in cancer management
Histone Serine ADP-Ribosylation Coordinates ALC1 Activity at DNA Strand Break Sites
No full textDeficiencies in DNA repair pathways give rise to high mutagenic rates and genome instability, a hallmark of cancer. Post-translational modifications (PTMs) to nucleosomes at DNA damage sites are important in repair signaling in higher eukaryotes. Poly-ADP-ribose polymerase 1 (PARP1) is an enzyme that is allosterically activated upon binding to DNA strand breaks. DNA damage-induced ADP-ribosylation (ADPr) by PARP1 is majorly on serine residues and targets a range of substrate proteins to stimulate DNA repair; however, the precise biochemical pathways that are regulated by ADPr remain an active area of research. We investigated the unique peptide ADPr activities catalyzed by PARP1 in the absence and presence of HPF1. Our findings enabled development of a chemoenzymatic approach to install ADP-ribose polymers onto full-length proteins with precise control over chain length and modification site. We utilized this technology to synthesize a series of mono- and poly-ADP-ribosylated versions of the histones H3 and H2B, which we assembled into nucleosomes to study ADPr-dependent DNA repair mechanisms. Our data support the hypothesis that histone serine ADP-ribosylation is critical for robust activation of the ATP-dependent chromatin remodeling enzyme ALC1 at DNA strand break sites. Working with the Deindl group, we were able to solve the structure of ALC1 ATPase domain bound to homogenously ADP-ribosylated nucleosomes at an overall resolution of ~3Å, which showed that the remodeler is bound to the super helical location 2 (SHL2) position on the nucleosome on the side near the ADP-ribosylated histone tail. Further biochemical studies reveal that ALC1 preferentially slides nucleosomes away from the DNA proximal to the ADPr site. Our study identifies a biochemical function for nucleosome serine ADPr and describes a method that is broadly applicable to explore the impact that site-specific serine mono- and poly-ADPr have on protein function
Pleiotrophin and Midkine Confer Metastatic Ability to Disseminated Breast Cancer Cells
No full textMetastasis is a highly inefficient process with several rate limiting steps. It is estimated that only 0.01% of disseminating tumor cells are successful in forming overt metastasis. To understand the biology behind successful metastasis formation, we performed differential transcriptomic analyses between a pair of highly metastatic and poorly metastatic syngeneic mouse breast cancer lines. We found Pleiotrophin (PTN) to be enriched in metastatic breast cancer in murine and human patient samples. By developing tools to visualize the tumor microenvironment, we found that PTN produced by metastasis initiating cells in secondary organs can create an immune suppressive niche made up of neutrophils that induce T cell dysfunction. Consequently, blocking PTN function reversed local immune suppression and sensitized triple negative metastatic breast cancer to immune checkpoint blockade and chemotherapy. Encouraged by the promising results from PTN blockade, we studied the function of its only other family member Midkine (MDK) in breast cancer progression. We found MDK expression to correlate with poor prognosis in breast cancer patients. Unlike PTN, MDK was widely expressed in primary and secondary tumors suggesting a more diverse function of MDK. Blocking MDK in vivo led to a significant decrease in metastasis to lungs. Given their functional importance in metastatic disease, further investigation into the functional overlap and differences between MDK and PTN is warranted. Understanding their unique biology will lead to development of novel therapeutic strategies that break the immune suppression of immunological hot cancers such as triple negative breast cancers