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Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia
No full textBackground: Gestational sleep apnea affects 8-26% of pregnancies and can increase the risk for autism spectrum disorder (ASD) in offspring. ASD is a neurodevelopmental disorder associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. To examine the relationship between gestational sleep apnea and ASD, we used a chronic intermittent hypoxia (CIH) protocol between gestational days (GD) 15-19 in pregnant rats to model gestational sleep apnea during the third trimester of pregnancy. We hypothesized that late gestational CIH would produce sex- and age-specific social, mood, and cognitive impairments in offspring.
Methods: Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15-19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine ASD phenotype, we quantified ASD-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, neuronal activation, and neurogenesis), and circulating hormones in offspring.
Results: Late gestational CIH induced sex- and age-specific differences in social, repetitive and memory functions in offspring. These effects were mostly transient and present during puberty. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, suppressed circulating estradiol but did not impact memory. In contrast, CIH impaired spatial memory and suppressed circulating estradiol in pubertal male offspring but did not impact social or repetitive functions. Long term effects of gestational CIH were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating estradiol during puberty was maintained in young adulthood. No effects of gestational CIH were observed on anxiety-like behaviors, hippocampal activity, circulating testosterone, or circulating corticosterone, regardless of sex or age of offspring.
Conclusions: Our results indicate that hypoxia-associated pregnancy complications during the third trimester can increase the risk for ASD, such as pubertal social dysfunction, neuroendocrine suppression, and memory impairments. Current clinical recommendations support ASD screening for all children up to their 24-month checkup. Based on our findings, children from hypoxia-associated pregnancies should be screened for ASD throughout puberty.This study was supported by NIH R01 NS0091359 and UNTHSC Seed grant funding to RLC, NIH R01 HL146562-02S1 to SG, AHA 22PRE-900431 to JG, AHA 22POST-903250 to JB, NIH R25HL125447 to EVJ, and NIH T32 AG020494 to SM
A Multisite Qualitative Analysis of Perceived Roles in Medication Safety: Older Adults' Perspectives
No full textOlder adults and caregivers play an essential role in medication safety; however, self-perception of their and health professionals' roles in medication safety is not well-understood. The objective of our study was to identify the roles of patients, providers, and pharmacists in medication safety from the perspective of older adults. Semi-structured qualitative interviews were held with 28 community-dwelling older adults over 65 years who took five or more prescription medications daily. Results suggest that older adults' self-perceptions of their role in medication safety varied widely. Older adults perceived that self-learning about their medications and securing them are critical to avoiding medication-related harm. Primary care providers were perceived as coordinators between older adults and specialists. Older adults expected pharmacists to inform them of any changes in the characteristics of medications to ensure medications were taken correctly. Our findings provide an in-depth analysis of older adults' perceptions and expectations of their providers' specific roles in medication safety. Educating providers and pharmacists about the role expectations of this population with complex needs can ultimately improve medication safety.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Agency for Healthcare Research and Quality, (grant number R18HS027277)
Analysis of Key Cellular Changes of Triple Negative Breast Cancer Cells in Response to Kinase-Inhibiting BI2536 and Associated Derivatives
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2023 Department of Microbiology, Immunology & Genetics Award - 2nd PlacePurpose: Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer that grows quickly and has higher rates of metastasis and reoccurrence relative to other Breast Cancer subtypes that make it, in general, a much more dangerous subtype of breast cancer. The Kinase Chemogenomic Set (KCGS) is a collection of 187 kinase-inhibiting compounds with broad activity across 215 different kinases. We hypothesize that this plate contains compounds with the potential to inhibit TNBC and that exploring the transcriptomic and proteomic changes in TNBC cells may give insights into novel treatment targets. Methods: To test this hypothesis, we have utilized two main cell lines, the MDA-MB-231 line and a patient-derived xenograft line, the TuX-BxC-4IC cell line. Measurements have been taken at various time points up until 72 hours at various concentrations of a compound of interest, BI2536, between 1nM and 1uM. Primarily, data will be collected using qRT-PCR to gain insight into the transcriptomic changes during the potential EMT changes. Additionally, various other experiments related to migration, staining, and other essential markers will be conducted on the compound of interest and derivatives of the compound. Results: Initial results and prior work indicate that the compound of interest has moderate success in slowing cancer cell growth. Additionally, initial findings indicate that the compound may succeed in halting and potentially even reversing the EMT process. Conclusion: With this primary data set, we believe that the kinases targeted by the compound may hold potential key targets for the treatment of TNBC.UNTHS
Hemodynamic Responses to Oscillatory Thigh Cuff Inflations
Get PDFExperimental generation of 0.1 Hz oscillations (~10-s cycle) in arterial pressure and cerebral blood flow (CBF) increases tolerance to simulated hemorrhage, and protects cerebral tissue oxygenation. In this study we evaluated a clinically applicable method of inducing 0.1 Hz oscillations in arterial pressure and CBF via repeated thigh cuff inflations. We also characterized the effect of common carotid artery (CCA) stiffness on the magnitude of cerebral blood flow oscillations, and evaluated the effects of intermittent thigh cuff inflation on several markers of cardiac function. We hypothesized that: 1) the amplitude of arterial pressure and CBF oscillations at 0.1 Hz would increase in response to repeated thigh cuff inflations at 0.1 Hz, 2) the magnitude of 0.1 Hz CBF oscillations would be positively correlated to the stiffness of the CCA, and 3) measurements of cardiac function would increase in response to thigh cuff induced oscillations of arterial pressure at 0.1 Hz. Thirteen healthy human participants were tested (6 male, 7 female; 27.1 ± 4.3 y). In response to 10-min of intermittent thigh cuff inflations at 0.1 Hz, the amplitude of 0.1 Hz oscillations increased for mean arterial pressure (MAP; 24.4 ± 20.1 mmHg2 vs. 932.0 ± 758.1 mmHg2; P<0.01) and middle cerebral artery velocity (MCAv; 17.5 ± 13.8 (cm/s)2 vs. 325.5 ± 279.9 (cm/s)2; P<0.01). There was also a large increase in MAP-MCAv coherence at 0.1 Hz (0.60 ± 0.24 a.u. vs. 0.90 ± 0.11 a.u.; P<0.01) during the oscillatory period compared to baseline. There was a moderate positive relationship between CCA stiffness and amplitude of MCAv power at 0.1 Hz during intermittent thigh cuff inflations (r=0.68, P=0.01), but not at rest (r=-0.08, P=0.80). When compared to baseline, no changes were observed during the oscillatory period for heart rate (P=0.47), stroke volume (P=0.87), cardiac output (P=0.55), MAP (P=0.20), or dP/dTmax (P=0.61). Future studies directly examining sympathetic nerve activity are needed to better elucidate the effects of induced 0.1 Hz hemodynamic oscillations on neural regulation of the cardiovascular system. In conclusion, we have shown that intermittent thigh cuff inflations can be used to increase hemodynamic variability at a target frequency, and therefore could be a therapy for treating tissue hypoperfusion following severe blood loss injuries
Influence of Gender on the Association between Race and Disability: California Health Interview Survey
No full textPurpose: Disability is common in older adults: 40% of those 65 years or older live with a disability in the US. Women typically have higher rates of disability than men in later life. Moreover, minority groups have also been shown to have a higher prevalence of disability than their White counterpart. However, there is very little research regarding the role of gender in the association of race with disability. We aimed to examine whether the association between race and disability differed by men and women.
Method: We conducted a cross-sectional analysis using data from the 2015-2016 California Health Interview Survey (CHIS) in adults aged 65 years or older (n=15,044). Due to the complex survey design in CHIS, we accounted for complex sampling weights in all analyses using SAS v9.4. Physical, mental, and emotional disabilities were recorded by participants, and disability was dichotomized as present or absent. Race was classified as Hispanic, Asian, Black, White, and Other. We generated sex- and race-specific descriptive statistics and used multivariable logistic regression to estimate sex-stratified associations between race and disability, adjusting for age, education, marital status, cigarette smoking, arthritis, hypertension, diabetes, mental distress, and walking for work or pleasure.
Results: The mean age was 71.5 years for men (range 65-85 years) and 72.2 years for women (range 65-85 years). Participants were predominantly female (59.4%). The majority of participants were White (71.0%) followed by Hispanic (11.4%), Asian (10.7%), Black (4.3%), and other race/ethnicity (2.5%). The prevalence of reported disability was higher among females than males (52% vs. 47%, P=0.0002). The prevalence of disability was highest for Hispanics (60%), followed by Other race/ethnicity (50%), White (48%), Black (48%), and Asian (43%) individuals. Among women, in fully adjusted models, Hispanic individuals were more likely to have reported a disability when compared with white women (OR=1.67, 95% CI= 1.07–2.60). Among males, Hispanic individuals were as likely to have reported a disability as White males (OR=1.03, 95% CI=0.68-1.56). The association between race/ethnicity and disability was not statistically significant for other race/ethnicities.
Conclusion: We observed that Hispanic women were more likely to report disability when compared with White women. Further research should be conducted to understand possible factors that contribute to the association between race and disability differently in women than men
Control Case Study: E-Health Text Messaging Based Intervention on Developing Lifestyle Changes Related to the Improvement of Childhood Obesity
No full textBackground:
The prevalence of chronic diseases in the United States including heart disease and cancer is majorly attributable to adverse lifestyle factors such as smoking, physical inactivity, poor diet, stress, negative emotion, etc. (CDC, 2012). Recent studies have shown that mothers with unhealthy lifestyles serve as an impetus for childhood obesity (Dhana et al, 2018). Community health promotion efforts and lifestyle interventions are successful in introducing healthy behaviors and promoting its adherence (Dickinson et al., 2006; Kent et al., 2015; Pekmezi, Marquez, & Marcus-Blank, 2010; Tucker et al., 2014; Tucker et al., 2016). Our study evaluates the utilization of an E-health text message system as an effective intervention for caregivers of obese pediatric patients to improve lifestyle behaviors that influence childhood obesity.
Case Presentation:
A 30 year old African American female presented to the Pediatric Mobile Clinic with her 3 year old child who had a BMI in the 82nd percentile. The caregiver and child met the inclusion and exclusion criteria including adequate biometric markers before they were randomized to one of 2 intervention arms: control health group or e-health group. This subject was randomized into the control intervention arm. Participants of the control arm received weekly text messages for 6 months inquiring subjects on any SMART goal and duration of their choosing as well as assessing their motivation and confidence related to that goal (scored on a scale of 10). They also received follow-up messages asking introspective questions regarding habit formation and messages with self-scripted inspirational statements. The intervention arm differed in that the SMART goal chosen by subjects had to focus on one of six lifestyle medicine factors emphasized for that week's duration. The SMART goals input by this subject centered on improving the outlook, organization, and control of her finances and career. The subject's motivation scores were similar to her confidence scores for each specific goal even though they varied overall. More importantly, both scores trended upwards within self chosen goal periods lasting ≥ 3 weeks. Additionally, a common theme emphasized in the subject’s responses to introspective questions regarding her goals focused on maintaining "positivity”. The patient indicated a 7/10 on her 6-month exit survey, highlighting that the program "somewhat” supported the patient on a road to wellness by helping her "break things down into achievable goals each week”.
Conclusions:
This case illustrates the role an E-health intervention program had in helping the patient construct and keep track of achievable goals. The program was still beneficial to the control-intervention arm subject as indicated by her exit survey. Observed increases in confidence and motivation scores within prolonged goal periods highlights the impact this program had in establishing the self-accountability necessary for conceiving new goals and maintaining consistency. In effect, this case emphasizes how the intervention aids in promoting a subject’s intrinsic motivation in relation to the development of their goals and eventual habits. Overall, this case suggests that having any intervention in place, even to the degree involved within case controls, is significant compared to no intervention.Ardmore Institute of Health, NI
Sleep Insufficiency, Circadian Rhythms, and Metabolomics: The Connection to Metabolic and Sleep Disorders
No full textResearch Appreciation Day Award Winner - Texas College of Osteopathic Medicine, 2023 Student Research Award - 2nd PlacePurpose
The majority of US adults who report experiencing insufficient sleep are more likely to suffer from metabolic disorders such as hyperlipidemia, diabetes, and obesity than those with sufficient sleep. Less is understood about the underlying molecular mechanisms connecting these phenomena. A systematic, qualitative review of metabolomics studies exploring metabolic changes in response to sleep insufficiency, sleep deprivation, or circadian disruption was conducted in accordance with PRISMA guidelines.
Methods
An electronic literature review in the PubMed database was performed considering publications through May 2021 and screening and eligibility criteria were applied to articles retrieved. The following keywords were used: "metabolomics” and "sleep disorders” or "sleep deprivation” or "sleep disturbance” or "circadian rhythm.” After screening and addition of studies included from reference lists of retrieved studies, 16 records were identified for review.
Results
Consistent changes in metabolites were observed across studies between individuals experiencing sleep deprivation as compared to non-sleep deprivation controls. Significant increases in phosphatidylcholines, acylcarnitines, sphingolipids, and other lipids are consistent across studies. Increased levels of amino acids such as tryptophan and phenylalanine are also noted. However, studies are limited to small samples of young, healthy, mostly male participants conducted in short inpatient sessions, limiting generalizability.
Conclusion
Changes in lipid and amino acid metabolites accompanying sleep deprivation and/or circadian rhythms may indicate cellular membrane and protein breakdown underlying the connection between sleep disturbance, hyperlipidemia, and other metabolic disorders. Larger epidemiological studies examining changes in the human metabolome in response to chronic insufficient sleep would help elucidate this relationship
Multi-hazard assessment in Kyrgyzstan’s Osh Region using Maximum Entropy
No full textResearch Appreciation Day Award Winner - School of Public Health, 2023 Research Award - 3rd PlacePurpose:
Climate change impacts natural processes that lead to increased warming and extreme precipitation. As global temperatures continue to rise, an increase in the frequency of climate- and weather-related disasters is expected. Over the past decade, approximately 200 million people were affected by disaster events, with 81,000 deaths per year on average. Majority of the impacts occurred in the 40 most mountainous countries, including Kyrgyzstan in Central Asia. More than 80% of the land area in Kyrgyzstan is mountainous and highly hazardous. The Osh Region in Kyrgyzstan, in particular, is a site that suffers multiple types of natural hazards, such as floods, landslides, earthquake, and drought. These hazards pose a great risk to the mountain communities. Currently, the susceptibility distribution of the multiple hazards in the Osh Region, and the populations exposed to it remain to be assessed. The goal of this study was to harmonize three natural hazards – flood, landslides, and wildfire – of the Osh Region in a generalized multi-hazard susceptibility map (MHSM) that incorporates bioclimatic and geo-environmental factors for disaster risk management and response planning.
Methods:
Inventory maps for single hazard susceptibility were prepared by processing thematic layers from remotely-sensed data, hazard catalogs, and bioclimatic data. A total of 37 covariates (19 bioclimatic variables and 18 geo-environmental factors) were selected as predictors using Maximum Entropy (MaxEnt) machine learning algorithm. Accuracy metric of the predictive model was evaluated using the "receiver operating characteristic” (ROC) curve and computing for the "area under the ROC curve” (AUC-ROC). Moreover, MaxEnt was able to estimate percent variable contributions and permutation importance for each of the predictors. The generated single-hazard susceptibility maps were harmonized into a multi-hazard susceptibility map in ArcGIS 10.8.
Results:
The results show significant predictive performance and degree of fitting of MaxEnt for flood, landslides, and wildfire, obtaining high AUC-ROC (> 0.9). The land cover covariate contributed to wildfire and landslide. Elevation covariate occurred most to wildfire and flood susceptibility. Distance to faults contributed to landslides, while precipitation of the coldest quarter contributed to flood. A MHSM was then generated after overlaying and fitting the single-hazard maps. The MHSM showed that 37% of Osh Region’s area is susceptible to the three hazards. Within this area, 33% is susceptible to landslides, 17% to flood, and 5% to wildfire. The population exposed to these hazards will be investigated in a future study.
Conclusion:
The multi-hazard susceptibility map can be a useful planning tool for government administrators in the Osh Region to identify areas susceptible to hazards at a regional scale. This information can promote risk-informed policy and investment decisions to minimize disaster-induced losses and damages, such as fatalities and infrastructure damage, in the long term
Design of mini Cas9 proteins using computational tools
No full textPurpose: Adeno-associated viral (AAV) vectors are routinely used for the delivery of CRISPR-Cas systems. These vectors can only package molecules up to ~4.7 kilobase pair (kbp) in size. The most widely used Cas protein is Streptococcus pyogenes Cas9 (SpCas9), which is comprised of 1368 amino acid (aa) residues and is 4.3 kbp in size. Therefore, delivery of the CRISPR-Cas9 and the guide RNA (gRNA) requires the use of two separate vectors, which decreases the overall effectiveness of the system. In this study we used computational tools to facilitate the design of mini Neisseria Meningitidis Cas9 (Nme1Cas9) nucleases, of 900 aa in length or less, that can be packed with its associated guide gRNA in a single vector. Nme1Cas9 is a promising system, given that in its wild-type conformation, it already is 286 aa residues smaller than the widely used SpCas9[LJ1] ; and it has shown promising effectiveness in mammalian cells. Additionally, Nme1Cas9 also has a longer spacer derived guide sequence than other orthologs, and a longer protospacer adjacent motif (PAM[LJ2] )consensus, which reduces the propensity to off-target effects. For these reasons, Nme1Cas9 provides an ideal starting point for the development of engineered mini Cas9 protein, allowing us to exploit its natural features and optimize them with the use of computational tools including artificial intelligence (AI) and machine learning.
Methods: We used The Protein Data Bank (PDB) database, UniProt database, and ChEMBL database to obtain the sequences and crystal structures of Cas orthologs and their associated gRNA and DNA sequences. Next, we identified the known DNA and RNA interacting residues of Nme1Cas9 from the available literature. Sequence alignments were performed with CLUSTAL OMEGA. Structural visualizations and reductions were performed with ChimeraX and Yasara software. AlphaFold2 was used for 3D structure prediction and molecular dynamics (MD) simulations were used to determine the stability of designed proteins.
Results/Conclusions: We generated a library of mini Nme1Cas9 sequences that are less than 900 aa in length. The AI based modeling studies using the Alphafold2 have shown similar folding of these mini Cas proteins compared to their original counterparts. MD simulations confirm their stability in the presence of DNA and gRNA. Further validation of the designed proteins and their experimental testing is under investigation at this point of the study.
Keywords: CRISPR-Cas9, Cas9, mini Cas9, Cas9 orthologs, AI.Initiative to Maximize Student Diversity (IMSD
Expression of Specificity protein 1 in tumor tissues and its impact on the prognosis of cancer patients with an emphasis on race/ethnicity
No full textTitle: Expression of Specificity protein 1 in tumor tissues and its impact on the prognosis of cancer patients with an emphasis on race/ethnicity
Background: Specificity protein (Sp) transcription factors (eg., Sp1, Sp3 and Sp4) play a vital role in growth and development. Sp1 is known to regulate genes that are critical for angiogenesis, tumor growth and metastasis. The overexpression of Sp1 is associated with poor prognosis in some cancers for all populations, however, it may vary depending on the demographic background.
Objective: The objective of this project is to analyze the expression of Sp1 in various tumor tissues and evaluate the association with the prognosis of cancer patients using the publicly available online data sets. The other goal is to understand the impact on prognosis with race/ethnicity.
Methods: Data was obtained from the publicly available resources, The Cancer Genome Atlas (TCGA) (a landmark cancer genomics program developed by the National Cancer Institute and the National Human Genome Research Institute). Information was collected for 34 cancers and screened for the expression status (upregulated or downregulated), significance and relevance to prognosis of all patients and in relation to race/ethnicity.
Results: The information on the level of Sp1 expression was not available for 11 of the cancers in the database. The results are presented for the cancers that TCGA provided Sp1 expression information for. In 60% of the 23 cancers screened, Sp1 expression significantly impacted patient survival resulting in a poorer prognosis. The significance range was between 1.2E-02 to 4.43E-10. In a third of cancers evaluated, Sp1 expression affected the prognosis of patients depending on race/ethnicity. Interestingly, the association of Sp1 with poorer prognosis was found in certain racial/ethnic patients, despite there being no significant effect on the prognosis when combining the data for all patients. Glioblastoma, lung squamous cell carcinoma and prostate cancer are among the cancers that showed relevance to prognosis based on race/ethnicity even though there was no response on the overall survival of all patients combined.
Conclusion: These preliminary observations suggest an association between Sp1 expression in tumor tissues with the prognosis of some cancers. The results also suggest that Sp1 can differentially affect the population and may contribute to a poorer prognosis for patients belonging to a certain race/ethnicity in some cancers