DigitalCommons@The Texas Medical Center
Not a member yet
41791 research outputs found
Sort by
Racial Differences in Systemic Immune Parameters in Individuals With Lung Cancer
No full textIntroduction: Racial and ethnic disparities in the presentation and outcomes of lung cancer are widely known. To evaluate potential factors contributing to these observations, we measured systemic immune parameters in Black and White patients with lung cancer.
Methods: Patients scheduled to receive cancer immunotherapy were enrolled in a multi-institutional prospective biospecimen collection registry. Clinical and demographic information were obtained from electronic medical records. Pretreatment peripheral blood samples were collected and analyzed for cytokines using a multiplex panel and for immune cell populations using mass cytometry. Differences between Black and White patients were determined and corrected for multiple comparisons.
Results: A total of 187 patients with NSCLC (Black, 19; White, 168) were included in the analysis. Compared with White patients, Black patients had greater comorbidity (median Charlson Comorbidity Index 5 versus 3; p = 0.04) and were more likely to have received previous chemotherapy (79% versus 47%; p = 0.03). Black patients had significantly lower levels of CCL23 and CCL27 and significantly higher levels of CCL8, CXCL1, CCL26, CCL25, CCL1, IL-1b, CXCL16, and IFN-γ (all p \u3c 0.05, false discovery rate \u3c 0.1). Black patients also exhibited greater populations of nonclassical CD16+ monocytes, NKT-like cells, CD4+ cells, CD38+ monocytes, and CD57+ gamma delta T cells (all p \u3c 0.05).
Conclusions: Black and White patients with lung cancer exhibit several differences in immune parameters, with Black patients exhibiting greater levels of numerous proinflammatory cytokines and cell populations. The etiology and clinical significance of these differences warrant further evaluation
Structural Insights Into Light-Gating of Potassium-Selective Channelrhodopsin
No full textStructural information on channelrhodopsins\u27 mechanism of light-gated ion conductance is scarce, limiting its engineering as optogenetic tools. Here, we use single-particle cryo-electron microscopy of peptidisc-incorporated protein samples to determine the structures of the slow-cycling mutant C110A of kalium channelrhodopsin 1 from Hyphochytrium catenoides (HcKCR1) in the dark and upon laser flash excitation. Upon photoisomerization of the retinal chromophore, the retinylidene Schiff base NH-bond reorients from the extracellular to the cytoplasmic side. This switch triggers a series of side chain reorientations and merges intramolecular cavities into a transmembrane K+ conduction pathway. Molecular dynamics simulations confirm K+ flux through the illuminated state but not through the resting state. The overall displacement between the closed and the open structure is small, involving mainly side chain rearrangements. Asp105 and Asp116 play a key role in K+ conductance. Structure-guided mutagenesis and patch-clamp analysis reveal the roles of the pathway-forming residues in channel gating and selectivity
Functional Investigation of a Putative Calcium-Binding Site Involved in the Inhibition of Inositol 1,4, 5-Trisphosphate Receptor Activity
No full textThe regulation of inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) activity is thought to define the spatiotemporal patterns of Ca2+ signals necessary for the appropriate activation of downstream effectors. The binding of both IP3 and Ca2+ is obligatory for IP3R channel opening. Ca2+ however regulates IP3R activity in a biphasic manner. Ca2+ binding to a high-affinity pocket formed by the third armadillo repeat domain and linker domain promotes IP3R channel opening without altering the Ca2+ dependency for channel inactivation. These data suggest that a distinct low-affinity Ca2+-binding site is responsible for the reduction in IP3R activity at higher [Ca2+]. We mutated a cluster of acidic residues in the second armadillo repeat domain and central linker domain of IP3R type 1, reported to coordinate Ca2+ in the cryo-EM structures of the IP3R type 3. This CD Ca2+-binding site is well conserved in all IP3R subtypes. CD site Ca2+-binding mutants where the negatively charged glutamic acid residues were mutated to alanine exhibited enhanced sensitivity to IP3-generating agonists. Ca2+-binding mutants displayed spontaneous elemental Ca2+ puffs, and the number of IP3-induced Ca2+ puffs was augmented in cells stably expressing Ca2+-binding site mutants. The inhibitory effect of high [Ca2+] on single-channel open probability (Po) was reduced in mutant channels, and this effect was dependent on [ATP]. This indicates that Ca2+ binding to the putative CD Ca2+ inhibitory site facilitates the reduction in IP3R channel activation at subsaturating, likely physiological cytosolic [ATP], and suggest that at higher [ATP], additional Ca2+-binding motifs may contribute to the biphasic regulation of IP3-induced Ca2+ release
Brain and Cerebrospinal Fluid 3D Center of Mass Shift After Spaceflight
No full textA subset of long-duration spaceflight astronauts at the International Space Station has been documented to develop spaceflight associated neuro-ocular syndrome (SANS). Researchers have sought to understand SANS by quantification of ocular and brain structural changes thought to be associated with weightlessness induced headward fluid shift. Brain tissue shift and cerebrospinal fluid (CSF) redistribution has been observed as measured by MRI on return to Earth, and not fully quantified. To improve the understanding of this phenomenon, we developed and applied automated methods to quantify 3D center of mass shift within the skull of the extra-axial cerebrospinal fluid (eaCSF) and brain after long-duration spaceflight in astronauts (N = 13) and controls not exposed to microgravity (N = 10). 3D center of mass shift of brain tissue and CSF was computed based on registration of an individual skull segmentation at a baseline timepoint versus follow-up. 3D center of mass shift was quantified in the Gx, Gy, and Gz axis defined as -posterior/+anterior, -left/+right, -inferior/+superior, respectively. For astronauts, average MRI follow-up time pre- to post-flight was 697 ± 137 days (average flight duration = 179 ± 59 days with post-flight MRIs collected an average of 2.23 ± 1.64 days after return to Earth). For controls, average MRI follow-up time was 307 ± 19 days. For astronauts, a superior Gz shift in whole brain was present (+ 0.74 ± 0.28 mm, p \u3c 0.0001) with a concomitant inferior Gz shift in eaCSF (-2.45 ± 0.99 mm, p \u3c 0.0001). In the control cohort, brain tissue Gz shift (-0.082 ± 0.048 mm) and eaCSF Gz shift (0.096 ± 0.26 mm) were not statistically significant. Gy shift lacked significance in both controls and astronauts. These findings support that sustained exposure to weightlessness impacts the overall position of fluids and tissues within the skull
Ethnoracial Disparities in Gray Matter Atrophy Are Mediated by Structural Disconnectivity in Multiple Sclerosis
No full textObjective: To investigate ethnoracial disparities in gray matter (GM) atrophy, the contribution of white matter lesions and consequent structural disconnectivity among patients with multiple sclerosis (MS).
Methods: This retrospective study included 297 patients with MS (pwMS), 98 Hispanic/Latinx (H-MS), 82 non-Hispanic Black (B-MS), and 117 non-Hispanic White (W-MS). GM atrophy was assessed using univariate, voxel-based morphometry, and multivariate techniques, source-based morphometry. Structural disconnectivity secondary to white matter lesions was evaluated using the network modification tool. Mediation analyses explored relationships between ethnoracial groups, white matter lesions, structural disconnectivity, and gray matter atrophy.
Results: B-MS and H-MS generally exhibited greater gray matter atrophy compared to W-MS, particularly in temporal, parahippocampal, precuneus, and cuneus GM. Structural disconnectivity differences were most prominent in the hippocampal, cingulate, precuneus, and deep gray matter regions. Mediation analyses revealed that lesion load significantly mediated group differences in global GM atrophy (percent mediated = 52.4%), while structural disconnectivity mediated some differences in specific gray matter components, notably in deep gray matter, insular, and anterior cingulate regions.
Interpretation: Significant ethnoracial disparities exist in GM atrophy and its patterns among diverse MS patients, partially mediated by white matter lesions and consequent structural disconnectivity. These findings underscore the importance of considering ethnoracial factors in MS research and clinical practice, potentially informing personalized treatment strategies and emphasizing the need for diverse representation in clinical trials
Cardiovascular Disease in Adults With Osteogenesis Imperfecta: Clinical Characteristics, Care Recommendations, and Research Priorities Identified Using a Modified Delphi Technique
No full textOsteogenesis imperfecta (OI) is a multisystem disorder most often caused by pathogenic variants in genes that encode type I collagen. Type I collagen is abundant not only in bone but also in multiple tissues including skin, tendons, cornea, blood vessels, and heart. Thus, OI can be expected to affect cardiovascular system, and there are numerous reports of cardiovascular disease (CVD) in people with OI. However, there is no consensus on how CVD in OI should be assessed or managed. To fill this gap, a multidisciplinary group was convened to develop clinical guidance. The work included a systematic review of the available literature and, using a modified Delphi approach, the development of a series of statements summarizing current knowledge. Fourteen clinical recommendations were developed to guide clinicians, patients, and stakeholders about an approach for CVD in adults with OI. This paper describes how the work was conducted and provides the background and rationale for each recommendation. Furthermore, we highlight knowledge gaps and suggest research priorities for the future study of CVD in OI
From Stable Teamwork to Dynamic Teaming in the Ambulatory Care Diagnostic Process
No full textDynamic teaming is required whenever people must coordinate with one another in a fluid context, particularly when the fundamental structures of a team, such as membership, priorities, tasks, modes of communication, and location are in near-constant flux. This is certainly the case in the contemporary ambulatory care diagnostic process, where circumstances and conditions require a shifting cast of individuals to coordinate dynamically to ensure patient safety. This article offers an updated perspective on dynamic teaming commonly required during the ambulatory diagnostic process. Drawing upon team science, it clarifies the characteristics of dynamic diagnostic teams, identifies common risk points in the teaming process and the practical implications of these risks, considers the role of providers and patients in averting adverse outcomes, and provides a case example of the challenges of dynamic teaming during the diagnostic process. Based on this, future research needs are offered as well as clinical practice recommendations related to team characteristics and breakdowns, team member knowledge/cognitions, teaming dynamics, and the patient as a team member
When the Right Ventricle Fails after Left Ventricular Assist Device Implantation: Prediction Tools, Recognition Strategies, and Support Options
No full textThe incidence of right heart failure (RHF) during durable left ventricular assist device (LVAD) surgery ranges from 9% to 42%, depending on the definition. RHF can be divided into three peri-implantation categories: early acute, early, and late. Despite many available risk models, predicting RHF before durable LVAD implantation has been difficult. Preemptive right-sided temporary mechanical circulatory support can improve outcomes; however, if intraoperative RHF is not suspected, early recognition and appropriate intervention after surgery are important
Maternal Dysbiosis Produces Long-Lasting Behavioral Changes in Offspring
No full textAdvanced maternal age (AMA) is defined as a pregnancy in a woman older than 35 years of age. AMA increases the risk for both maternal and neonatal complications, including miscarriage and stillbirth. AMA has also been linked to neurodevelopmental and neuropsychiatric disorders in the offspring. Recent studies have found that age-associated compositional shifts in the gut microbiota contribute to altered microbial metabolism and enhanced inflammation in the host. We investigated the specific contribution of the maternal microbiome on pregnancy outcomes and offspring behavior by recolonizing young female mice with aged female microbiome prior to pregnancy. We discovered that pre-pregnancy colonization of young dams with microbiome from aged female donors significantly increased fetal loss. There were significant differences in the composition of the gut microbiome in pups born from dams recolonized with aged female biome that persisted through middle age. Offspring born from dams colonized with aged microbiome also had significant changes in levels of neurotransmitters and metabolites in the blood and the brain. Adult offspring from dams colonized with an aged microbiome displayed persistent depressive- and anxiety-like phenotypes. Collectively, these results demonstrate that age-related changes in the composition of the maternal gut microbiome contribute to chronic alterations in the behavior and physiology of offspring. This work highlights the potential of microbiome-targeted approaches, even prior to birth, may reduce the risk of neuropsychiatric disorders
Sex Differences in Brain Iron Deposition and Microglial Ferritin in Alzheimer’s Disease
No full textObjective
Iron is the most abundant metal in the human brain, and plays a crucial role in many biological processes. However, disruptions in brain iron metabolism can lead to iron buildup, which occurs with aging and is linked to several brain disorders, including Alzheimer\u27s disease. Microglia, the brain\u27s resident immune cells, have the highest capacity to store iron, which is stored intracellularly within ferritin complexes. Importantly, women are at a higher risk of developing Alzheimer\u27s disease and experience faster disease progression compared to men. Methods
We used postmortem brain samples from patients with Alzheimer\u27s disease and small vessel disease patients of both sexes for immunohistochemical studies. Samples were stained with the Prussian blue method to visualize iron deposits and with antibodies against the microglia marker Iba1 and ferritin light chain. Results
Our study reveals that the number of iron deposits and the levels of ferritin light chain in microglia are positively correlated in men with Alzheimer\u27s disease, but negatively correlated in women. There is no correlation between brain iron deposition and ferritin in samples from patients with small vessel disease of both sexes. Conclusions
These results could inform more tailored approaches to the treatment and management of Alzheimer\u27s disease based on sex-specific differences in brain iron metabolism and microglial iron storage capacity