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Assessment of Antimicrobial Therapy in Eradicating Chlamydia muridarum in Research Mice: Immune Status and Its Impact on Outcomes.
No full textChlamydia muridarum (Cm) is a moderately prevalent, gram-negative, intracellular bacterium that affects laboratory mice, causing subclinical to severe disease, depending on the host\u27s immune status. The effectiveness of various antibiotic regimens aimed at eradicating Cm in both immunodeficient and immunocompetent laboratory mice was evaluated. NSG mice were cohoused with Cm-shedding BALB/cJ mice for 14 d to simulate natural exposure. Four groups of 8 infected NSG mice were treated for 7 d with either 0.08% sulfamethoxazole and 0.016% trimethoprim (TMS) in water, 0.0625% doxycycline in feed, 0.124%/0.025% TMS in feed, or 0.12% amoxicillin in feed. A control group was provided standard water and feed. The impact of treatment on gastrointestinal microbiota (GM) was investigated using next-generation shotgun sequencing on the last day of treatment. TMS and amoxicillin had negligible effects on GM, while doxycycline had the largest effect. All antibiotic-treated NSG mice exhibited clinical disease, including dehydration, hunched posture, greater than 20% weight loss, and dyspnea, leading to euthanasia 21 to 40 d posttreatment (32.6 ± 4.2 d; mean ± SD). Untreated controls were euthanized 14 to 33 d postexposure (23.75 ± 5.9 d). All mice were fecal PCR positive for Cm at euthanasia. Histologic evaluation revealed multifocal histiocytic and neutrophilic bronchointerstitial pneumonia and/or bronchiolitis featuring prominent intralesional chlamydial inclusion bodies in all mice. Subsequently, groups of 8 C57BL/6J, BALB/cJ, NOD.SCID, and NSG mice infected with Cm were treated with 0.124%/0.025% TMS in feed for 7 (BALB/cJ and C57BL/6J) or 21 d (NSG and NOD.SCID). All immunocompetent and NOD.SCID mice were negative for Cm by PCR 14 d posttreatment, remained clinically normal, and had no evidence of Cm infection at necropsy, and all NSG mice remained Cm positive and were euthanized. While these findings highlight the difficulties in eradicating Cm from highly immunodeficient mice, eradication of Cm from immunocompetent or moderately immunocompromised mice with antibiotics is feasible
Exploring the composition of placental microbiome and its potential origin in preterm birth.
Full text linkINTRODUCTION: For years, the placenta was believed to be sterile, but recent studies reveal it hosts a unique microbiome. Despite these findings, significant questions remain about the origins of the placental microbiome and its effects on pregnancy and fetal health. Some studies suggest it may originate from the vaginal tract, while others indicate that oral bacteria can enter the maternal bloodstream and seed the placenta. However, research analyzing the vaginal, oral, and placental microbiomes within the same cohort is lacking. Additionally, it\u27s unclear whether the placental microbiome differs between healthy pregnancies and those with complications like preterm birth (PTB), which remains a leading cause of neonatal morbidity and mortality worldwide.
METHODS: In this study, we performed 16S rRNA gene sequencing to investigate the composition of the oral and placental microbiome in samples collected from 18 women who experienced PTB and 36 matched controls who delivered at term (TB), all of whom were part of the Molecular Signature in Pregnancy (MSP) study. We leveraged on the multisite microbiome sampling from the MSP participants and on our previously published vaginal microbiome data to investigate the potential origins of the placental microbiome and assess whether its composition varies between healthy and complicated pregnancies.
RESULTS AND DISCUSSION: Our analysis revealed distinct profiles in the oral microbiome of PTB subjects compared to those who delivered at term. Specifically, we observed an increased abundance of Treponema maltophilum, Bacteroides sp, Mollicutes, Prevotella buccae, Leptotrichia, Prevotella_sp_Alloprevotella, in the PTB group. Importantly, Treponema maltophilum species showed higher abundance in the PTB group during the second trimester, suggesting its potential use as biomarkers. When we assessed the placenta microbiome composition, we found that Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria were the most dominant phyla. Interestingly, microorganisms such as Ureaplasma urealyticum were more abundant in PTB placenta samples. Our findings suggest that the placenta microbiome could originate from the oral or vaginal cavities, with a notable increase in the crosstalk between the vaginal and placental sites in cases of PTB. Specifically, our data revealed that in PTB cases, the placental microbiome exhibited a closer resemblance to the vaginal microbiome, whereas in term pregnancies, the placental microbiome was similar to the oral microbiome
Prediction of Patient Drug Response via 3D Bioprinted Gastric Cancer Model Utilized Patient-Derived Tissue Laden Tissue-Specific Bioink.
Full text linkDespite significant research progress, tumor heterogeneity remains elusive, and its complexity poses a barrier to anticancer drug discovery and cancer treatment. Response to the same drug varies across patients, and the timing of treatment is an important factor in determining prognosis. Therefore, development of patient-specific preclinical models that can predict a patient\u27s drug response within a short period is imperative. In this study, a printed gastric cancer (pGC) model is developed for preclinical chemotherapy using extrusion-based 3D bioprinting technology and tissue-specific bioinks containing patient-derived tumor chunks. The pGC model retained the original tumor characteristics and enabled rapid drug evaluation within 2 weeks of its isolation from the patient. In fact, it is confirmed that the drug response-related gene profile of pGC tissues co-cultured with human gastric fibroblasts (hGaFibro) is similar to that of patient tissues. This suggested that the application of the pGC model can potentially overcome the challenges associated with accurate drug evaluation in preclinical models (e.g., patient-derived xenografts) owing to the deficiency of stromal cells derived from the patient. Consequently, the pGC model manifested a remarkable similarity with patients in terms of response to chemotherapy and prognostic predictability. Hence, it is considered a promising preclinical tool for personalized and precise treatments
Spatiotemporal Profiling Defines Persistence and Resistance Dynamics during Targeted Treatment of Melanoma.
No full textResistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. A better understanding of the temporal dynamics and specific pathways leading into and out of the persister state is needed to identify strategies to prevent treatment failure. Using spatial transcriptomics in patient-derived xenograft models, we captured clonal lineage evolution during treatment. The persister state showed increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients. Phylogenetic tracing identified intrinsic and acquired resistance mechanisms (e.g., dual-specific phosphatases, reticulon-4, and cyclin-dependent kinase 2) and suggested specific temporal windows of potential therapeutic susceptibility. Deep learning-enabled analysis of histopathologic slides revealed morphologic features correlating with specific cell states, demonstrating that juxtaposition of transcriptomics and histologic data enabled identification of phenotypically distinct populations from using imaging data alone. In summary, this study defined state change and lineage selection during melanoma treatment with spatiotemporal resolution, elucidating how choice and timing of therapeutic agents will impact the ability to eradicate resistant clones. Significance: Tracking clonal progression during treatment uncovers conserved, global transcriptional changes and local clone-clone and spatial patterns underlying the emergence of resistance, providing insights into therapy-induced tumor evolution
Marmosets as model systems for the study of Alzheimer\u27s disease and related dementias: Substantiation of physiological tau 3R and 4R isoform expression and phosphorylation.
Full text linkINTRODUCTION: Marmosets spontaneously develop pathological hallmarks of Alzheimer\u27s disease (AD) including amyloid beta plaques. However, tau expression in the marmoset brain has been understudied.
METHODS: Isoforms of tau were examined by western blot, mass spectrometry, immunofluorescence, and immunohistochemical staining.
RESULTS: 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. Mass spectrometry analysis revealed that tau peptides in marmoset corresponded to the 3R and 4R peptides in human brain, with 3R predominating at birth and an ≈40%:60% 3R:4R ratios in adolescents and adults; tau was distributed widely in neurons, with localization in the soma and synaptic regions. Phosphorylation residues were observed on Threonine (Thr) Thr181, Thr217, Thr231, Serine (Ser) Ser202/Thr205, and Ser396/Ser404.
DISCUSSION: Our results confirm both 3R and 4R tau isoform expression and phosphorylation residues in the marmoset brain, and emphasize the significance of marmosets with natural expression of AD-related hallmarks as important translational models for AD. Highlights We report comprehensive characterization of tau isoform expression in marmoset brains across the lifespan. 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. These data emphasize the significance of marmosets with natural expression of primate-specific traits that are important for the study of Alzheimer\u27s disease
A Multimodal Therapeutic Strategy for Inflammatory Bowel Disease Using MicroRNA-146a Mimic Encapsulated in Lipid Nanoparticles.
Full text linkDysregulated microRNAs (miRNAs) have significant potential as diagnostic tools for various chronic diseases; however, their therapeutic applications remain largely unexplored. Given their capacity to regulate multiple pathways, miRNAs are promising candidates for treating pleiotropic diseases, such as inflammatory bowel disease (IBD). In our study, we conducted a comprehensive review of the literature of miRNA-146 levels in the inflamed tissues of IBD patients and murine colitis models. Initially, we quantified the expression of miRNA-146a and miRNA-146b in the colons of mice using the dextran sodium sulfate (DSS)-inducedacute model of IBD. We selected miRNA-146a for further study due to its anti-inflammatory properties and potential relevance in IBD treatment. We hypothesized that a macrophage model of inflammation would be well-suited to studying the effects of this miRNA. Subsequently, we investigated the use of lipid nanoparticles (LNPs) for the targeted delivery of miRNA-146a to macrophages, which play a key role in IBD. Our results indicated that miRNA-146a levels increased in the DSS model and LNP-mediated delivery effectively downregulated genes associated with inflammation. These findings highlight the critical role of miRNA-146a in modulating IBD and suggest that LNP-based delivery could be a promising therapeutic strategy for managing inflammatory responses
Hippocampal-prefrontal functional neural networks in a rat model of fragile X syndrome are poorly organized with limited resiliency.
Full text linkFragile X Syndrome (FXS) is a common cause of autism spectrum symptoms. The genetic mutation results in multiple molecular alterations that are hypothesized to negatively impact neural circuit development although the nature of any functional neural dynamic consequences remain unclear. Therefore, the characteristics of hippocampal-prefrontal (H-PFC) network dysfunction were investigated in a rat model of FXS. FMR-KO and control rats underwent behavioral tests assessing sociability, memory, and anxiety to validate and replicate previously recognized deficits. Single-unit electrophysiology in the H-PFC circuit during exploration was used to measure patterns of action potential firing that were then compared between groups using generalized linear mixed models. FMR-KO rats demonstrated significant behavioral deficits in sociability, spatial learning, and anxiety. These rats also exhibited abnormal firing patterns outside of times when specific behavioral tasks were being performed. The network firing is less precise, more fragmented and with poor H-PFC communication in FXS. These findings suggest that disruptions in \u27exploration\u27 neural network dynamics impair the ability of networks to be appropriately engaged during specific behavioral tasks, leading to the observed deficits in social behavior, memory, and anxiety
Challenges and opportunities for conceiving genetically diverse sickle cell mice.
Full text linkA milestone in sickle cell disease (SCD) therapeutics was achieved in December 2023 with the FDA-approved gene therapy for patients aged 12 years and older. However, these therapies may only suit a fraction of patients because of cost or health risks. A better understanding of SCD outcome heterogeneity is needed to propose patient-specific pharmacological interventions. To achieve this, humanized and genetically diverse mouse models are essential for associating candidate genotypes with specific hematological traits, organ function, and disease resilience. Here, we discuss the challenges and opportunities in developing genetically diverse sickle cell mice (GDS mice). These models are expected to complement current approaches in SCD research and enhance our understanding of SCD heterogeneity and anemia
Multiomic Network Analysis Identifies Dysregulated Neurobiological Pathways in Opioid Addiction.
No full textBACKGROUND: Opioid addiction is a worldwide public health crisis. In the United States, for example, opioids cause more drug overdose deaths than any other substance. However, opioid addiction treatments have limited efficacy, meaning that additional treatments are needed.
METHODS: To help address this problem, we used network-based machine learning techniques to integrate results from genome-wide association studies of opioid use disorder and problematic prescription opioid misuse with transcriptomic, proteomic, and epigenetic data from the dorsolateral prefrontal cortex of people who died of opioid overdose and control individuals.
RESULTS: We identified 211 highly interrelated genes identified by genome-wide association studies or dysregulation in the dorsolateral prefrontal cortex of people who died of opioid overdose that implicated the Akt, BDNF (brain-derived neurotrophic factor), and ERK (extracellular signal-regulated kinase) pathways, identifying 414 drugs targeting 48 of these opioid addiction-associated genes. Some of the identified drugs are approved to treat other substance use disorders or depression.
CONCLUSIONS: Our synthesis of multiomics using a systems biology approach revealed key gene targets that could contribute to drug repurposing, genetics-informed addiction treatment, and future discovery
A Survey Study of Roadblocks in Translational Science.
Full text linkClinical and translational science needs to address roadblocks to the translational processes. We conducted a survey at two institutions, a private medical school and a large public university, to understand the frequency and distribution of barriers and roadblocks to research. We reviewed the literature to compile a pool of barriers and roadblocks and convened a panel of relevant stakeholders to develop a 20-item questionnaire. Survey respondents were asked to select and prioritize the five leading clinical and translational roadblocks, provide information regarding their academic degrees and rank/position, complete open-ended items regarding their areas of research, and optionally add additional remarks in a comment box. The survey was disseminated in August 2022 to faculty and staff with active research protocols at Baylor College of Medicine and the University of Houston. In total, 227 respondents completed the survey. Their disciplines were basic science (29.5%), translational research (52.9%), clinical research (55.5%), community-engaged research (9.7%), and educational research (9.7%). Respondents identified (1) lack of access to trained research coordinators, (2) lack of understanding about different resources that facilitate research, (3) complex regulatory environment and delays, (4) fragmented infrastructure for administrative and fiscal processes, and (5) inadequate funding for pilot projects to foster new research. Other roadblocks included lack of established community stakeholder partnerships, inadequate access to medical record data, and limited biostatistical support. We identified leading roadblocks to research from the perspectives of scientists and staff conducting clinical and translational research. Operational innovations addressing these roadblocks can accelerate the pace of translation