a-neonatal-mouse-model-necrotizing-enterocolitis-lamina-propria

A Neonatal Mouse Model of Necrotizing Enterocolitis and Lamina Propria Isolation for Immune Cell Profiling

Necrotizing enterocolitis (NEC) is a severe inflammatory disease of the neonatal intestine, primarily affecting preterm infants. NEC is characterized by ...

University of North Carolina at Chapel Hill

Interactions between polycyclic aromatic hydrocarbons (PAHs) and soil are an important determinant of their chemical availability and transport. Laboratory examination of microscale PAH-soil interaction is limited by the availability of methods for particle-scale observation. Inverted epifluorescence microscopy, combined with digital photography and computer image analysis, was evaluated for specificity and linearity using dissolved PAHs. A pyrene filter (excitation wavelength, 360-400 nm; emission wavelength, 450-520 nm) gave nonspecific PAH fluorescence, and bias for fluoranthene, benzo[b]fluoranthene, benzo[g,h,i]perylene, and benz[a]anthracene was quantified in comparison to that for pyrene. Concentrations ranging from 1 to 10 mM for anthracene, fluoranthene, and pyrene and from 1 to 50 mM for naphthalene produced a linear response with low interpixel variability. Liquid-phase analyses validated use of the technique for the descriptive analysis of PAH distribution in solid samples, but liquid-phase calibration was not quantitative for spiked or field-contaminated soils. The mean luminance for three field soils was proportional to the values predicted from their chemically measured concentrations and to values from spiked, aged, uncontaminated materials. Image analysis of laboratory- and field-contaminated samples determined the area distribution of fluorescent intensity and the size of fluorescent areas exceeding a threshold luminance. These qualitative descriptions of the microscale spatial distribution of PAH contamination are presented as potential endpoints for future research on biogeochemical interactions in heavily contaminated solids.

Epifluorescence microscopy and image analysis of high-level polycyclic aromatic hydrocarbon contamination in soils.

In 2008 an estimated 40,000 North Carolinians will be diagnosed with cancer. This disease is the number one cause of death in our state and will claim more than 17,000 lives this year. North Carolina is swimming against a demographic tide of growth and aging that will bring 80,000 new cancer cases by 2050, despite continued improvements in cancer prevention, early detection, and treatment. By establishing the University Cancer Research Fund, North Carolina has taken a bold, nation-leading step forward toward improving the future health and well-being of its citizens. Research that creates new knowledge, turns that knowledge into advances in treatment, screening, and prevention, and then ensures delivery of those advances across the state-that research is the key that unlocks the doors to a new and better future. The Fund will make that research possible. As has often been the case, North Carolina was ahead of the national curve by creating the UCRF in July 2007. In November 2007, Texas passed a $3 billion bond referendum to provide $300 million annually to support cancer research over the next decade. In 2005, California passed a $3 billion bond referendum to support stem cell research. Perhaps noting the downturn in federal funding for biomedical research, other states are watching these states' investments to see if they improve their citizens' health and make researchers nationally competitive. We will rigorously evaluate the UCRF to show the nation that North Carolina has taken a bold and wise step. The North Carolina General Assembly and the people of North Carolina have presented the University of North Carolina at Chapel Hill, the UNC Lineberger Comprehensive Cancer Center, the North Carolina Cancer Hospital, and UNC Health Care with an astounding opportunity and responsibility. We embrace that opportunity and that responsibility and pledge ourselves to our shared vision of a better future for the citizens of North Carolina.

Research for North Carolina: The University Cancer Research Fund.

Coordination between different cytoskeletal systems is crucial for many cell biological functions, including cell migration and mitosis, and also plays an important role during tissue morphogenesis. Proteins of the class of cytoskeletal crosslinkers, or cytolinkers, have the ability to interact with more than one cytoskeletal system at a time and are prime candidates to mediate any coordination. One such class comprises the Gas2-like proteins, combining a conserved calponin-homology-type actin-binding domain and a Gas2 domain predicted to bind microtubules (MTs). This domain combination is also found in spectraplakins, huge cytolinkers that play important roles in many tissues in both invertebrates and vertebrates. Here, we dissect the ability of the single Drosophila Gas2-like protein Pigs to interact with both actin and MT cytoskeletons, both in vitro and in vivo, and illustrate complex regulatory interactions that determine the localisation of Pigs to and its effects on the cytoskeleton. 

The Gas2 family protein Pigs is a microtubule +TIP that affects cytoskeleton organisation.

Cardiovascular disparities remain pervasive in the United States. Unequal disease burden is evident among population groups based on sex, race, ethnicity, socioeconomic status, educational attainment, nativity, or geography. Despite the significant declines in cardiovascular disease mortality rates in all demographic groups during the last 50 years, large disparities remain by sex, race, ethnicity, and geography. Recent data from modeling studies, linked micromap plots, and small-area analyses also demonstrate prominent variation in cardiovascular disease mortality rates across states and counties, with an especially high disease burden in the southeastern United States and Appalachia. Despite these continued disparities, few large-scale intervention studies have been conducted in these high-burden populations to examine the feasibility of reducing or eliminating cardiovascular disparities. To address this challenge, on June 22 and 23, 2017, the National Heart, Lung, and Blood Institute convened experts from a broad range of biomedical, behavioral, environmental, implementation, and social science backgrounds to summarize the current state of knowledge of cardiovascular disease disparities and propose intervention strategies aligned with the National Heart, Lung, and Blood Institute mission. This report presents the themes, challenges, opportunities, available resources, and recommended actions discussed at the workshop.

Reducing Cardiovascular Disparities Through Community-Engaged Implementation Research: A National Heart, Lung, and Blood Institute Workshop Report.

Arteries and veins are specified by antagonistic transcriptional programs. However, during development and regeneration, new arteries can arise from pre-existing veins through a poorly understood process of cell fate conversion. Here, using single-cell RNA sequencing and mouse genetics, we show that vein cells of the developing heart undergo an early cell fate switch to create a pre-artery population that subsequently builds coronary arteries. Vein cells underwent a gradual and simultaneous switch from venous to arterial fate before a subset of cells crossed a transcriptional threshold into the pre-artery state. Before the onset of coronary blood flow, pre-artery cells appeared in the immature vessel plexus, expressed mature artery markers, and decreased cell cycling. The vein-specifying transcription factor COUP-TF2 (also known as NR2F2) prevented plexus cells from overcoming the pre-artery threshold by inducing cell cycle genes. Thus, vein-derived coronary arteries are built by pre-artery cells that can differentiate independently of blood flow upon the release of inhibition mediated by COUP-TF2 and cell cycle factors.

Single-cell analysis of early progenitor cells that build coronary arteries.

Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the NSAID sulindac suppresses the protumor effects of obesity in a mouse model of colon cancer. Azoxymethane-treated male FVB/N mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 15 weeks, then HFD mice were randomized to remain on HFD (obese) or switch to LFD [formerly obese (FOb-LFD)]. Within the control (LFD), obese, and FOb-LFD groups, half the mice started sulindac treatment (140 ppm in the diet). All mice were euthanized 7 weeks later. FOb-LFD mice had intermediate body weight levels, lower than obese but higher than control (P < 0.05). Sulindac did not affect body weight. Obese mice had greater tumor multiplicity and burden than all other groups (P < 0.05). Transcriptomic profiling indicated that weight loss and sulindac each modulate the expression of tumor genes related to invasion and may promote a more antitumor immune landscape. Furthermore, the fecal microbes Coprobacillus, Prevotella, and Akkermansia muciniphila were positively correlated with tumor multiplicity and reduced by sulindac in obese mice. Coprobacillus abundance was also decreased in FOb-LFD mice. In sum, weight loss and sulindac treatment, alone and in combination, reversed the effects of chronic obesity on colon tumor multiplicity and burden. Our findings suggest that an investigation regarding the effects of NSAID treatment on colon cancer risk and/or progression in obese individuals is warranted, particularly for those unable to achieve moderate weight loss.

Weight Loss and/or Sulindac Mitigate Obesity-associated Transcriptome, Microbiome, and Protumor Effects in a Murine Model of Colon Cancer.

Environmental hazards (e.g., pedestrian traffic) cause falls and testing environment impacts gait in older adults. However, most fall risk evaluations do not assess real-world moving hazard avoidance.

Fall history in older adults impacts acceleration profiles after a near collision with a moving pedestrian hazard.

Inflammatory bowel diseases (IBDs) are chronic debilitating conditions without cure, the etiologies of which are unknown, that shorten the lifespans of 7 million patients worldwide by nearly 10%. Here, we found that decreased autonomic parasympathetic tone resulted in increased IBD susceptibility and mortality in mouse models of disease. Conversely, vagal stimulation restored neuromodulation and ameliorated colitis by inhibiting the posttranslational modification SUMOylation through a mechanism independent of the canonical interleukin-10/α7 nicotinic cholinergic vagal pathway. Colonic biopsies from patients with IBDs and mouse models showed an increase in small ubiquitin-like modifier (SUMO)2 and SUMO3 during active disease. In global genetic knockout mouse models, the deletion of  protected against development of colitis and delayed onset of disease, whereas deletion of  halted the progression of colitis. Bone marrow transplants from -knockout (KO) but not -KO mice into wild-type mice conferred protection against development of colitis. Electric stimulation of the cervical vagus nerve before the induction of colitis inhibited SUMOylation and delayed the onset of colitis in -KO mice and resulted in milder symptoms in -KO mice. Treatment with TAK-981, a first-in-class inhibitor of the SUMO-activating enzyme, ameliorated disease in three murine models of IBD and reduced intestinal permeability and bacterial translocation in a severe model of the disease, suggesting the potential to reduce progression to sepsis. These results reveal a pathway of vagal neuromodulation that reprograms endogenous stress-adaptive responses through inhibition of SUMOylation and suggest SUMOylation as a therapeutic target for IBD.

Article	Year
Epifluorescence microscopy and image analysis of high-level polycyclic aromatic hydrocarbon contamination in soils. Environmental toxicology and chemistry\| PubMed ID: 17220076	2006
Research for North Carolina: The University Cancer Research Fund. North Carolina medical journal\| PubMed ID: 18828322	2008
The Gas2 family protein Pigs is a microtubule +TIP that affects cytoskeleton organisation. Journal of cell science\| PubMed ID: 26585311	2016
Reducing Cardiovascular Disparities Through Community-Engaged Implementation Research: A National Heart, Lung, and Blood Institute Workshop Report. Circulation research\| PubMed ID: 29348251	2018
Single-cell analysis of early progenitor cells that build coronary arteries. Nature\| PubMed ID: 29973725	2018
Weight Loss and/or Sulindac Mitigate Obesity-associated Transcriptome, Microbiome, and Protumor Effects in a Murine Model of Colon Cancer. Cancer prevention research (Philadelphia, Pa.)\| PubMed ID: 35653548	2022
Fall history in older adults impacts acceleration profiles after a near collision with a moving pedestrian hazard. Aging clinical and experimental research\| PubMed ID: 36705894	2023
Vagal stimulation ameliorates murine colitis by regulating SUMOylation. Science translational medicine\| PubMed ID: 39565873	2024

Journie N. Roper

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