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IntroductionIntrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) result in selective respiratory (e.g., phrenic) motor neuron death and mimics aspects of motor neuron disease [(e.g., amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)], such as breathing deficits. This rodent model allows us to study the impact motor neuron death has on the output of surviving phrenic motor neurons as well as the compensatory mechanisms that are recruited. Microglial density in the phrenic motor nucleus as well as cervical gene expression of markers associated with inflammation (e.g., tumor necrosis factor α; TNF-α) are increased following CTB-SAP-induced phrenic motor neuron death, and ketoprofen (nonsteroidal anti-inflammatory drug) delivery attenuated phrenic long-term facilitation (pLTF) in 7 day (d) CTB-SAP rats but enhanced pLTF in 28d CTB-SAP rats. MethodsHere, we worked to determine the impact of TNF-α in the phrenic motor nucleus by: 1) quantifying TNFR1 (a high affinity transmembrane receptor for TNF-α) expression; 2) investigating astrocytes (glial cells known to release TNF-α) by performing a morphological analysis in the phrenic motor nucleus; and 3) determining whether acute TNFR1 inhibition differentially affects phrenic plasticity over the course of CTB-SAP-induced motor neuron loss by delivering an inhibitor for TNF-α receptor 1 (sTNFR1i) in 7d and 28d male CTB-SAP and control rats. ResultsResults revealed that TNFR1 expression was increased on phrenic motor neurons of 28d CTB-SAP rats (p< 0.05), and that astrocytes were increased and exhibited reactive morphology (consistent with an activated phenotype;p< 0.05) in the phrenic motor nucleus of CTB-SAP rats. Additionally, we found that pLTF was attenuated in 7d CTB-SAP rats but enhanced in 28d CTB-SAP rats (p< 0.05) following intrathecal sTNFR1i delivery. ConclusionThis work suggests that we could harness TNFR1 as a potential therapeutic agent in CTB-SAP rats and patients with respiratory motor neuron disease by increasing compensatory plasticity in surviving neurons to improve phrenic motor neuron function and breathing as well as quality of life. Future studies will focus on microglial and astrocytic cytokine release, the role they play in the differential mechanisms of pLTF utilized by 7d and 28d CTB-SAP rats, and potential therapies that target them. 

ABSTRACT Chromatin is more than a simple genome packaging system, and instead locally distinguished by histone post-translational modifications (PTMs) that can directly change nucleosome structure and / or be “read” by chromatin-associated proteins to mediate downstream events. An accurate understanding of histone PTM binding preference is vital to explain normal function and pathogenesis, and has revealed multiple therapeutic opportunities. Such studies most often use histone peptides, even though these cannot represent the full regulatory potential of nucleosome context. Here we apply a range of complementary and easily adoptable biochemical and genomic approaches to interrogate fully defined peptide and nucleosome targets with a diversity of mono or multivalent chromatin readers. In the resulting data, nucleosome context consistently refined reader binding, and multivalent engagement was more often regulatory than simply additive. This included abrogating the binding of the Polycomb group L3MBTL1 MBT to histone tails with lower methyl states (me1 or me2 at H3K4, H3K9, H3K27, H3K36 or H4K20); and confirmation that the CBX7 chromodomain and AT-hook-like motif (CD-ATL) tandem act as a functional unit to confer specificity for H3K27me3. Further,in vitronucleosome preferences were confirmed byin vivoreader-CUT&RUN genomic mapping. Such data confirms that more representative chromatin substrates provide greater insight to biological mechanism and its disorder in human disease. 

Malaria infection in pregnancy is a major cause of maternal and foetal morbidity and mortality worldwide. Mouse models for gestationalmalaria allow for the exploration of themechanisms linking maternal malaria infection and poor pregnancy outcomes in a tractable model system. The composition of the gut microbiota has been shown to influence susceptibility to malaria infection in inbred virgin mice. In this study, we explore the ability of the gutmicrobiota tomodulatemalaria infection severity in pregnant outbred SwissWebster mice.