The role of CFP1 in maintaining liver homeostasis in a murine model

Indiana University-Purdue University Indianapolis (IUPUI)CXXC finger protein 1 (CFP1) is an epigenetic regulator of H3K4 and cytosine methylation. Due to its role in establishing and maintaining methylation patterns, CFP1 determines whether DNA is found in its euchromatin or heterochromatin state and as such whether genes are transcriptionally active or inactive. In stem cells, deficiency of CFP1 results in inability to differentiate and in murine embryos it results in periimplantation death. Despite the demonstrated importance in developing tissue, the role of CFP1 in mature tissues, such as the liver, has yet to be elucidated. This study examined the role of CFP1 in maintaining liver homeostasis under conditions involving hepatocellular stress by examining liver regeneration, pregnancy-induced hepatomegaly, and non-alcoholic steatohepatitis (NASH) disease progression. The liver’s ability to recover was analyzed through liver:body mass ratios, blood serum analysis, liver histology, and qualitative observations. Deficiency of CFP1 in the livers of animals subjected to partial hepatectomies (PH) resulted in decreased liver regeneration capacity with liver mass restoration becoming significantly different starting at 48H post-PH and remaining so until 10D post-PH. This decreased regeneration appeared to be the result of reduced hepatocyte mitosis. Mouse dams lacking hepatic CFP1 mated with males expressing CFP1 displayed a proclivity for dystocia. Mice subjected to a fast food diet resulting in NASH while lacking hepatic CFP1 experienced decreased weight gain and hepatic lipid accumulation compared to their CFP1 expressing counterparts. Through these three studies, the critical role of CFP1 for the maintenance of liver homeostasis was demonstrated

NG2-expressing cells in the subventricular zone are type C–like cells and contribute to interneuron generation in the postnatal hippocampus

The subventricular zone (SVZ) is a source of neural progenitors throughout brain development. The identification and purification of these progenitors and the analysis of their lineage potential are fundamental issues for future brain repair therapies. We demonstrate that early postnatal NG2-expressing (NG2+) progenitor cells located in the SVZ self-renew in vitro and display phenotypic features of transit-amplifier type C–like multipotent cells. NG2+ cells in the SVZ are highly proliferative and express the epidermal growth factor receptor, the transcription factors Dlx, Mash1, and Olig2, and the Lewis X (LeX) antigen. We show that grafted early postnatal NG2+ cells generate hippocampal GABAergic interneurons that propagate action potentials and receive functional glutamatergic synaptic inputs. Our work identifies Dlx+/Mash1+/LeX+/NG2+/GFAP-negative cells of the SVZ as a new class of postnatal multipotent progenitor cells that may represent a specific cellular reservoir for renewal of postnatal and adult inhibitory interneurons in the hippocampus

Studies of Plasma Gastrin and Helicobacter pylori Infection in Duodenal Ulcer Disease

Chronic Helicobacter pylori infection of the gastric antrum is seen in over 95% of duodenal ulcer patients. Eradication of this infection results in a lowering of circulating gastrin concentration. A considerable proportion of the population are infected with H. pylori but only some of them develop duodenal ulceration. In this thesis I looked at the possibility that the development of duodenal ulceration in subjects with H. pylori infection is determined by the degree of hypergastrinaemia induced. In addition, I attempted to determine the mechanism by which this hypergastrinaemia may be brought about. Consistent with earlier studies eradication of H. pylori infection in duodenal ulcer patients resulted in a fall in both basal and meal stimulated plasma gastrin concentrations. These values were similar in H. pylori positive duodenal ulcer patients and H. pylori positive asymptomatic volunteers. This suggests that factors in addition to elevated plasma gastrin are responsible for predisposition to duodenal ulceration in these patients. The mechanism by which H. pylori infection induces hypergastrinaemia is unclear. It has been postulated that by virtue of its high urease activity the organism produces ammonia locally at the gastric antrum and this may directly stimulate gastrin release by the G cells or may act indirectly by elevating antral surface pH. There was, however, no change in plasma gastrin concentrations with either increased bacterial ammonia production by intragastric urea infusion or suppression of bacterial urease activity by triple therapy (amoxycillin, metronidazole, tripotassium dicitrato bismuthate). In addition, examining the effect of gastric alkalinisation on basal and meal stimulated plasma gastrin concentrations before and after eradication of H. pylori did not support this hypothesis. It was also noted that reversal of the acute inflammatory component of the antral gastritis produced by the infection is not associated with a change in plasma gastrin concentrations. The possibility that the hypergastrinaemia is a physiological response to inhibition of parietal cell function by H. pylori was examined. There was no change in parietal cell sensitivity to pentagastrin after eradication of H. pylori. The mechanism by which chronic H. pylori infection of the gastric antrum induces hypergastrinaemia remains unclear. Further research is needed to elucidate this

Hippocampal gabaergic inhibitory interneurons

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this record In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage-and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies.National Institute of Child Health and Human Developmen

Classification of binary fracture using CNN.

One of the major problems faced by any living organism since infancy are musculoskeletal injuries. To keep it quite simple musculoskeletal injuries are a range of disorders involving muscles, bones, tendons, blood vessels, nerves and other soft tissues. However one of the most common forms of musculoskeletal injuries are fractures. Fractures are one of the most prevalent sores that are faced by any living organism. They are also easily overlooked by the best of physicians. Even with the help of an X-ray, they are one of the hardest symptoms to diagnose. We believe that we can provide a solution to this problem by implementing convolutional neural networks (CNN) image processing algorithms into the field of medicine. We have designed a model using three layers of architecture which has been properly trained to identify the X-ray images that have fractures. To accomplish this we used large datasets that consist of 200 images of human hands, ribs, legs and neck. These large datasets are clearly segregated to identify those images which contain fractures from those images which are perfectly fine. The results gave us accurate predictions using some graphical representations as well as epochs of the various patients

Hippocampal GABAergic inhibitory interneurons

In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage- and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies

Regulation of Proliferation by a Mitochondrial Potassium Channel in Pancreatic Ductal Adenocarcinoma Cells

Previous results link the mitochondrial potassium channel Kv1.3 (mitoKv1.3) to the regulation of apoptosis. By synthesizing new, mitochondria-targeted derivatives (PAPTP and PCARBTP) of PAP-1, a specific membrane-permeant Kv1.3 inhibitor, we have recently provided evidence that both drugs acting on mitoKv1.3 are able to induce apoptosis and reduce tumor growth in vivo without affecting healthy tissues and cells. In the present article, by exploiting these new drugs, we addressed the question whether mitoKv1.3 contributes to the regulation of cell proliferation as well. When used at low concentrations, which do not compromise cell survival, both drugs slightly increased the percentage of cells in S phase while decreased the population at G0/G1 stage of cells from two different pancreatic ductal adenocarcinoma lines. Our data suggest that the observed modulation is related to ROS levels within the cells, opening the way to link mitochondrial ion channel function to downstream, ROS-related signaling events that might be important for cell cycle progression

Afferent specific role of NMDA receptors for the circuit integration of hippocampal neurogliaform cells.

This is the final version of the article. Available from Nature Publishing Group via the DOI in this record.Appropriate integration of GABAergic interneurons into nascent cortical circuits is critical for ensuring normal information processing within the brain. Network and cognitive deficits associated with neurological disorders, such as schizophrenia, that result from NMDA receptor-hypofunction have been mainly attributed to dysfunction of parvalbumin-expressing interneurons that paradoxically express low levels of synaptic NMDA receptors. Here, we reveal that throughout postnatal development, thalamic, and entorhinal cortical inputs onto hippocampal neurogliaform cells are characterized by a large NMDA receptor-mediated component. This NMDA receptor-signaling is prerequisite for developmental programs ultimately responsible for the appropriate long-range AMPAR-mediated recruitment of neurogliaform cells. In contrast, AMPAR-mediated input at local Schaffer-collateral synapses on neurogliaform cells remains normal following NMDA receptor-ablation. These afferent specific deficits potentially impact neurogliaform cell mediated inhibition within the hippocampus and our findings reveal circuit loci implicating this relatively understudied interneuron subtype in the etiology of neurodevelopmental disorders characterized by NMDA receptor-hypofunction.Proper brain function depends on the correct assembly of excitatory and inhibitory neurons into neural circuits. Here the authors show that during early postnatal development in mice, NMDAR signaling via activity of long-range synaptic inputs onto neurogliaform cells is required for their appropriate integration into the hippocampal circuitry.We thank Daniel Abebe for mouse colony maintenance and Kurt Auville for additional assistance with confocal imaging. We thank UNC Vector Core and Ed Boyden, MIT, Cambridge, MA, USA for generously providing AAV9-syn-Chrimson-TdTomato and AAV9-syn-Chronos-GFP. This work was supported by an intramural award to C.J.M. from the Eunice Kennedy–Shriver National Institute of Child Health and Human Development and a Competitive Fellowship Award to J.C.W. from the National Institute of Neurological Disorders and Strok

Presynaptic Kainate Receptor Activation Preserves Asynchronous GABA Release Despite the Reduction in Synchronous Release from Hippocampal Cholecystokinin Interneurons

Inhibitory synaptic transmission in the hippocampus in mediated by a wide variety of different interneuron classes which are assumed to play different roles in network activity. Activation of presynaptic kainate receptors (KARs) has been shown to reduce inhibitory transmission but the interneuron class(es) at which they act is only recently beginning to emerge. Using paired recordings we show that KAR activation causes a decrease in presynaptic release from CCK- but not PV-containing interneurons and that this decrease is observed when pyramidal cells, but not interneurons, are the postsynaptic target. We also show that although the synchronous release component is reduced, the barrage of asynchronous GABA release from CCK interneurons during sustained firing is unaffected by KAR activation. This indicates that presynaptic KARs preserve and act in concert with asynchronous release to switch CCK interneurons from a phasic inhibition mode to produce prolonged inhibition during periods of intense activity