Biology subjects

Roberts, G.

Publications and source records attributed to Roberts, G..

22 records · Page 2Linked to original sources

bioRxiv2019

Bridging of nucleosome-proximal DNA double-strand breaks by PARP2 enhances its interaction with HPF1

Poly(ADP-ribose) Polymerase 2 (PARP2) is one of three DNA-dependent PARPs involved in the detection of DNA damage. Upon binding to DNA double-strand breaks, PARP2 uses nicotinamide adenine dinucleotide to synthesize poly(ADP-ribose) (PAR) onto itself and other proteins, including histones. PAR chains in turn promote the DNA damage response by recruiting downstream repair factors. These early steps of DNA damage signaling are relevant for understanding how genome integrity is maintained and how their failure leads to genome instability or cancer. There is no structural information on DNA double-strand break detection in the context of chromatin. Here we present a cryo-EM structure of two nucleosomes bridged by human PARP2 and confirm that PARP2 bridges DNA ends in the context of nucleosomes bearing short linker DNA. We demonstrate that the conformation of PARP2 bound to damaged chromatin provides a binding platform for the regulatory protein Histone PARylation Factor 1 (HPF1), and that the resulting HPF1*PARP2*nucleosome complex is enzymatically active. Our results contribute to a structural view of the early steps of the DNA damage response in chromatin.

biochemistry↗

bioRxiv2019

First report on the effective intraperitoneal therapy of insulin-dependent diabetes mellitus in pet dogs using \"Neo-Islets\", aggregates of adipose stem and pancreatic islet cells

We previously reported that allogeneic, intraperitoneally administered \"Neo-Islets,\" composed of cultured pancreatic islet cells co-aggregated with high numbers of immunoprotective and cytoprotective Adipose-derived Stem Cells, reestablished, through omental engraftment, redifferentiation and splenic and omental up-regulation of Regulatory T-cells, normoglycemia in autoimmune Type-1 Diabetic Non-Obese Diabetic (NOD) mice without the use of immunosuppressive agents or encapsulation devices. Based on these observations, we are currently testing this Neo-Islet technology in an FDA guided Pilot Study (INAD 012-776) in insulin-dependent, spontaneously diabetic pet dogs by the intraperitoneal administration of 2x10e5 Neo-Islets/kilogram body weight to metabolically controlled (blood glucose, triglycerides, thyroid and adrenal functions) animals under sedation and local anesthesia and ultrasound guidance. We report here initial observations on the first 4 Neo-Islet-treated, insulin dependent pet dogs that are now in the intermediate-term follow-up phase of the study (> 6 months post treatment). Current results indicate that in dogs, Neo-Islets appear to engraft, redifferentiate and physiologically produce insulin, and are neither rejected by auto- or allo-immune attacks, as evidenced by (a) an absent IgG response to the allogeneic cells contained in the administered Neo-Islets, and (b) progressively improved glycemic control that achieves up to a 50% reduction in daily insulin needs paralleled by a significant fall in serum glucose levels. This is accomplished without the use of anti-rejection drugs or encapsulation devices. No adverse or serious adverse events related to the Neo-Islet administration have been observed to date. We conclude that this minimally invasive therapy has significant translational relevance to veterinary and clinical Type 1 Diabetes Mellitus by achieving complete and at this point partial glycemic control in two species, i.e., diabetic mice and dogs, respectively.

cell biology↗

bioRxiv2018

Metastable brain waves

Traveling patterns of neuronal activity - brain waves - have been observed across a breadth of neuronal recordings, states of awareness, and species, but their emergence in the human brain lacks a firm understanding. Here, we analyze the complex nonlinear dynamics that emerge from modeling large-scale spontaneous neural activity on a whole-brain network derived from human tractography. We find a rich array of three-dimensional wave patterns, including traveling waves, spiral waves, sources, and sinks. These patterns are metastable, such that multiple spatiotemporal wave patterns are visited in sequence. Transitions between states correspond to reconfigurations of underlying phase flows, characterized by nonlinear instabilities. These metastable dynamics accord with empirical data from multiple imaging modalities, including electrical waves in cortical tissue, sequential spatiotemporal patterns in resting-state MEG data, and large-scale waves in human electrocorticography. By moving the study of functional networks from a spatially static to an inherently dynamic (wave-like) frame, our work unifies apparently diverse phenomena across functional neuroimaging modalities and makes specific predictions for further experimentation.

neuroscience↗

bioRxiv2017

Fronto-limbic dysconnectivity leads to impaired brain network controllability in young people with bipolar disorder and those at high genetic risk

Recent investigations have used diffusion-weighted imaging to reveal disturbances in the neurocircuitry that underlie cognitive-emotional control in bipolar disorder (BD) and in unaffected siblings or children at high genetic risk (HR). It has been difficult to quantify the mechanism by which structural changes disrupt the superimposed brain dynamics, leading to the emotional lability that is characteristic of BD. Average controllability is a concept from network control theory that extends structural connectivity data to estimate the manner in which local neuronal fluctuations spread from a node or subnetwork to alter the state of the rest of the brain. We used this theory to ask whether structural connectivity deficits previously observed in HR (n=84, mean age 22.4) individuals, patients with BD (n=38, mean age 23.9), and age- and gender-matched controls (n=96, mean age 22.6) translate to differences in the ability of brain systems to be manipulated between states. Localized impairments in network controllability were seen in the left parahippocampal, left middle occipital, left superior frontal, right inferior frontal, and right precentral gyri in BD and HR groups. Subjects with BD had distributed deficits in a subnetwork containing the left superior and inferior frontal gyri, postcentral gyrus, and insula (p=0.004). HR participants had controllability deficits in a right-lateralized subnetwork involving connections between the dorsomedial and ventrolateral prefrontal cortex, the superior temporal pole, putamen, and caudate nucleus (p=0.008). Between-group controllability differences were attenuated after removal of topological factors by network randomization. Some previously reported differences in network connectivity were not associated with controllability-differences, likely reflecting the contribution of more complex brain network properties. These analyses highlight the potential functional consequences of altered brain networks in BD, and may guide future clinical interventions.\n\nHighlightsO_LIControl theory estimates how neuronal fluctuations spread from local networks.\nC_LIO_LIWe compare brain controllability in bipolar disorder and their high-risk relatives.\nC_LIO_LIThese groups have impaired controllability in networks supporting cognitive and emotional control.\nC_LIO_LIWeaker connectivity as well as topological alterations contribute to these changes.\nC_LI

neuroscience↗