Biology subjects

Agarwal, S.

Publications and source records attributed to Agarwal, S..

5 recordsLinked to original sources

bioRxiv2018

Deep structural brain lesions associated with consciousness impairment early after haemorrhagic stroke

BackgroundThe significance of deep structural lesions on level of consciousness early after intracerebral haemorrhage (ICH) is largely unknown.\n\nMethodsWe studied a consecutive series of patients with spontaneous ICH that underwent MRI within 7 days of the bleed. We assessed consciousness by testing for command following from time of MRI to hospital discharge, and determined 3-months functional outcomes using the Glasgow Outcome Scale-Extended (GOS-E). ICH and oedema volumes, intraventricular haemorrhage (IVH), and midline shift (MLS) were quantified. Presence of blood and oedema in deep brain regions previously implicated in consciousness were assessed. A machine learning approach using logistic regression with elastic net regularization was applied to identify parameters that best predicted consciousness at discharge controlling for confounders.\n\nResultsFrom 158 ICH patients that underwent MRI, 66% (N=105) were conscious and 34% (N=53) unconscious at the time of MRI. Almost half of unconscious patients (49%, N= 26) recovered consciousness by ICU discharge. Focal lesions within subcortical structures predicted persistent impairment of consciousness at discharge together with MLS, IVH, and ICH and oedema volumes (AUC 0.74; 95%-CI 0.73-0.75). Caudate nucleus, midbrain peduncle, and pontine tegmentum were implicated as critical structures. Unconscious patients predicted to recover consciousness had better 3-month functional outcomes than those predicted to remain unconscious (35% vs 0% GOS-E [≥]4; p-value=0.02).\n\nConclusionMRI lesions within key subcortical structures together with measures reflecting the mass effect of the haemorrhage (lesion volumes, IVH, MLS) obtained within one week of ICH can help predict early recovery of consciousness and 3-month functional outcome.

neuroscience↗

bioRxiv2017

Human replication licensing factor Cdt1 directly links mitotic kinetochores to spindle microtubules

Robust kinetochore-microtubule (kMT) attachment is critical for accurate chromosome segregation. G2/M-specific depletion of human Cdt1 that localizes to kinetochores in an Ndc80 complex-dependent manner, leads to abnormal kMT attachments and mitotic arrest. This indicates an independent mitotic role for Cdt1 in addition to its prototypic function in DNA replication origin licensing. Here, we show that Cdt1 directly binds to microtubules (MTs). Endogenous or transiently expressed Cdt1 localizes to both mitotic spindle MTs and kinetochores. Deletion mapping of Cdt1 revealed that the regions comprising the middle and C-terminal winged-helix domains but lacking the N-terminal unstructured region was required for efficient MT-binding. Mitotic kinase Aurora B interacts with and phosphorylates Cdt1. Aurora B-phosphomimetic Cdt1 exhibited attenuated MT-binding and its cellular expression induced defective kMT attachments with a concomitant delay in mitotic progression. Thus we provide mechanistic insight into how Cdt1 affects overall kMT stability in an Aurora B kinase phosphorylation-dependent manner; which is envisioned to augment the MT-binding of the Ndc80 complex.\n\neTOC summary* Cdt1 binds to microtubules\n\n* The middle and the C-terminal winged-helix domains of Cdt1 are involved in MT-binding\n\n* Aurora B Kinase phosphorylates Cdt1 and influences its MT-binding\n\n* Aurora B-mediated Cdt1 phosphorylation is necessary for kMT stability and mitotic progression

cell biology↗

bioRxiv2017

LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers

Transcriptional enhancers enable exquisite spatiotemporal control of gene expression in metazoans. Enrichment of mono-methylation of histone H3 lysine 4 (H3K4me1) is a major chromatin signature that distinguishes enhancers from gene promoters. Lysine Specific Demethylase 1 (LSD1, aka KDM1A), an enzyme specific for demethylating H3K4me2/me1, has been shown to \"decommission\" stem cell enhancers during the differentiation of mouse embryonic stem cells (mESC). However, the roles of LSD1 in undifferentiated mESC remain obscure. Here, we show that LSD1 occupies a large fraction of enhancers (63%) that are primed with binding of transcription factors (TFs) and H3K4me1 in mESC. In contrast, LSD1 is largely absent at latent enhancers, which are not yet primed by TF binding. Unexpectedly, LSD1 levels at enhancers exhibited a clear positive correlation with its substrate, H3K4me2 and enhancer activity. These enhancers gain additional H3K4 methylation upon the loss of LSD1 in mESC. The aberrant increase in H3K4me at enhancers was accompanied with increases in enhancer H3K27 acetylation and expression of enhancer RNAs (eRNAs) and their target genes. In post-mitotic neurons, loss of LSD1 resulted in premature activation of enhancers and genes that are normally induced after neuronal activation. These results demonstrate that LSD1 is a versatile suppressor of primed enhancers, and is involved in homeostasis of enhancer activity.

biochemistry↗

bioRxiv2017

Improved Outcome And Cost Effectiveness In Ablation Of Persistent Atrial Fibrillation Under General Anaesthetic

AimsOutcome of persistent atrial fibrillation (AF) ablation remains suboptimal. Techniques employed to reduce arrhythmia recurrence rate are more likely to be embraced if cost-effectiveness can be demonstrated. A single-centre observational study assessed whether use of general anaesthesia (GA) in persistent AF ablation improved outcome and was cost-effective.\n\nMethods292 patients undergoing first ablation procedures for persistent AF under conscious sedation or GA were followed. End points were freedom from listing for repeat ablation at 18 months and freedom from recurrence of atrial arrhythmia at one year.\n\nResultsFreedom from atrial arrhythmia was higher in patients who underwent ablation under GA rather than sedation (63.9% vs 42.3%, HR 1.87, 95% CI: 1.23 to 2.86, p = 0.002). Significantly fewer GA patients were listed for repeat procedures (29.2% vs 42.7%, HR 1.62, 95% CI: 1.01 to 2.60, p = 0.044). Despite GA procedures costing slightly more, a saving of {pound}177 can be made per patient in our centre for a maximum of 2 procedures if all persistent AF ablations are performed under GA.\n\nConclusionsIn patients with persistent AF, it is both clinical and economically more effective to perform ablation under GA rather than sedation.\n\nWhats New?O_LIThere is very little known regarding the clinical outcome of catheter ablation of AF under GA compared with sedation; to our knowledge there is one study only in paroxysmal AF and no studies examining cost effectiveness.\nC_LIO_LIThis study shows that in patients with persistent AF, it is both clinical and economically more effective to perform ablation under GA rather than sedation.\nC_LIO_LIThis study leads us to recommend the use of GA for the ablation of persistent AF. As PAF ablation is now increasingly being undertaken by single shot techniques which do not have the same requirements for analgesia and immobility, GA resources may be allocated for persistent AF ablation.\nC_LI

systems biology↗

bioRxiv2017

Ablation Of Complex Fractionated Electrograms Improves Outcome In Long Standing Persistent Atrial Fibrillation

PurposeThere is controversy and sparse data on whether substrate based techniques in addition to pulmonary vein isolation (PVI) confer benefit in the catheter ablation of persistent atrial fibrillation (AF), especially if long standing. We performed an observational study to assess whether substrate based ablation improved freedom from atrial arrhythmia.\n\nMethods286 patients undergoing first ablation procedures for persistent AF with PVI only, PVI plus linear ablation, or PVI plus complex fractionated electrogram (CFAE) and linear ablation were followed. Primary end point was freedom from atrial arrhythmia at one year.\n\nResultsMean duration of pre-procedure time in AF was 28+/-27 months. Freedom from atrial arrhythmia was higher with a PVI+CFAE+lines strategy then for PVI alone (HR 1.56, 95% CI: 1.04-2.34, p=0.032) but was not higher with PVI+lines. Benefit of substrate modification was conferred for pre-procedure times in AF of over 30 months. The occurrence of atrial tachycardia was higher when lines were added to the ablation strategy (HR 0.08, 95% CI: 0.01-0.59, p=0.014). Freedom from atrial arrhythmia at 1 year was higher with lower patient age, use of general anaesthetic (GA), normal or mildly dilated left atrium and decreasing time in AF.\n\nConclusionsIn patients with long standing persistent AF of over 30 months duration, CFAE ablation resulted in improved freedom from atrial arrhythmia. Increased freedom from atrial arrhythmia occurs in patients who are younger and have smaller atria, and with GA procedures. Linear ablation did not improve outcome and resulted in a higher incidence of atrial tachycardia.

systems biology↗