47 research outputs found
Extended Self-similarity in Kinetic Surface Roughening
We show from numerical simulations that a limited mobility solid-on-solid
model of kinetically rough surface growth exhibits extended self-similarity
analogous to that found in fluid turbulence. The range over which
scale-independent power-law behavior is observed is significantly enhanced if
two correlation functions of different order, such as those representing two
different moments of the difference in height between two points, are plotted
against each other. This behavior, found in both one and two dimensions,
suggests that the `relative' exponents may be more fundamental than the
`absolute' ones.Comment: 4 pages, 4 postscript figures included (some changes made according
to referees' comments. accepted for publication in PRE Rapid Communication
Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.
Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial
Background:
Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.
Methods:
The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).
Findings:
Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).
Interpretation:
These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention
Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial
Background:
Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.
Methods:
The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).
Findings:
Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).
Interpretation:
These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention
SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion
Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era
Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial
BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation
Autonomous Navigation for Micro Aerial Vehicles
In this thesis we have experimented in building a Micro Aerial Vehicle navigation system with completely open source components. The system consists of a DIY quadrotor with an opensource flightcontroller and a onboard raspberry pi which communicates with the ground station laptop over wifi. The sensors used are a monocular camera and an Inertial Measurement Unit (IMU).The flight controller communicates with the raspberry pi over usb. The monocular camera is connected to the raspberry pi, which communicates with the ground station laptop over wifi. Thus resource heavy algorithms like for example the Visual SLAM algorithm used could be shifted to the ground station. This was done to demonstrate the feasibility of building an autonomous navigation controller using only open source components. Also this is to facilitate further work on autonomous navigation and path planning using the developed system.
On the software side ROS (Robot Operating System) was used on both the on board raspberry pi and the ground station laptop. This facilitated the use a distributed computing paradigm with the processing heavy Visual SLAM being done on the ground station and the control commands being relayed to the flight controller through the raspberry pi.
Thus, a cheap open source MAV platform can be developed with open source software and hardware. Advanced state of the art SLAM and control algorithms can be tested and developed with little requirement of high end products. We using the above setup demonstrate the feasibility of using an single camera in conjunction with an IMU to localize the MAV in an unknown GPS constrained environment and use it to compute required controller and navigational commands for autonomous navigation
An Analytical Device for On-Site Immunoassay. Demonstration of Its Applicability in Semiquantitative Detection of Aflatoxin B1 in a Batch of Samples with Ultrahigh Sensitivity
A simple analytical device has been developed for performing
noninstrumental immunofiltration-based assay on
a batch of samples. The device consists of membrane
strips, with antibody-immobilized zones, attached to a
polyethylene card. A moist filter paper placed between the
membrane and the polyethylene card acts as the absorbent
body. The device was used to estimate very low
concentrations of aflatoxin B1 (AFB1) present in food
samples by using an improved catalyzed reporter deposition
(Super-CARD) method of signal amplification involving
biotinylated tyramine (B-T) and avidin-horseradish
peroxidase conjugate. 4-Chloro-1-naphthol was used as
the substrate for visualization. Semiquantitative results
are obtained by visual comparison of the color intensity
(inversely related to the analyte concentration) of a sample
spot with those of reference standards. Quantitative
estimation is possible by densitometric analysis (detection
limit 0.25 pg/spot, 0.01 ng mL-1). Dilute samples can
be assayed by in situ concentration with improved doseresponse
characteristics. A batch of 12 extracted samples
can be analyzed in a single test card within 12 min. Spiked
and contaminated samples of groundnut, corn, wheat,
cheese, and chilli were analyzed without sample cleanup.
The matrix interferences were eliminated by using appropriate
dilution of the aqueous methanol extracts. Mean
recoveries from different food samples were between 91
and 104%. The values obtained for infected corn and
groundnut samples correlated well (R2 ) 0.99) with the
estimates by HPLC. The method is well-suited for visual
screening of agricultural and food samples for AFB1 under
field conditions
Development of a Membrane-Based Immunofiltration Assay for the Detection of T-2 Toxin
An improved analytical device capable of performing
simultaneous immunofiltration-based immunoassay on
30 samples in the presence of reference standards has
been developed. The device consists of a rectangular
membrane with 36 antibody spotted zones, one end of
which was attached to a semirigid polyethylene card. A
piece of wetted filter paper between the membrane and
the polyethylene card absorbs the added reagent. The
assay is a competitive one using T-2 toxin-horseradish
peroxidase (T-2 toxin-HRP) as the labeled analyte and
4-chloro-1 naphthol (4CN) as the substrate. Signal amplification
was done by the Super-CARD signal amplification
method. Semiquantitative results were obtained by
visual comparison of the color intensity of a sample spot
with those of reference standards. Densitometric analysis
was used for quantitation. The method allows rapid and
easy determination of T-2 toxin in wheat and poultry feed
with detection limits of 12.5 and 25 Ìg kg-1, respectively,
with accuracy and precision. Matrix interference was
eliminated by appropriate dilution of sample extracts with
assay buffer. The detection sensitivity in ELISA was 10-
fold higher than that in the membrane-based method.
Noninfected samples were spiked with T-2 toxin at several
concentrations and analyzed by the present method and
rapid ELISA. Mean recoveries by both methods were
between 80 and 108%. The correlation between the two
methods was excellent (R2 ) 0.99)