Brecciation at the grain scale within the lithologies of the Winchcombe Mighei‐like carbonaceous chondrite

The Mighei‐like carbonaceous (CM) chondrites have been altered to various extents by water–rock reactions on their parent asteroid(s). This aqueous processing has destroyed much of the primary mineralogy of these meteorites, and the degree of alteration is highly heterogeneous at both the macroscale and nanoscale. Many CM meteorites are also heavily brecciated juxtaposing clasts with different alteration histories. Here we present results from the fine‐grained team consortium study of the Winchcombe meteorite, a recent CM chondrite fall that is a breccia and contains eight discrete lithologies that span a range of petrologic subtypes (CM2.0–2.6) that are suspended in a cataclastic matrix. Coordinated multitechnique, multiscale analyses of this breccia reveal substantial heterogeneity in the extent of alteration, even in highly aqueously processed lithologies. Some lithologies exhibit the full range and can comprise nearly unaltered coarse‐grained primary components that are found directly alongside other coarse‐grained components that have experienced complete pseudomorphic replacement by secondary minerals. The preservation of the complete alteration sequence and pseudomorph textures showing tochilinite–cronstedtite intergrowths are replacing carbonates suggest that CMs may be initially more carbonate rich than previously thought. This heterogeneity in aqueous alteration extent is likely due to a combination of microscale variability in permeability and water/rock ratio generating local microenvironments as has been established previously. Nevertheless, some of the disequilibrium mineral assemblages observed, such as hydrous minerals juxtaposed with surviving phases that are typically more fluid susceptible, can only be reconciled by multiple generations of alteration, disruption, and reaccretion of the CM parent body at the grain scale

Brecciation at the grain scale within the lithologies of the Winchcombe Mighei-like carbonaceous chondrite

The Mighei‐like carbonaceous (CM) chondrites have been altered to various extents by water–rock reactions on their parent asteroid(s). This aqueous processing has destroyed much of the primary mineralogy of these meteorites, and the degree of alteration is highly heterogeneous at both the macroscale and nanoscale. Many CM meteorites are also heavily brecciated juxtaposing clasts with different alteration histories. Here we present results from the fine‐grained team consortium study of the Winchcombe meteorite, a recent CM chondrite fall that is a breccia and contains eight discrete lithologies that span a range of petrologic subtypes (CM2.0–2.6) that are suspended in a cataclastic matrix. Coordinated multitechnique, multiscale analyses of this breccia reveal substantial heterogeneity in the extent of alteration, even in highly aqueously processed lithologies. Some lithologies exhibit the full range and can comprise nearly unaltered coarse‐grained primary components that are found directly alongside other coarse‐grained components that have experienced complete pseudomorphic replacement by secondary minerals. The preservation of the complete alteration sequence and pseudomorph textures showing tochilinite–cronstedtite intergrowths are replacing carbonates suggest that CMs may be initially more carbonate rich than previously thought. This heterogeneity in aqueous alteration extent is likely due to a combination of microscale variability in permeability and water/rock ratio generating local microenvironments as has been established previously. Nevertheless, some of the disequilibrium mineral assemblages observed, such as hydrous minerals juxtaposed with surviving phases that are typically more fluid susceptible, can only be reconciled by multiple generations of alteration, disruption, and reaccretion of the CM parent body at the grain scale

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

LIMK2 regulates microtubule drug-dependent cell cycle arrest.

<p>(A) LIMK2 knockdown enhances the G2/M block induced by microtubule-targeted drugs. Cell cycle analysis of SHEP cells transfected with LIMK2 or non-targeting control (NT) siRNA for 72 hours followed by treatment with 0.5 µM taxol or 0.1 µM vincristine (VCR) for 24 hours. The extent of the G2/M arrest, represented by G2/G1 ratio, is shown on the right as mean ± S.E.M of three independent experiments (*, p < 0.05, unpaired t-test). (B) LIMK2 overexpressing cells reduce the G2/M arrest induced by microtubule-targeted drugs. Cell cycle analysis of LIMK2a or LIMK2b expressing cells treated with 0.5 µM taxol or 0.1 µM vincristine (VCR) for 24 hours. The extent of the G2/M arrest, represented by G2/G1 ratio, is shown on the right as mean ± S.E.M of three independent experiments (*, p < 0.05; **, p < 0.001; ns, non significant, unpaired t-test). (C) LIMK2 overexpressing cells recover faster from the cell cycle block induced by microtubule-targeted drugs. Analysis of the cell cycle recovery after drug wash-out of SHEP cells expressing LIMK2a or LIMK2b treated with 0.5 µM taxol or 0.1 µM vincristine (VCR) for 24 hours. The right panels show the cell cycle profile of the cells 8 hours after drug removal.</p

LIMK2 overexpression results in increased number of multinucleated cells.

<p>(A) A high percentage of BE/VCR10 cells are multinucleated. Fixed BE(2)-C and BE/VCR10 cells were stained with FITC-conjugated anti-α-tubulin antibody and Hoechst. White arrowheads indicate multinucleated cells. Scale bar = 20 µm. The percentage of multinucleated cells shown on the right panel is represented as mean ± S.E.M of three independent experiments (***, p < 0.0001, unpaired t-test). The blots on the left show whole cell lysates of the BE(2)-C and BE/VCR10 cells analyzed by immunoblotting with the indicated antibodies. The numbers below the top panel represent the fold changes in the indicated protein levels. (B) Overexpression of LIMK2a or LIMK2b proteins in SHEP cells increases ploidy. Stable SHEP cell lines expressing HA-tagged LIMK2a or LIMK2b or vector control (pMSCV) were generated by transduction with retroviruses. The left panel shows the relative expression of the ectopic LIMK2 proteins. Cells expressing LIMK2a or LIMK2b were fixed and stained with an anti-HA antibody and Hoechst (middle panel). White arrowheads indicate multinucleated cells. Scale bar = 20 µm. The percentage of multinucleated cells is shown on the right panel represented as mean ± S.E.M of three independent experiments (**, p < 0.001, unpaired t-test). (C) LIMK2 localizes to the mitotic spindle microtubules. An unsynchronized population of NIH-3T3 cells was fixed and immuno-stained with an anti-LIMK2 antibody (red), FITC-conjugated anti-α-tubulin antibody (green) and Hoechst (blue). Scale bar = 20 µm. (D) LIMK2 levels do not change during cell division. SHEP cells were treated with 0.5 µM taxol, 0.1 µM vincristine (VCR) or 1 µM dimethylenastron (DIMEN) for 20 hours and mitotic cells were collected by mitotic shake-off. Half of the cells were used to prepare whole cell lysates that were immunoblotted with anti-LIMK2 as well as anti-GAPDH antibodies. The rest of the cells were fixed, stained with propidium iodide and analyzed by flow cytometry (bottom panels). The cell cycle profiles show the G2/M arrest with the different treatments.</p

LIMK2 knockdown sensitizes cells to apoptosis induced by microtubule-targeted drugs.

<p>(A) LIMK2 knockdown increases the sensitivity of SHEP cells to microtubule-targeted drugs. SHEP cells were transfected with LIMK2 or non-targeting control (NT) siRNA. 72 hours after transfection, cells were treated with 0.5 µM taxol or 0.1 µM vincristine (VCR) for 48 hours and cell viability was analyzed by MTT assay. Results are expressed as percentage of the control (vehicle) and represented as mean ± S.E.M of three independent experiments (*, p < 0.05, unpaired t-test). The efficiency of the LIMK2 knockdown in a representative experiment is shown on the right panel. (B) LIMK2-depleted cells show enhanced apoptosis induced by microtubule-targeted drugs. SHEP cells transfected with the indicated siRNAs were treated with 0.5 µg/ml nocodazole (Noc), 0.5 µM taxol or 0.1 µM vincristine (VCR) for 24 hours and analyzed by immunoblots probed with the indicated antibodies. The graph on the right that indicates the relative cleaved PARP levels compared to control (vehicle) as mean ± S.E.M of three independent experiments (*, p < 0.05; **, p < 0.001, unpaired t-test). (C) SHEP cells were transfected with the indicated siRNAs and treated with 0.5 µM taxol or 0.1 µM vincristine (VCR) for 72 hours. Apoptosis was determined by flow cytometry and is shown as the mean percentage of AnnexinV+/PI- cells ± S.E.M of three independent experiments (*, p < 0.05; **, p < 0.001, unpaired t-test).</p

LIMK2 participates in DNA damage response.

<p>(A) BE/VCR10 cells are more resistant to genotoxic stress compared with the BE(2)-C parental cell line. Confluent monolayers of the BE(2)-C and BE/VCR10 cells were irradiated with 8 mJ/cm² ultraviolet B (UV-B). After 24 hours recovery, adherent and non-adherent cells were collected, stained with propidium iodide and analyzed by flow cytometry. Cell death is represented as the mean percentage of propidium iodide positive cells ± S.E.M of three independent experiments (*, p < 0.05, unpaired t-test) (B) Knockdown of LIMK2 in SHEP cells increases their sensitivity to genotoxic stress. SHEP cells were transfected with LIMK2 or non-targeting control (NT) siRNA and 72 hours later they were treated with 10 µM doxorubicin (Doxo) or 10 µM etoposide (Eto) for 48 hours before cell viability was analyzed by MTT assay. Results are expressed as percentage of the control (vehicle). Mean ± S.E.M of three independent experiments (*, p < 0.05; **, p < 0.001, unpaired t-test). (C) LIMK2 knockdown sensitizes cells to apoptosis induced by DNA damage agents. SHEP cells transfected with the indicated siRNAs were treated with 10 µM doxorubicin (Doxo) or 100 µM etoposide (Eto) for 24 hours and analyzed by immunoblotting. Two different exposures of the cleaved PARP immunoblot are shown (low and high). The graph indicates the relative cleaved PARP levels compared to control (vehicle) and is represented as the mean ± S.E.M of three independent experiments (*, p < 0.05, unpaired t-test). (D) SHEP cells transfected with the indicated siRNAs were treated as in A for 72 hours and apoptosis was analyzed by flow cytometry. The percentage of apoptotic cells is represented by the mean percentage of AnnexinV+/PI- cells ± S.E.M of three independent experiments (*, p < 0.05; **, p < 0.001, unpaired t-test). (E) LIMK2 knockdown promotes G2/M arrest induced by DNA damage. Cell cycle analysis of SHEP cells transfected with the indicated siRNAs and treated with 10 µM doxorubicin (Doxo) for 24 hours. The G2/G1 ratio of three independent experiments is shown on the right as the mean ± S.E.M (*, p < 0.05, unpaired t-test). (F) Cell cycle analysis of LIMK2a or LIMK2b overexpressing cells treated with 10 µM doxorubicin (Doxo) for 24 hours. The extent of the G2/M arrest, represented by G2/G1 ratio, is shown on the right as mean ± S.E.M of three independent experiments (*, p < 0.05; ***, p < 0.0001, unpaired t-test). (G) LIMK2 overexpressing cells are more resistant to DNA damage-induced cell cycle arrest. SHEP cells expressing LIMK2a or LIMK2b were treated with 10 µM doxorubicin (Doxo) for 24 hours before washing out the drugs and the cell cycle recovery was analyzed by flow cytometry. The panel on the right depicts the cells cycle profile 8 hours after drug removal.</p