A hybrid fluoride layered perovskite, (enH2)MnF4

We acknowledge the University of St Andrews and the China Scholarship Council (studentship to TL) and the EPSRC (DTG: EP/K503162/1) for a studentship (to RC). The are no conflicts of interest to declare.The title compound is the first example of a layered fluoroperovskite containing an interlayer organic cation. Preliminary magnetic characterisation is reported, and structural relationships to related layered perovskites are discussed.PostprintPostprintPeer reviewe

Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression

Changes in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy

Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression

Changes in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy

Treatment Strategies Targeting Excess Hippocampal Activity Benefit Aged Rats with Cognitive Impairment

Excess neural activity in the CA3 region of the hippocampus has been linked to memory impairment in aged rats. We tested whether interventions aimed at reducing this excess activity would improve memory performance. Aged (24 to 28 months old) male Long–Evans rats were characterized in a spatial memory task known to depend on the functional integrity of the hippocampus, such that aged rats with identified memory impairment were used in a series of experiments. Overexpression of the inhibitory neuropeptide Y 13–36 in the CA3 via adeno-associated viral transduction was found to improve hippocampal-dependent long-term memory in aged rats, which had been characterized with impairment. Subsequent experiments with two commonly used antiepileptic agents, sodium valproate and levetiracetam, similarly produced dose-dependent memory improvement in such aged rats. Improved spatial memory with low doses of these agents was observed in both appetitve and aversive spatial tasks. The benefits of these different modalities of treatment are consistent with the concept that excess activity in the CA3 region of the hippocampus is a dysfunctional condition that may have a key role underlying age-related impairment in hippocampal-dependent memory processes. Because increased hippocampal activation occurs in age-related memory impairment in humans as observed in functional neuroimaging, the current findings also suggest that low doses of certain antiepileptic drugs in cognitively impaired elderly humans may have therapeutic potential and point to novel targets for this indication

Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator

BackgroundThrombolytic agents such as tissue plasminogen activator (tPA) are the only drug class approved to treat ischemic stroke and are usually administered within 4.5 h. However, only ~20% of ischemic stroke patients are eligible to receive the therapy. We previously demonstrated that early intravenous administration of human amnion epithelial cells (hAECs) can limit brain inflammation and infarct growth in experimental stroke. Here, we have tested whether hAECs exert cerebroprotective effects in combination with tPA in mice.MethodsMale C57Bl/6 mice were subjected to middle cerebral artery occlusion for 60 min followed by reperfusion. Immediately following reperfusion, vehicle (saline, n = 31) or tPA (10 mg/kg; n = 73) was administered intravenously. After 30 min of reperfusion, tPA-treated mice were injected intravenously with either hAECs (1×106; n = 32) or vehicle (2% human serum albumin; n = 41). A further 15 sham-operated mice were treated with vehicle (n = 7) or tPA + vehicle (n = 8). Mice were designated to be euthanised at 3, 6 or 24 h post-stroke (n = 21, 31, and 52, respectively), and brains were collected to assess infarct volume, blood–brain barrier (BBB) disruption, intracerebral bleeding and inflammatory cell content.ResultsThere was no mortality within 6 h of stroke onset, but a high mortality occurred in tPA + saline-treated mice between 6 h and 24 h post-stroke in comparison to mice treated with tPA + hAECs (61% vs. 27%, p = 0.04). No mortality occurred within 24 h of sham surgery in mice treated with tPA + vehicle. We focused on early infarct expansion within 6 h of stroke and found that infarction was ~50% larger in tPA + saline- than in vehicle-treated mice (23 ± 3 mm3 vs. 15 ± 2 mm3, p = 0.02) but not in mice receiving tPA + hAECs (13 ± 2 mm3, p < 0.01 vs. tPA + saline) in which intracerebral hAECs were detected. Similar to the profiles of infarct expansion, BBB disruption and intracerebral bleeding in tPA + saline-treated mice at 6 h was 50–60% greater than in vehicle-treated controls (2.6 ± 0.5 vs. 1.6 ± 0.2, p = 0.05) but not after tPA + hAECs treatment (1.7 ± 0.2, p = 0.10 vs. tPA + saline). No differences in inflammatory cell content were detected between treatment groups.ConclusionWhen administered following tPA in acute stroke, hAECs improve safety and attenuate infarct growth in association with less BBB disruption and lower 24 h mortality

Wet scavenging of soluble gases in DC3 deep convective storms using WRF-Chem simulations and aircraft observations

We examine wet scavenging of soluble trace gases in storms observed during the Deep Convective Clouds and Chemistry (DC3) field campaign. We conduct high-resolution simulations with the Weather Research and Forecasting model with Chemistry (WRF-Chem) of a severe storm in Oklahoma. The model represents well the storm location, size, and structure as compared with Next Generation Weather Radar reflectivity, and simulated CO transport is consistent with aircraft observations. Scavenging efficiencies (SEs) between inflow and outflow of soluble species are calculated from aircraft measurements and model simulations. Using a simple wet scavenging scheme, we simulate the SE of each soluble species within the error bars of the observations. The simulated SEs of all species except nitric acid (HNO_3) are highly sensitive to the values specified for the fractions retained in ice when cloud water freezes. To reproduce the observations, we must assume zero ice retention for formaldehyde (CH_2O) and hydrogen peroxide (H_2O_2) and complete retention for methyl hydrogen peroxide (CH_3OOH) and sulfur dioxide (SO_2), likely to compensate for the lack of aqueous chemistry in the model. We then compare scavenging efficiencies among storms that formed in Alabama and northeast Colorado and the Oklahoma storm. Significant differences in SEs are seen among storms and species. More scavenging of HNO_3 and less removal of CH_3OOH are seen in storms with higher maximum flash rates, an indication of more graupel mass. Graupel is associated with mixed-phase scavenging and lightning production of nitrogen oxides (NO_x), processes that may explain the observed differences in HNO_3 and CH_3OOH scavenging

Isoprene NO_3 Oxidation Products from the RO_2 + HO_2 Pathway

We describe the products of the reaction of the hydroperoxy radical (HO_2) with the alkylperoxy radical formed following addition of the nitrate radical (NO_3) and O_2 to isoprene. NO_3 adds preferentially to the C_1 position of isoprene (>6 times more favorably than addition to C_4), followed by the addition of O_2 to produce a suite of nitrooxy alkylperoxy radicals (RO_2). At an RO_2 lifetime of ∼30 s, δ-nitrooxy and β-nitrooxy alkylperoxy radicals are present in similar amounts. Gas-phase product yields from the RO_2 + HO_2 pathway are identified as 0.75–0.78 isoprene nitrooxy hydroperoxide (INP), 0.22 methyl vinyl ketone (MVK) + formaldehyde (CH_2O) + hydroxyl radical (OH) + nitrogen dioxide (NO_2), and 0–0.03 methacrolein (MACR) + CH_2O + OH + NO_2. We further examined the photochemistry of INP and identified propanone nitrate (PROPNN) and isoprene nitrooxy hydroxyepoxide (INHE) as the main products. INHE undergoes similar heterogeneous chemistry as isoprene dihydroxy epoxide (IEPOX), likely contributing to atmospheric secondary organic aerosol formation

Atmospheric fates of Criegee intermediates in the ozonolysis of isoprene

We use a large laboratory, modeling, and field dataset to investigate the isoprene + O_3 reaction, with the goal of better understanding the fates of the C_1 and C_4 Criegee intermediates in the atmosphere. Although ozonolysis can produce several distinct Criegee intermediates, the C_1 stabilized Criegee (CH_2OO, 61 ± 9%) is the only one observed to react bimolecularly. We suggest that the C_4 Criegees have a low stabilization fraction and propose pathways for their decomposition. Both prompt and non-prompt reactions are important in the production of OH (28% ± 5%) and formaldehyde (81% ± 16%). The yields of unimolecular products (OH, formaldehyde, methacrolein (42 ± 6%) and methyl vinyl ketone (18 ± 6%)) are fairly insensitive to water, i.e., changes in yields in response to water vapor (≤4% absolute) are within the error of the analysis. We propose a comprehensive reaction mechanism that can be incorporated into atmospheric models, which reproduces laboratory data over a wide range of relative humidities. The mechanism proposes that CH_2OO + H_2O (k_((H_2O)) ∼ 1 × 10^(−15) cm^3 molec^(−1) s^(−1)) yields 73% hydroxymethyl hydroperoxide (HMHP), 6% formaldehyde + H_2O_2, and 21% formic acid + H_2O; and CH_2OO + (H_2O)_2 (k_((H_2O)_2) ∼ 1 × 10^(−12) cm^3 molec^(−1) s^(−1)) yields 40% HMHP, 6% formaldehyde + H_2O_2, and 54% formic acid + H_2O. Competitive rate determinations (k_(SO_2/k(H_2O)n=1,2) ∼ 2.2 (±0.3) × 10^4) and field observations suggest that water vapor is a sink for greater than 98% of CH2OO in a Southeastern US forest, even during pollution episodes ([SO_2] ∼ 10 ppb). The importance of the CH_2OO + (H_2O)n reaction is demonstrated by high HMHP mixing ratios observed over the forest canopy. We find that CH_2OO does not substantially affect the lifetime of SO_2 or HCOOH in the Southeast US, e.g., CH_2OO + SO_2 reaction is a minor contribution (<6%) to sulfate formation. Extrapolating, these results imply that sulfate production by stabilized Criegees is likely unimportant in regions dominated by the reactivity of ozone with isoprene. In contrast, hydroperoxide, organic acid, and formaldehyde formation from isoprene ozonolysis in those areas may be significant

Comparison of empirically derived and model-based estimates of key population HIV incidence and the distribution of new infections by population group in sub-Saharan Africa

Background: The distribution of new HIV infections among key populations, including female sex workers (FSWs), gay men and other men who have sex with men (MSM), and people who inject drugs (PWID) are essential information to guide an HIV response, but data are limited in sub-Saharan Africa (SSA). We analyzed empirically derived and mathematical model-based estimates of HIV incidence among key populations and compared with the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates.Methods: We estimated HIV incidence among FSW and MSM in SSA by combining meta-analyses of empirical key population HIV incidence relative to the total population incidence with key population size estimates (KPSE) and HIV prevalence. Dynamic HIV transmission model estimates of HIV incidence and percentage of new infections among key populations were extracted from 94 country applications of 9 mathematical models. We compared these with UNAIDS-reported distribution of new infections, implied key population HIV incidence and incidence-to-prevalence ratios.Results: Across SSA, empirical FSW HIV incidence was 8.6-fold (95% confidence interval: 5.7 to 12.9) higher than total population female 15–39 year incidence, and MSM HIV incidence was 41.8-fold (95% confidence interval: 21.9 to 79.6) male 15–29 year incidence. Combined with KPSE, these implied 12% of new HIV infections in 2021 were among FSW and MSM (5% and 7% respectively). In sensitivity analysis varying KPSE proportions within 95% uncertainty range, the proportion of new infections among FSW and MSM was between 9% and 19%. Insufficient data were available to estimate PWID incidence rate ratios. Across 94 models, median proportion of new infections among FSW, MSM, and PWID was 6.4% (interquartile range 3.2%–11.7%), both much lower than the 25% reported by UNAIDS.Conclusion: Empirically derived and model-based estimates of HIV incidence confirm dramatically higher HIV risk among key populations in SSA. Estimated proportions of new infections among key populations in 2021 were sensitive to population size assumptions and were substantially lower than estimates reported by UNAIDS.</div