GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, ...schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABA
receptor-associated protein (GABARAP) to stabilize cell surface GABA
receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.
The properties of whistler waves near lower‐hybrid frequencies within Earth's quasi‐perpendicular bow shock are examined using data from the Magnetospheric Multiscale (MMS) mission. These waves ...appear as right‐hand polarized wave packets propagating upstream obliquely to the magnetic field and shock normal with phase speeds from a few hundred up to 1,600 km/s. The wavelengths are near the ion inertial length scale (λ∼ 0.3–1.3 λi). Detailed analysis finds characteristics consistent with the modified two‐stream instability mechanism driven by the reflected ion and electron drift. Correlations between wave and electron anisotropy variations reveal that the whistlers are affecting electron dynamics and thus their perpendicular and parallel temperatures. The electron signatures are explainable via the interaction of magnetized electrons in the whistler induced nonmonotonic magnetic fields. These waves have intense magnetic fields (δB/B∘∼ 0.1–1) and carry sizable currents that are a significant fraction of the thermal current (|J/Jvte|∼ 0.1–0.5). The whistler‐induced currents and the electron anisotropies are sufficiently large to respectively excite high‐frequency (HF) electrostatic (>100 Hz) and HF whistler waves (f∼ 0.1–0.5 fce). Energy dissipation J·E from whistlers at 30 Hz and below range from a few thousandths to few hundredths of μW/m3. Comparisons reveal that plasma energy is converted to wave energy in the foot, whereas wave energy gets dissipated into the plasma in the ramp, where irreversible heating occurs. These observed features are indicative of an intricate coupling between small‐scale interaction processes and larger‐scale structure transpiring within the layer. Such a characterization is only made possible now with the MMS high‐time‐resolution measurements.
Key Points
Whistlers near lower‐hybrid frequencies are consistent with the modified two‐stream instability due to the reflected ion and electron drift
Whistlers are associated with large currents that can excite electrostatic waves and contribute to energy exchange processes within shocks
Lower‐hybrid whistler waves interact with the electrons and induce anisotropies that can drive quasiparallel high‐frequency whistlers
RISK MANAGEMENT AND FINANCIAL INSTITUTIONS THE GOLD STANDARD IN FINANCIAL RISK MANAGEMENT TEXTBOOKS In the newly revised sixth edition of Risk Management and Financial Institutions, celebrated risk ...and derivatives expert John C. Hull delivers an incisive and comprehensive discussion of financial risk and financial institution regulation. In the book, you'll learn to understand the financial markets, the risks they pose to various kinds of financial institutions, and how those risks are affected by common regulatory structures. This book blends discussion of best practices in risk management with holistic treatments of how financial institutions are regulated. It explores market, credit, liquidity, model, climate, cyber, and operational risk. This latest edition also offers: Updated ancillary and digital materials covering all the latest content, including software, practice questions, and teaching supplements Access to an updated website that reflects the new content Fulsome coverage of the most important financial market developments since the publication of the fifth edition, including regulatory changes, the growing importance of climate risk, the use of machine learning models, and the disappearance of LIBOR A must-have resource for undergraduate and graduate students of business and finance, Risk Management and Financial Institutions, Sixth Edition, cements this celebrated text as the gold standard in risk management resources.
Nonlinear optical processes at soft x-ray wavelengths have remained largely unexplored due to the lack of available light sources with the requisite intensity and coherence. Here we report the ...observation of soft x-ray second harmonic generation near the carbon K edge (∼284 eV) in graphite thin films generated by high intensity, coherent soft x-ray pulses at the FERMI free electron laser. Our experimental results and accompanying first-principles theoretical analysis highlight the effect of resonant enhancement above the carbon K edge and show the technique to be interfacially sensitive in a centrosymmetric sample with second harmonic intensity arising primarily from the first atomic layer at the open surface. This technique and the associated theoretical framework demonstrate the ability to selectively probe interfaces, including those that are buried, with elemental specificity, providing a new tool for a range of scientific problems.
Electrons are accelerated to non-thermal energies at shocks in space and astrophysical environments. While different mechanisms of electron acceleration have been proposed, it remains unclear how ...non-thermal electrons are produced out of the thermal plasma pool. Here, we report in situ evidence of pitch-angle scattering of non-thermal electrons by whistler waves at Earth's bow shock. On 2015 November 4, the Magnetospheric Multiscale (MMS) mission crossed the bow shock with an Alfvén Mach number ∼11 and a shock angle ∼84°. In the ramp and overshoot regions, MMS revealed bursty enhancements of non-thermal (0.5-2 keV) electron flux, correlated with high-frequency (0.2-0.4 , where is the cyclotron frequency) parallel-propagating whistler waves. The electron velocity distribution (measured at 30 ms cadence) showed an enhanced gradient of phase-space density at and around the region where the electron velocity component parallel to the magnetic field matched the resonant energy inferred from the wave frequency range. The flux of 0.5 keV electrons (measured at 1 ms cadence) showed fluctuations with the same frequency. These features indicate that non-thermal electrons were pitch-angle scattered by cyclotron resonance with the high-frequency whistler waves. However, the precise role of the pitch-angle scattering by the higher-frequency whistler waves and possible nonlinear effects in the electron acceleration process remains unclear.
Objective
Antenatal anaemia is associated with increased peripartum transfusion requirement in South Africa. We studied whether HIV was associated with the response to treatment of iron‐deficiency ...anaemia.
Design
Prospective cohort study.
Setting
Hospital‐based antenatal anaemia clinic in South Africa.
Sample
Equal‐sized cohorts of pregnant women testing positive for HIV (HIV+) and testing negative for HIV (HIV−) with iron‐deficiency anaemia.
Methods
Haemoglobin trajectories of women with confirmed iron‐deficiency anaemia (ferritin < 50 ng/ml) were estimated from the initiation of iron supplementation using mixed‐effects modelling, adjusted for baseline HIV status, ferritin level, maternal and gestational ages and time‐varying iron supplementation.
Main outcome measures
Haemoglobin trajectories.
Results
Of 469 women enrolled, 51% were HIV+, 90% of whom were on antiretroviral therapy (with a mean CD4+ lymphocyte count of 403 cells/mm3). Anaemia diagnoses did not differ by HIV status. A total of 400 women with iron‐deficiency anaemia were followed during treatment with oral or intravenous (6%) iron therapy. In multivariable analysis, haemoglobin recovery was 0.10 g/dl per week slower on average in women who were HIV+ versus women who were HIV− (P = 0.001), 0.01 g/dl per week slower in women with higher baseline ferritin (P < 0.001) and 0.06 g/dl per week faster in women who were compliant with oral iron therapy (P = 0.002).
Conclusions
Compared with women who were HIV−, women who were HIV+ with iron‐deficiency anaemia had slower but successful haemoglobin recovery with iron therapy. Earlier effective management of iron deficiency could reduce the incidence of peripartum blood transfusion.
Tweetable
Among pregnant women with iron‐deficiency anaemia in South Africa, HIV slows haemoglobin recovery in response to oral iron therapy.
Tweetable
Among pregnant women with iron‐deficiency anaemia in South Africa, HIV slows haemoglobin recovery in response to oral iron therapy.
Summary
The black soldier fly, Hermetia illucens, is an emerging biotechnological agent with its larvae being effective converters of organic waste into usable bio‐products including protein and ...lipids. To date, most operations use unimproved commercial populations produced by mass rearing, without cognisance of specific breeding strategies. The genetic and phenotypic consequences of these commercial practices remain unknown and could have a significant impact on long‐term population viability and productivity. The aim of this study was thus to assess the genetic and phenotypic changes during the early phases of colony establishment and domestication in the black soldier fly. An experimental colony was established from wild founder flies and a new microsatellite marker panel was developed to assess population genetic parameters along with the phenotypic characteristics of each generational cohort under captive breeding. The experimental colony was characterised by a small effective population size, subsequent loss of genetic diversity and rapid genetic and phenotypic differentiation between the generational cohorts. Ultimately, the population collapsed by the fifth generation, most likely owing to the adverse effect of inbreeding depression following the fixation of deleterious alleles. Species with r‐selected life history characteristics (e.g. short life‐span, high fecundity and low larval survival) are known to pose particular challenges for genetic management. The current study suggests that sufficient genetic and phenotypic variations exist in the wild population and that domestication and strain development could be achieved with careful population augmentation and selection during the early stages of colony establishment.
•RvE1 and 15-epi-LXA4 were not detectable (>20 pg/ml).•18-HEPE and 15-HETE were present in ng/ml amounts in plasma.•EPA treatment was associated with increased levels of 18-HEPE.•18-HEPE levels did ...not predict colorectal polyp risk reduction by EPA.
Aspirin and eicosapentaenoic acid (EPA) have colorectal polyp prevention activity, alone and in combination. This study measured levels of plasma and rectal mucosal oxylipins in participants of the seAFOod 2 × 2 factorial, randomised, placebo-controlled trial, who received aspirin 300 mg daily and EPA 2000 mg free fatty acid, alone and in combination, for 12 months.
Resolvin (Rv) E1, 15-epi-lipoxin (LX) A4 and respective precursors 18-HEPE and 15-HETE (with chiral separation) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry in plasma taken at baseline, 6 months and 12 months, as well as rectal mucosa obtained at trial exit colonoscopy at 12 months, in 401 trial participants.
Despite detection of S- and R- enantiomers of 18-HEPE and 15-HETE in ng/ml concentrations, RvE1 or 15‑epi-LXA4 were not detected above a limit of detection of 20 pg/ml in plasma or rectal mucosa, even in individuals randomised to both aspirin and EPA. We have confirmed in a large clinical trial cohort that prolonged (12 months) treatment with EPA is associated with increased plasma 18-HEPE concentrations (median inter-quartile range total 18-HEPE 0.51 0.21–1.95 ng/ml at baseline versus 0.95 0.46–4.06 ng/ml at 6 months P<0.0001 in those randomised to EPA alone), which correlate strongly with respective rectal mucosal 18-HEPE levels (r = 0.82; P<0.001), but which do not predict polyp prevention efficacy by EPA or aspirin.
Analysis of seAFOod trial plasma and rectal mucosal samples has not provided evidence of synthesis of the EPA-derived specialised pro-resolving mediator RvE1 or aspirin-trigged lipoxin 15‑epi-LXA4. We cannot rule out degradation of individual oxylipins during sample collection and storage but readily measurable precursor oxylipins argues against widespread degradation.
Colorectal cancers (CRCs) detected through the NHS Bowel Cancer Screening Programme (BCSP) have been shown to have a more favourable outcome compared to non-screen-detected cancers. The aim was to ...identify whether this was solely due to the earlier stage shift of these cancers, or whether other factors were involved.
A combination of a regional CRC registry (Northern Colorectal Cancer Audit Group) and the BCSP database were used to identify screen-detected and interval cancers (diagnosed after a negative faecal occult blood test, before the next screening round), diagnosed between April 2007 and March 2010, within the North East of England. For each Dukes' stage, patient demographics, tumour characteristics, and survival rates were compared between these two groups.
Overall, 322 screen-detected cancers were compared against 192 interval cancers. Screen-detected Dukes' C and D CRCs had a superior survival rate compared with interval cancers (P=0.014 and P=0.04, respectively). Cox proportional hazards regression showed that Dukes' stage, tumour location, and diagnostic group (HR 0.45, 95% CI 0.29-0.69, P<0.001 for screen-detected CRCs) were all found to have a significant impact on the survival of patients.
The improved survival of screen-detected over interval cancers for stages C and D suggest that there may be a biological difference in the cancers in each group. Although lead-time bias may have a role, this may be related to a tumour's propensity to bleed and therefore may reflect detection through current screening tests.
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