bluuebunny/crossref_metadata_2025 huggingface dataset:
PROBABILITY OF SUFFICIENCY OF SOLVENCY II RESERVE RISK MARGINS: PRACTICAL APPROXIMATIONS
Authors: Moro Eric Dal , Krvavych Yuriy
Published: June 2017

The new Solvency II Directive and the upcoming IFRS 17 regime bring significant changes to current reporting of insurance entities, and particularly in relation to valuation of insurance liabilities. Insurers will be required to valuate their insurance liabilities on a risk-adjusted basis to allow for uncertainty inherent in cash flows that arise from the liability of insurance contracts. Whilst most European-based insurers are expected to adopt the Cost of Capital approach to calculate reserve risk margin — the risk adjustment method commonly agreed under Solvency II and IFRS 17, there is one additional requirement of IFRS 17 to also disclose confidence level of the risk margin.

Given there is no specific guidance on the calculation of confidence level, the purpose of this paper is to explore and examine practical ways of estimating the risk margin confidence level measured by Probability of Sufficiency (PoS). The paper provides some practical approximation formulae that would allow one to quickly estimate the implied PoS of Solvency II risk margin for a given non-life insurance liability, the risk profile of which is specified by the type and characteristics of the liability (e.g. type/nature of business, liability duration and convexity, etc.), which, in turn, are associated with

•

the level of variability measured by Coefficient of Variation (CoV);

•

the degree of Skewness per unit of CoV; and

•

the degree of Kurtosis per unit of CoV2.

The approximation formulae of PoS are derived for both the standalone class risk margin and the diversified risk margin at the portfolio level.
The impact of attention deficit hyperactivity disorder (ADHD) in adulthood: a qualitative study
Authors: Watters C. , Adamis D. , McNicholas F. , Gavin B.
Published: June 2017

Objectives

There is limited evidence of the unmet needs and experiences of adults with attention deficit hyperactivity disorder (ADHD). Previous research in this area is predominantly quantitative by nature, few studies employing qualitative approaches. This study seeks to provide a deeper insight into the lived experiences of adults with ADHD within Western Ireland.

Methods

A qualitative design, consisting of semi-structured face-to-face interviews with a clinical sample in the Sligo/Leitrim area. Participants were eligible for this study if they screened positive for symptoms of ADHD, and diagnosed with ADHD with the Conners’ Adult ADHD Diagnostic Interview for DSM-IV. In total, 11 participants completed this research. The interviews were open ended and exploratory, adopting a phenomenological approach.

Results

Thematic analysis was used to explore three main themes; The Burden of symptoms of ADHD, Perceived Positive and Negative Effects of ADHD and Challenge of Accessing Services, each with several subthemes.

Conclusion

This research highlights the experiences of adults with ADHD. It is important for practitioners to be aware of the perceived positive and negative effects of the disorder, and how it can impact on their patient’s lives. In addition, becoming aware of the stigma associated with ADHD can help clinicians improve upon individual treatment plans to meet their patient’s needs. It is important to note that this sample experienced co-morbid diagnoses and so this may limit the interpretation of the findings. Further research in this area could explore patient’s attitudes towards receiving a formal diagnosis of ADHD.
Diapycnal mixing in layered stratified plane Couette flow quantified in a tracer-based coordinate
Authors: Zhou Qi , Taylor J. R. , Caulfield C. P. , Linden P. F.
Published: June 2017

The mixing properties of statically stable density interfaces subject to imposed vertical shear are studied using direct numerical simulations of stratified plane Couette flow. The simulations are designed to investigate possible self-maintaining mechanisms of sharp density interfaces motivated by Phillips’ argument (Deep-Sea Res., vol. 19, 1972, pp. 79–81) by which layers and interfaces can spontaneously form due to vertical variations of diapycnal flux. At the start of each simulation, a sharp density interface with the same initial thickness is introduced at the midplane between two flat, horizontal walls counter-moving at velocities$\pm U_{w}$. Particular attention is paid to the effects of varying Prandtl number$\mathit{Pr}\equiv \unicode[STIX]{x1D708}/\unicode[STIX]{x1D705}$, where$\unicode[STIX]{x1D708}$and$\unicode[STIX]{x1D705}$are the molecular kinematic viscosity and diffusivity respectively, over two orders of magnitude from 0.7, 7 and 70. Varying$\mathit{Pr}$enables the system to access a considerable range of characteristic turbulent Péclet numbers$\mathit{Pe}_{\ast }\equiv {\mathcal{U}}_{\ast }{\mathcal{L}}_{\ast }/\unicode[STIX]{x1D705}$, where${\mathcal{U}}_{\ast }$and${\mathcal{L}}_{\ast }$are characteristic velocity and length scales, respectively, of the motion which acts to ‘scour’ the density interface. The dynamics of the interface varies with the stability of the interface which is characterised by a bulk Richardson number$\mathit{Ri}\,\equiv \,b_{0}h/U_{w}^{2}$, where$b_{0}$is half the initial buoyancy difference across the interface and$h$is the half-height of the channel. Shear-induced turbulence occurs at small$\mathit{Ri}$, whereas internal waves propagating on the interface dominate at large$\mathit{Ri}$. For a highly stable (i.e. large$\mathit{Ri}$) interface at sufficiently large$\mathit{Pe}_{\ast }$, the complex interfacial dynamics allows the interface to remain sharp. This ‘self-sharpening’ is due to the combined effects of the ‘scouring’ induced by the turbulence external to the interface and comparatively weak molecular diffusion across the core region of the interface. The effective diapycnal diffusivity and irreversible buoyancy flux are quantified in the tracer-based reference coordinate proposed by Winters & D’Asaro (J. Fluid Mech., vol. 317, 1996, pp. 179–193) and Nakamura (J. Atmos. Sci., vol. 53, 1996, pp. 1524–1537), which enables a detailed investigation of the self-sharpening process by analysing the local budget of buoyancy gradient in the reference coordinate. We further discuss the dependence of the effective diffusivity and overall mixing efficiency on the characteristic parameters of the flow, such as the buoyancy Reynolds number and the local gradient Richardson number, and highlight the possible role of the molecular properties of fluids on diapycnal mixing.
Conditional sampling of a high Péclet number turbulent plume and the implications for entrainment
Authors: Burridge H. C. , Parker D. A. , Kruger E. S. , Partridge J. L. , Linden P. F.
Published: June 2017

We present simultaneous two-dimensional velocity and scalar measurements on a central vertical plane in an axisymmetric pure turbulent plume. We use an edge-detection algorithm to determine the edge of the plume, and compare the data obtained in both a fixed Eulerian frame and a frame relative to local coordinates defined in terms of the instantaneous plume edge. In an Eulerian frame we observe that the time-averaged distributions of vertical and horizontal velocity are self-similar, the vertical velocity being well represented by a Gaussian distribution. We condition these measurements on whether fluid is inside or outside of the plume, and whether fluid inside is mixed plume fluid or engulfed ambient fluid. We find that, on average, 5 % of the total vertical volume transport occurs outside the plume and this figure rises to nearly 14 % at heights between large-scale coherent structures. We show that the fluxes of engulfed fluid within the plume envelope are slightly larger than the vertical transport outside the plume – indicating that ambient fluid is engulfed into the plume envelope before being nibbled across the turbulent/non-turbulent interface (TNTI) and then ultimately irreversibly mixed. Our new measurements in the plume coordinate (following the meandering fluctuating plume) show the flow within the plume and in the nearby ambient fluid is strongly influenced by whether an eddy is present locally within the plume, or absent. When an eddy is present and the plume is wide, the vertical velocities near the plume edge are small and hence all vertical transport is inside the plume. In regions where the plume is narrow and there is no eddy, large vertical velocities and hence transport are observed outside the plume suggesting that pressure forces associated with the eddies accelerate ambient fluid which is then engulfed into the plume. Finally, we show that observing significant vertical velocities beyond the scalar edge of the plume does not suggest that the characteristic width of the velocity distribution is greater than that of the scalar field; on the contrary, we show our observations to be consistent with a buoyancy distribution that is up to 20 % wider than that of the velocity. Measurements in the plume coordinates show that the mixing of momentum across the plume results in a distribution for which the differential entropy is close to maximal and the mixing of momentum is uninhibited (i.e. not bounded) by the TNTI of the plume. Furthermore, our measurements suggest that the scalar mixing across the plume may also result in a distribution for which the differential entropy is close to maximal but, in contrast to the momentum, the scalar mixing is strictly bounded by the plume edge.
Lyness cycles
Authors: Dolan Stan
Published: June 2017

In 1942, R. C. Lyness noted that some recurrence relations generate cycles, irrespective of the initial values. For example, the order 2 recurrence relation

generates a cycle of period 5 for almost all values of u1 and u2 [1].

The globally periodic nature of sequences generated by this recurrence relation can be seen by setting u1 = x and u2 = y. The sequence is then

Lyness gave other examples of such recurrence relations but had been unable to find one with period 7 and challenged readers of the Gazette to find such a recurrence relation or prove it to be impossible.

No answer to this challenge was forthcoming. However, since Lyness's time, interest in these cycles has been maintained due to links with cross-ratios and elliptic curves. In recent years, Jonny Griffiths has done much to popularise these cycles [2].
Properties of bisect-diagonal quadrilaterals
Authors: Josefsson Martin
Published: June 2017

The general class of quadrilaterals where one diagonal is bisected by the other diagonal has appeared very rarely in the geometrical literature, but they have been named several times in connection with quadrilateral classifications. Günter Graumann strangely gave these objects two different names in [1, pp. 192, 194]: sloping-kite and sliding-kite. A. Ramachandran called them slant kites in [2, p. 54] and Michael de Villiers called them bisecting quadrilaterals in [3, pp. 19, 206]. The latter is a pretty good name, although a bit confusing: what exactly is bisected?

We have found no papers and only two books where any theorems on such quadrilaterals are studied. In each of the books, one necessary and sufficient condition for such quadrilaterals is proved (see Theorem 1 and 2 in the next section). The purpose of this paper is to investigate basic properties of convex bisecting quadrilaterals, but we have chosen to give them a slightly different name. Let us first remind the reader that a quadrilateral whose diagonals have equal lengths is called an equidiagonal quadrilateral and one whose diagonals are perpendicular is called an orthodiagonal quadrilateral.
Finding sums of powers using physical arguments
Authors: Treeby David
Published: June 2017

In an earlier issue of the Mathematical Gazette, Nick Lord established the familiar formula for the sum of the first n squares using a physical argument based on the centroid of a configuration of masses in the plane [1]. In [2] we demonstrate an alternative configuration that gives the same result. This article is a follow-up to these papers, in which we find physical derivations of the formula for

for each k ∈ {1, 2, 3, 4, 5}. Let us first summarise the required theory. Take any region X ⊆ ℝ2 with uniform density and total area A. The centroid of is the arithmetic mean position of all of the points in X. If a region has a line of symmetry then the centroid will be located on that line.
Stratigraphic and palaeoecological evidence for late medieval to early modern peat extraction from bogs in Het Gooi (Western Netherlands)
Authors: Sevink Jan , van Geel Bas
Published: June 2017

In the Monnikenberg estate, built in the mid-19th century in a Pleistocene coversand area to the south of Hilversum (the Netherlands), a depression with a small man-made mire was found to contain the remains of a complex peaty fill of a larger mire. Microfossil study and radiocarbon dating showed that its development started at the beginning of the third millennium BC through water stagnation on a podzol in combination with a high groundwater level, and about two millennia ago the vegetation had progressed from a mesotrophic mire to an ombrotrophic bog. Such origin, development and age are in conformity with the results for some other recently studied mires in the Het Gooi region (Gijzenveen; Van Geel et al., 2016). In the Monnikenberg mire, a discrepancy was found between the radiocarbon age of the upper part of the peaty fill and its clearly medieval or younger age as evidenced by its microfossil content, notably the occurrence of pollen of buckwheat (Fagopyrum) and cornflower (Centaurea cyanus). These species were first introduced in the Netherlands during the late Middle Ages. From further observations in a large pit in the former border zone of the mire, it is concluded that this discrepancy and the unique sedimentary structures, observed in this pit, result from peat exploitation and contemporary reworking of its sandy overburden during the Late Middle Ages or Early Modern Times. This is the first evidence for local early peat exploitation for such mires in Het Gooi. The results underpin the importance of microfossil analyses for proper interpretation of radiocarbon data, when studying mire fills. Additionally, they provide further proof for the development of podzols and ericaceous vegetation prior to and independent of early prehistoric agriculture in the Dutch Pleistocene coversand areas, and for the early (pre-medieval) start of wind erosion and deposition of drift sands.
The Club Approach: A Gateway to Effective Climate Co-operation?
Authors: Hovi Jon , Sprinz Detlef F. , Sælen Håkon , Underdal Arild
Published: June 2017

Although the Paris Agreement arguably made some progress, interest in supplementary approaches to climate change co-operation persist. This article examines the conditions under which a climate club might emerge and grow. Using agent-based simulations, it shows that even with less than a handful of major actors as initial members, a club can eventually reduce global emissions effectively. To succeed, a club must be initiated by the ‘right’ constellation of enthusiastic actors, offer sufficiently large incentives for reluctant countries and be reasonably unconstrained by conflicts between members over issues beyond climate change. A climate club is particularly likely to persist and grow if initiated by the United States and the European Union. The combination of club-good benefits and conditional commitments can produce broad participation under many conditions.
When and Why Do Venture-Capital-Backed Companies Obtain Venture Lending?
Authors: Tykvová Tereza
Published: June 2017

I model the decision of an informed early-stage venture capital (VC) investor that considers involving an uninformed VC or venture lending (VL) investor to finance the late stage. Early-stage VC investors that own high-quality value companies tend to signal their quality and they frequently turn to VL investors. Early-stage VC investors prefer VC if the proportion of high-quality companies in the population is high, if their companies have a high upside potential, if they can benefit from the value that late-stage VC investors add, or if uncertainty is high. I find empirical evidence consistent with these predictions.
The Diminishing Benefits of U.S. Cross-Listing: Economic Consequences of SEC Rule 12h-6
Authors: Ghosh Chinmoy , He Fan
Published: June 2017

On Mar. 21, 2007, the U.S. Securities and Exchange Commission (SEC) passed Exchange Act Rule 12h-6 to make it easier for cross-listed firms to deregister from the U.S. market and escape its regulatory costs. Using difference-in-difference (DD) tests, we find that, on average, Rule 12h-6’s passage induced an increase in voting premium, a decline in equity raising, and a decline in cross-listing premium. These effects are observed for exchange-listed firms and for firms from countries with weak investor protection. We conclude that although cross-listed firms are still valued at a significant premium over non-cross-listed firms, the rule decreased the value of commitment to the U.S. regulatory system.
Short-Term Interest Rates and Stock Market Anomalies
Authors: Maio Paulo , Santa-Clara Pedro
Published: June 2017

We present a simple 2-factor model that helps explain several capital asset pricing model (CAPM) anomalies (value premium, return reversal, equity duration, asset growth, and inventory growth). The model is consistent with Merton’s intertemporal CAPM (ICAPM) framework, and the key risk factor is the innovation on a short-term interest rate, the federal funds rate, or the T-bill rate. This model explains a large fraction of the dispersion in the average returns of the joint market anomalies. Moreover, the model compares favorably with alternative multifactor models widely used in the literature. Hence, short-term interest rates seem to be relevant for explaining several dimensions of cross-sectional equity risk premia.
Investor Attrition and Fund Flows in Mutual Funds
Authors: Christoffersen Susan E. K. , Xu Haoyu
Published: June 2017

We explore the properties of equity mutual funds that experience a loss of assets after poor performance. We document that both inflows and outflows are less sensitive to performance, because performance-sensitive investors leave or decide not to invest after bad performance. Consistent with the idea that attrition measures the sorting of performance-sensitive investors, we find that attrition has less of an impact on the fund’s flow–performance sensitivity for institutional funds where there is less dispersion in investor performance sensitivity. Also, attrition has no effect on the flow–performance sensitivity when attrition arises after good performance or investors invest for nonperformance reasons.
Firm Default Prediction: A Bayesian Model-Averaging Approach
Authors: Traczynski Jeffrey
Published: June 2017

I develop a new predictive approach using Bayesian model averaging to account for incomplete knowledge of the true model behind corporate default and bankruptcy filing. I find that uncertainty over the correct model is empirically large, with far fewer variables being significant predictors of default compared with conventional approaches. Only the ratio of total liabilities to total assets and the volatility of market returns are robust default predictors in the overall sample and individual industry groups. Model-averaged forecasts that aggregate information across models or allow for industry-specific effects substantially outperform individual models.
Stock Market Mean Reversion and Portfolio Choice over the Life Cycle
Authors: Michaelides Alexander , Zhang Yuxin
Published: June 2017

We solve for optimal consumption and portfolio choice in a life-cycle model with short-sales and borrowing constraints; undiversifiable labor income risk; and a predictable, time-varying, equity premium and show that the investor pursues aggressive market timing strategies. Importantly, in the presence of stock market predictability, the model suggests that the conventional financial advice of reducing stock market exposure as retirement approaches is correct on average, but ignoring changing market information can lead to substantial welfare losses. Therefore, enhanced target-date funds (ETDFs) that condition on expected equity premia increase welfare relative to target-date funds (TDFs). Out-of-sample analysis supports these conclusions.
Complementary length in vowel–consonant sequences: Acoustic and perceptual evidence for a sound change in progress in Bavarian German
Authors: Kleber Felicitas
Published: June 2017

This study is concerned with the Bavarian German dialect feature of complementary length in vowel plus consonant sequences according to which tense (long) vowels always precede lenis stops (short closure) and lax (short) vowels always precede fortis stops (long closure). The study investigates whether a vowel length contrast is developing before fortis stops due to dialect leveling. We measured vowel and consonant duration in trochaic words differing only in vowel length which were read by 40 older and younger Bavarian and Saxon (control group) German speakers. Older Bavarians distinguished tense and lax vowels by means of vowel to vowel plus consonant ratios that indicate an inverse timing pattern. Saxons and younger Bavarians signal the tense–lax distinction independently of the following stop length. A perception test showed that this sound change in progress also affects perception. We argue for a contact-induced change which is triggered by external as opposed to internal factors.
No perceptual reorganization for Limburgian tones? A cross-linguistic investigation with 6- to 12-month-old infants
Authors: RAMACHERS STEFANIE , BROUWER SUSANNE , FIKKERT PAULA
Published: June 2017

Despite the fact that many of the world's languages use lexical tone, the majority of language acquisition studies has focused on non-tone languages. Research on tone languages has typically investigated well-known tone languages such as Mandarin and Cantonese Chinese. The current study looked at a Limburgian dialect of Dutch that uses lexical pitch differences, albeit in a rather restricted way. Using a visual habituation paradigm, 6- to 12-month-old Limburgian and Dutch infants were tested for their ability to discriminate Limburgian tones. The results showed that both Limburgian and Dutch infants discriminate the Limburgian tones throughout their first year of life. The role of linguistic experience, acoustic salience, and the degree of similarity to the native prosodic system are discussed.
Parkinson’s Disease Subtypes Show Distinct Tradeoffs Between Response Initiation and Inhibition Latencies
Authors: Tolleson Christopher , Turchan Maxim , van Wouwe Nelleke , Isaacs David , Phibbs Fenna , Wylie Scott
Published: June 2017

Objectives: In unpredictable situations, individuals often show tradeoffs between response initiation and inhibition speeds. We tested the hypothesis that Parkinson’s disease (PD) motor subtypes differentially impact tradeoffs between these two action-oriented processes. We predicted that, compared to tremor dominant (TD) patients, predominant postural instability and gait dysfunction (PIGD) patients would show exacerbated tradeoffs between response initiation and inhibition in situations requiring the sudden potential need to interrupt an action. Methods: Fifty-one PD patients (subdivided into PIGD [n=27] and TD [n=24]) and 21 healthy controls (HCs) completed a choice reaction task to establish baseline response initiation speed between groups. Subsequently, participants completed a stop-signal task which introduced an occasional, unpredictable stop stimulus. We measured changes in initiation speed in preparation of an unpredictable stop (i.e., proactive slowing) and inhibition latency (i.e., stop-signal reaction time). Results: Compared to HCs, PD patients showed slower response initiation speeds in the choice reaction task. All groups showed proactive slowing in the stop-signal task but the magnitude was considerably larger in PIGD patients, almost twice as large as TD patients. PD patients, irrespective of motor subtype, showed longer inhibition latencies than HCs. Conclusions: PIGD and TD subtypes both showed exacerbated response inhibition deficits. However, PIGD patients showed much more pronounced proactive slowing in situations with an expected yet unpredictable need to stop action abruptly. This suggests that PIGD is accompanied by exaggerated tradeoffs between response initiation and inhibition processes to meet situational action demands. We discuss putative neural mechanisms and clinical implications of these findings. (JINS, 2017, 23, 665–674)
ENDOGENOUS CREDIT AND INVESTMENT CYCLES WITH ASSET PRICE VOLATILITY
Authors: Carli Francesco , Modesto Leonor
Published: June 2017

It is commonly accepted that credit market frictions are an important source of macroeconomic fluctuations. But what is the link between the two? And what is the driving factor of asset prices volatility? To answer these questions, we have introduced a specific credit friction, limited commitment, in a general equilibrium model with production and investment in productive capital, where agents can trade bonds. The model always displays a stationary equilibrium where bonds are traded. More importantly, limited commitment may generate stochastic endogenous fluctuations driven by self-fulfilling volatile expectations (sunspots), yielding credit and investment cycles and bond price volatility consistent with data.
Damming and Infrastructural Development of the Indus River Basin: Strengthening the Provisions of the Indus Waters Treaty
Authors: RAMAN Durgeshree
Published: June 2017

Whilst the Indus Waters Treaty of 1960 allows for damning and infrastructural development in the Indus River Basin, it does so without factoring in environmental considerations. This is because environmental standards in international law, except those related to pollution control, were largely absent when the Treaty was negotiated in the 1950s. Given the increasing list of development-related disputes between India and Pakistan, and their aspirations for further damming and other infrastructural works in the Basin, this paper seeks to close the gaps in the Treaty’s provisions and developments in international environmental law to date. To do so effectively, the paper analyzes the relevant provisions of the UN Watercourses Convention, supplemented with an examination of the European regional framework. Based on these, it proposes changes to the Treaty so that both India and Pakistan are able to work within a legal framework which not only provides for environmental impact assessments for planned projects, but enhances monitoring, assessments, and reporting. This will ensure that such developments are not only environmentally sound but also help to alleviate some of the disputes between India and Pakistan.
Shedding Light on Intermittent Rainfall
Authors: Witman Sarah
Published: June 2017

A study provides a new modeling method to simulate rain when it pours and when it doesn’t.
Interaction between autophagy and senescence is required for dihydroartemisinin to alleviate liver fibrosis
Authors: Zhang Zili , Yao Zhen , Zhao Shifeng , Shao Jiangjuan , Chen Anping , Zhang Feng , Zheng Shizhong
Published: June 2017

Autophagy and cellular senescence are stress responses essential for homeostasis. Therefore, they may represent new pharmacologic targets for drug development to treat diseases. In this study, we sought to evaluate the effect of dihydroartemisinin (DHA) on senescence of activated hepatic stellate cells (HSCs), and to further elucidate the underlying mechanisms. We found that DHA treatment induced the accumulation of senescent activated HSCs in rat fibrotic liver, and promoted the expression of senescence markers p53, p16, p21 and Hmga1 in cell model. Importantly, our study identified the transcription factor GATA6 as an upstream molecule in the facilitation of DHA-induced HSC senescence. GATA6 accumulation promoted DHA-induced p53 and p16 upregulation, and contributed to HSC senescence. By contrast, siRNA-mediated knockdown of GATA6 dramatically abolished DHA-induced upregulation of p53 and p16, and in turn inhibited HSC senescence. Interestingly, DHA also appeared to increase autophagosome generation and autophagic flux in activated HSCs, which was underlying mechanism for DHA-induced GATA6 accumulation. Autophagy depletion impaired GATA6 accumulation, while autophagy induction showed a synergistic effect with DHA. Attractively, p62 was found to act as a negative regulator of GATA6 accumulation. Treatment of cultured HSCs with various autophagy inhibitors, led to an inhibition of DHA-induced p62 degradation, and in turn, prevented DHA-induced GATA6 accumulation and HSC senescence. Overall, these results provide novel implications to reveal the molecular mechanism of DHA-induced senescence, by which points to the possibility of using DHA based proautophagic drugs for the treatment of liver fibrosis.
Heme oxygenase-1 derived carbon monoxide suppresses Aβ1–42 toxicity in astrocytes
Authors: Hettiarachchi Nishani T , Boyle John P , Dallas Mark L , Al-Owais Moza M , Scragg Jason L , Peers Chris
Published: June 2017

Neurodegeneration in Alzheimer’s disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid β peptides ((Aβ; the widely accepted major toxic factor in AD) is less well understood. Here, we show that Aβ
(1-42)
is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca
2+
homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, Aβ
(1-42)
raises peroxynitrite levels in astrocytes, and Aβ
(1-42)
toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following Aβ
(1-42)
application were derived from NADPH oxidase. Induction of haem oxygenase-1 (HO-1) protected astrocytes from Aβ
(1-42)
toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by Aβ
(1-42)
. Under hypoxic conditions (0.5% O
2
, 48 h) HO-1 was induced in astrocytes and Aβ
(1-42)
toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that Aβ
(1-42)
is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system.
RETRACTED ARTICLE:LISPRO mitigates β-amyloid and associated pathologies in Alzheimer’s mice
Authors: Habib Ahsan , Sawmiller Darrell , Li Song , Xiang Yang , Rongo David , Tian Jun , Hou Huayan , Zeng Jin , Smith Adam , Fan Shengnuo , Giunta Brian , Mori Takashi , Currier Glenn , Shytle Douglas Ronald , Tan Jun
Published: June 2017

Lithium has been marketed in the United States of America since the 1970s as a treatment for bipolar disorder. More recently, studies have shown that lithium can improve cognitive decline associated with Alzheimer’s disease (AD). However, the current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate chemical forms) have a narrow therapeutic window and unstable pharmacokinetics that, without careful monitoring, can cause serious adverse effects. Here, we investigated the safety profile, pharmacokinetics, and therapeutic efficacy of LISPRO (ionic co-crystal of lithium salicylate and l-proline), lithium salicylate, and lithium carbonate (Li2CO3). We found that LISPRO (8-week oral treatment) reduces β-amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3β in transgenic Tg2576 mice. Specifically, cytokine profiles from the brain, plasma, and splenocytes suggested that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines, and suppresses renal cyclooxygenase 2 expression in transgenic Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain lithium levels and more steady plasma lithium levels in both B6129SF2/J (2-week oral treatment) and transgenic Tg2576 (8-week oral treatment) mice compared with Li2CO3. Oral administration of LISPRO for 28 weeks significantly reduced β-amyloid plaques and tau-phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Taken together, our data suggest that LISPRO may be a superior form of lithium with improved safety and efficacy as a potential new disease modifying drug for AD.
Water scarcity hotspots travel downstream due to human interventions in the 20th and 21st century
Authors: Veldkamp T.I.E. , Wada Y. , Aerts J.C.J.H. , Döll P. , Gosling S. N. , Liu J. , Masaki Y. , Oki T. , Ostberg S. , Pokhrel Y. , Satoh Y. , Kim H. , Ward P. J.
Published: June 2017

Water scarcity is rapidly increasing in many regions. In a novel, multi-model assessment, we examine how human interventions (HI: land use and land cover change, man-made reservoirs and human water use) affected monthly river water availability and water scarcity over the period 1971–2010. Here we show that HI drastically change the critical dimensions of water scarcity, aggravating water scarcity for 8.8% (7.4–16.5%) of the global population but alleviating it for another 8.3% (6.4–15.8%). Positive impacts of HI mostly occur upstream, whereas HI aggravate water scarcity downstream; HI cause water scarcity to travel downstream. Attribution of water scarcity changes to HI components is complex and varies among the hydrological models. Seasonal variation in impacts and dominant HI components is also substantial. A thorough consideration of the spatially and temporally varying interactions among HI components and of uncertainties is therefore crucial for the success of water scarcity adaptation by HI.
Tidal dynamics and mangrove carbon sequestration during the Oligo–Miocene in the South China Sea
Authors: Collins Daniel S. , Avdis Alexandros , Allison Peter A. , Johnson Howard D. , Hill Jon , Piggott Matthew D. , Hassan Meor H. Amir , Damit Abdul Razak
Published: June 2017

Modern mangroves are among the most carbon-rich biomes on Earth, but their long-term (≥106 years) impact on the global carbon cycle is unknown. The extent, productivity and preservation of mangroves are controlled by the interplay of tectonics, global sea level and sedimentation, including tide, wave and fluvial processes. The impact of these processes on mangrove-bearing successions in the Oligo–Miocene of the South China Sea (SCS) is evaluated herein. Palaeogeographic reconstructions, palaeotidal modelling and facies analysis suggest that elevated tidal range and bed shear stress optimized mangrove development along tide-influenced tropical coastlines. Preservation of mangrove organic carbon (OC) was promoted by high tectonic subsidence and fluvial sediment supply. Lithospheric storage of OC in peripheral SCS basins potentially exceeded 4,000 Gt (equivalent to 2,000 p.p.m. of atmospheric CO2). These results highlight the crucial impact of tectonic and oceanographic processes on mangrove OC sequestration within the global carbon cycle on geological timescales.
Terahertz saturable absorbers from liquid phase exfoliation of graphite
Authors: Bianchi Vezio , Carey Tian , Viti Leonardo , Li Lianhe , Linfield Edmund H. , Davies A. Giles , Tredicucci Alessandro , Yoon Duhee , Karagiannidis Panagiotis G. , Lombardi Lucia , Tomarchio Flavia , Ferrari Andrea C. , Torrisi Felice , Vitiello Miriam S.
Published: June 2017

Saturable absorbers (SA) operating at terahertz (THz) frequencies can open new frontiers in the development of passively mode-locked THz micro-sources. Here we report the fabrication of THz SAs by transfer coating and inkjet printing single and few-layer graphene films prepared by liquid phase exfoliation of graphite. Open-aperture z-scan measurements with a 3.5 THz quantum cascade laser show a transparency modulation ∼80%, almost one order of magnitude larger than that reported to date at THz frequencies. Fourier-transform infrared spectroscopy provides evidence of intraband-controlled absorption bleaching. These results pave the way to the integration of graphene-based SA with electrically pumped THz semiconductor micro-sources, with prospects for applications where excitation of specific transitions on short time scales is essential, such as time-of-flight tomography, coherent manipulation of quantum systems, time-resolved spectroscopy of gases, complex molecules and cold samples and ultra-high speed communications, providing unprecedented compactness and resolution.
Cryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification
Authors: Kugel Susann , Baunach Martin , Baer Philipp , Ishida-Ito Mie , Sundaram Srividhya , Xu Zhongli , Groll Michael , Hertweck Christian
Published: June 2017

Terpenoid natural products comprise a wide range of molecular architectures that typically result from C–C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report thein vitroreconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis. The crystal structure of XiaF with bound FADH2(at 2.4 Å resolution) and phylogenetic analyses reveal that XiaF is, surprisingly, most closely related to xenobiotic-degrading enzymes. Biotransformation assays show that XiaF is a designated indole hydroxylase that can be used for the production of indigo and indirubin. We unveil a cryptic hydroxylation step that sets the basis for terpenoid cyclization and suggest that the cyclase has evolved from xenobiotics detoxification enzymes.
The genomic landscape of tuberous sclerosis complex
Authors: Martin Katie R. , Zhou Wanding , Bowman Megan J. , Shih Juliann , Au Kit Sing , Dittenhafer-Reed Kristin E. , Sisson Kellie A. , Koeman Julie , Weisenberger Daniel J. , Cottingham Sandra L. , DeRoos Steven T. , Devinsky Orrin , Winn Mary E. , Cherniack Andrew D. , Shen Hui , Northrup Hope , Krueger Darcy A. , MacKeigan Jeffrey P.
Published: June 2017

Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. Here, we present the genomic landscape of TSC hamartomas. We determine that TSC lesions contain a low somatic mutational burden relative to carcinomas, a subset feature large-scale chromosomal aberrations, and highly conserved molecular signatures for each type exist. Analysis of the molecular signatures coupled with computational approaches reveals unique aspects of cellular heterogeneity and cell origin. Using immune data sets, we identify significant neuroinflammation in TSC-associated brain tumours. Taken together, this molecular catalogue of TSC serves as a resource into the origin of these hamartomas and provides a framework that unifies genomic and transcriptomic dimensions for complex tumours.
Insufficient antibody validation challenges oestrogen receptor beta research
Authors: Andersson Sandra , Sundberg Mårten , Pristovsek Nusa , Ibrahim Ahmed , Jonsson Philip , Katona Borbala , Clausson Carl-Magnus , Zieba Agata , Ramström Margareta , Söderberg Ola , Williams Cecilia , Asplund Anna
Published: June 2017

The discovery of oestrogen receptor β (ERβ/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ERα (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ERβ antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ERβ in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ERβ protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray.
Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway
Authors: Morizawa Yosuke M. , Hirayama Yuri , Ohno Nobuhiko , Shibata Shinsuke , Shigetomi Eiji , Sui Yang , Nabekura Junichi , Sato Koichi , Okajima Fumikazu , Takebayashi Hirohide , Okano Hideyuki , Koizumi Schuichi
Published: June 2017

Astrocytes become reactive following various brain insults; however, the functions of reactive astrocytes are poorly understood. Here, we show that reactive astrocytes function as phagocytes after transient ischemic injury and appear in a limited spatiotemporal pattern. Following transient brain ischemia, phagocytic astrocytes are observed within the ischemic penumbra region during the later stage of ischemia. However, phagocytic microglia are mainly observed within the ischemic core region during the earlier stage of ischemia. Phagocytic astrocytes upregulate ABCA1 and its pathway molecules, MEGF10 and GULP1, which are required for phagocytosis, and upregulation of ABCA1 alone is sufficient for enhancement of phagocytosis in vitro. Disrupting ABCA1 in reactive astrocytes result in fewer phagocytic inclusions after ischemia. Together, these findings suggest that astrocytes are transformed into a phagocytic phenotype as a result of increase in ABCA1 and its pathway molecules and contribute to remodeling of damaged tissues and penumbra networks.
MRI-derived diffusion parameters in the human optic nerve and its surrounding sheath during head-down tilt
Authors: Gerlach Darius A. , Marshall-Goebel Karina , Hasan Khader M. , Kramer Larry A. , Alperin Noam , Rittweger Joern
Published: June 2017

More than half of astronauts present with significant neuro-ophthalmic findings during 6-month missions onboard the International Space Station. Although the underlying cause of this Microgravity Ocular Syndrome is currently unknown, alterations in cerebrospinal fluid dynamics within the optic nerve sheath may play a role. In the presented study, diffusion tensor imaging was used to assess changes in diffusivity of the optic nerve and its surrounding sheath during head-down tilt, a ground-based model of microgravity. Nine healthy male subjects (mean age ± SD: 25 ± 2.4 years; mean body mass index ± SD: 24.1 ± 2.4 kg/m2) underwent 5 head-down tilt conditions: −6°,−12°, −18°,−12° and 1% CO2, and −12° and lower body negative pressure. Mean diffusivity, fractional anisotropy, axial diffusivity, radial diffusivity were quantified in the left and right optic nerves and surrounding sheaths at supine baseline and after 4.5 h head-down tilt for each condition. In the optic nerve sheath, mean diffusivity was increased with all head-down tilt conditions by (Best Linear Unbiased Predictors) 0.147 (SE: 0.04) × 10−3 mm2/s (P < 0.001), axial diffusivity by 0.188 (SE: 0.064) × 10−3 mm2/s (P < 0.001), and radial diffusivity by 0.126 (SE: 0.04) × 10−3 mm2/s (P = 0.0019). Within the optic nerve itself, fractional anisotropy was increased by 0.133 (SE: 0.047) (P = 0.0051) and axial diffusivity increased by 0.135 (SE: 0.08) × 10−3 mm2/s (P = 0.014) during head-down tilt, whilst mean diffusivity and radial diffusivity were unaffected (P > 0.3). These findings could be due to increased perioptic cerebral spinal fluid hydrodynamics during head-down tilt, as well as increased cerebral spinal fluid volume and movement within the optic nerve sheath.
Acute loss of the hepatic endo-lysosomal system in vivo causes compensatory changes in iron homeostasis
Authors: Metzendorf Christoph , Zeigerer Anja , Seifert Sarah , Sparla Richard , Najafi Bahar , Canonne-Hergaux François , Zerial Marino , Muckenthaler Martina U.
Published: June 2017

Liver cells communicate with the extracellular environment to take up nutrients via endocytosis. Iron uptake is essential for metabolic activities and cell homeostasis. Here, we investigated the role of the endocytic system for maintaining iron homeostasis. We specifically depleted the small GTPase Rab5 in the mouse liver, causing a transient loss of the entire endo-lysosomal system. Strikingly, endosome depletion led to a fast reduction of hepatic iron levels, which was preceded by an increased abundance of the iron exporter ferroportin. Compensatory changes in livers of Rab5-depleted mice include increased expression of transferrin receptor 1 as well as reduced expression of the iron-regulatory hormone hepcidin. Serum iron indices (serum iron, free iron binding capacity and total iron binding capacity) in Rab5-KD mice were increased, consistent with an elevated splenic and hepatic iron export. Our data emphasize the critical importance of the endosomal compartments in hepatocytes to maintain hepatic and systemic iron homeostasis in vivo. The short time period (between day four and five) upon which these changes occur underscore the fast dynamics of the liver iron pool.
Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains
Authors: Puž Vid , Pavšič Miha , Lenarčič Brigita , Djinović-Carugo Kristina
Published: June 2017

Myotilin is a component of the sarcomere where it plays an important role in organisation and maintenance of Z-disk integrity. This involves direct binding to F-actin and filamin C, a function mediated by its Ig domain pair. While the structures of these two individual domains are known, information about their relative orientation and flexibility remains limited. We set on to characterise the Ig domain pair of myotilin with emphasis on its molecular structure, dynamics and phylogeny. First, sequence conservation analysis of myotilin shed light on the molecular basis of myotilinopathies and revealed several motifs in Ig domains found also in I-band proteins. In particular, a highly conserved Glu344 mapping to Ig domain linker, was identified as a critical component of the inter-domain hinge mechanism. Next, SAXS and molecular dynamics revealed that Ig domain pair exists as a multi-conformation species with dynamic exchange between extended and compact orientations. Mutation of AKE motif to AAA further confirmed its impact on inter-domain flexibility. We hypothesise that the conformational plasticity of the Ig domain pair in its unbound form is part of the binding partner recognition mechanism.