Modest Loss Research Articles

Behaviour and neuropathology in mice injected with human contactin-associated protein 2 antibodies.

Serum antibodies that bind to the surface of neurons or glia are associated with a wide range of rare but treatable CNS diseases. In many, if not most instances, the serum levels are higher than CSF levels yet most of the reported attempts to reproduce the human disease in mice have used infusion of antibodies into the mouse cerebral ventricle(s) or intrathecal space. We used the intraperitoneal route and injected purified plasma IgG from either a CASPR2-antibody-positive patient (n = 10 mice) or healthy individual (n = 9 mice) daily for 8 days. Lipopolysaccharide was injected intraperitoneally on Day 3 to cause a temporary breach in the blood brain barrier. A wide range of baseline behaviours, including tests of locomotion, coordination, memory, anxiety and social interactions, were established before the injections and tested from Day 5 until Day 11. At termination, brain tissue was analysed for human IgG, CASPR2 and c-fos expression, lymphocyte infiltration, and neuronal, astrocytic and microglial markers. Mice exposed to CASPR2-IgG, compared with control-IgG injected mice, displayed reduced working memory during the continuous spontaneous alternation test with trends towards reduced short-term and long-term memories. In the open field tests, activities were not different from controls, but in the reciprocal social interaction test, CASPR2-IgG injected mice showed longer latency to start interacting, associated with more freezing behaviour and reduced non-social activities of rearing and grooming. At termination, neuropathology showed more IgG deposited in the brains of CASPR2-IgG injected mice, but a trend towards increased CASPR2 expression; these results were mirrored in short-term in vitro experiments where CASPR2-IgG binding to hippocampal neurons and to CASPR2-transfected HEK cells led to some internalization of the IgG, but with a trend towards higher surface CASPR2 expression. Despite these limited results, in the CASPR2-IgG injected mouse brains there was increased c-fos expression in the piriform-entorhinal cortex and hypothalamus, and a modest loss of Purkinje cells. There was also increased microglia density, morphological changes in both microglia and astrocytes and raised complement C3 expression on astrocytes, all consistent with glial activation. Patients with CASPR2 antibodies can present with a range of clinical features reflecting central, autonomic and peripheral dysfunction. Although the behavioural changes in mice were limited to social interactions and mild working-memory defects, the neuropathological features indicate potentially widespread effects of the antibodies on different brain regions.

Chlorine and lithium behavior in metasedimentary rocks during prograde metamorphism: A comparative study of exhumed subduction complexes (Catalina Schist and Schistes Lustrés)

Lithium and chlorine concentrations and isotopic compositions of well-characterized metasedimentary suites from the Schistes Lustrés and Lago di Cignana (Western Alps) and the Catalina Schist (southern California, USA) were compared to determine Li and Cl behavior during prograde subduction-zone metamorphism. New data were obtained for Cl from both suites and for Li from the Western Alps. The Catalina Schist contains lawsonite-albite to amphibolite grade rocks recording peak temperatures of 200 to 750 °C and depths of 15 to 45 km, with the higher-grade units representing relatively warm subduction P-T paths. Bulk Cl concentrations decrease from ~100–500 μg/g to ~10–25 μg/g across metamorphic grades, largely due to Cl loss from chlorite and white mica, with most of this loss occurring at the lower grades. This loss mirrors the previously documented decreases in N, B, Cs, As, and Sb concentrations, with relatively little loss at higher metamorphic grade, and contrasts with the behavior of Li showing only modest loss and change in δ7Li values across all grades. Metapelitic rocks from the Western Alps representing a relatively “cool” geothermal gradient of ~8 °C/km, record peak temperatures of 350 to 550 °C and depths of up to 90 km. In this suite, both Cl and Li concentrations are uniform across grade, showing no obvious change in concentration. Lithium concentrations range to somewhat higher values compared to those previously measured in the Catalina Schist. Chlorine isotope compositions of the Schistes Lustrés overlap with those measured in the Catalina Schist, whereas Li isotope compositions of the Schistes Lustrés samples range to somewhat higher values than those from the Catalina Schist. Both suites show significant isotopic heterogeneity within single metamorphic grades and no systematic change in δ37Cl or δ7Li values with increasing grade. These heterogeneities are interpreted to be inherited from the protolith. Lithium isotope compositions correlate well with the chemical index of alteration (CIA), an observation also supporting minimal metamorphic alteration of the isotopic composition reflecting the protolith. These data demonstrate that, although some Cl is retained to great depths during subduction, most Cl is lost from metasedimentary rocks at shallow depths, similar behavior to that of B, Cs, As, and Sb. In contrast, Li loss is minimal across the full range of grade, more similar in behavior to Rb, Ba, and K.

Use of Zirconium Phosphate-Sulphate as Acid Catalyst for Synthesis of Glycerol-Based Fuel Additives

In the present work, zirconium phosphates and mixed zirconium phosphate–sulphate acid catalysts have been investigated in the acetylation of glycerol in order to obtain acetins as fuel additives. The following catalysts with chemical composition, Zr3(PO4)4, Zr(SO4)2, Zr2(PO4)2SO4, Zr3(PO4)2(SO4)3 and Zr4(PO4)2(SO4)5 have been prepared and characterized by acid capacity measurements, BET, XRD, FT-IR, XPS. The surface chemical composition in terms of P/Zr and S/Zr atomic ratios was monitored in the fresh and used catalysts. Zr3(PO4)2(SO4)3 and Zr4(PO4)2(SO4)5 showed the highest acidity associated with the synergic effect of two main crystalline phases, Zr2(PO4)2SO4 and Zr(SO4)2·4H2O. The reactions of glycerol acetylation were carried out by using a mass ratio of catalyst/glycerol equal to 5 wt% and molar ratio acetic acid/glycerol equal to 3:1. The glycerol conversion versus time was investigated over all the prepared samples in order to identify the best performing catalysts. Over Zr3(PO4)2(SO4)3 and Zr4(PO4)2(SO4)5 full glycerol conversion was achieved in 1 h only. Slightly lower conversion values were registered for Zr3(PO4)4 and Zr2(PO4)2SO4, while Zr(SO4)2 was the worst catalyst. Zr4(PO4)2(SO4)5 was the most selective catalyst and was used for recycling experiments up to five cycles. Despite a modest loss of activity, a drastic decrease of selectivity to tri- and diacetin was observed already after the first cycle. This finding was attributed to the leaching of sulphate groups as detected by XPS analysis of the spent catalyst.

Outcome Analysis of Pediatric Pyeloplasty in Varied Presentation in Developing Countries

Objectives: The objective was to study the various presentations of pelviureteric junction (PUJ) obstruction in developing countries and its outcomes. Materials and Methods: We retrospectively reviewed the medical records of 239 children (260 renal units) who underwent surgery for PUJ obstruction between January 1994 and December 2016. Data on the patients presenting with symptoms and preoperative imaging findings of ultrasonography, intravenous urography, or diuretic renography were analyzed. Results: In all cases, we preferred dismembered Anderson-Hynes pyeloplasty with or without JJ stenting. Complications of pyeloplasty included prolonged urine leakage in 13 patients, of whom 4 responded to conservative management, 5 required percutaneous nephrostomy (PCN), and 4 were treated with endoscopic JJ stenting. Six patients had persistent obstruction: two responded to endopyelotomy, and in four, redo pyeloplasty was successful. Five patients with renal function of <10% were initially treated with PCN and ultimately required nephrectomy. Conclusions: In patients born with PUJ obstruction and impaired renal function, pyeloplasty fails to significantly improve function, possibly because of cortical loss. However, in patients with antenatal PUJ obstruction managed expectantly, there is a small but significant risk of modest permanent loss of renal function.

Chemical weathering in subtropical basalt-derived laterites: A mass balance interpretation (Misiones, NE Argentina)

Subtropical laterites are partially found in the Argentinian province of Misiones, covering the Jurassic-Cretaceous Serra Geral flood basalts (known as Posadas Formation in Argentina). Two hypotheses have been proposed to explain the origin of these laterites. The autochthonous theory attributes the origin of these deposits to the chemical weathering of the underlying tholeiitic basalts. However, during the last decade, an allochthonous “tropical loess” model was proposed. Several mineralogical/geochemical characteristics of a lateritic profile (~2 m thick, 26°9′58″S–54°35′3″W) are analyzed in this paper in order to constrain the nature of weathering processes in this region and the provenance of the lateritic layer. The basaltic bedrock at the sampling site exhibits intergranular texture and is mainly composed of clinopyroxene, plagioclase and opaque minerals (likely titanomagnetite and ilmenite). Altered glass and apatite were also identified in lower proportions. The X-ray diffraction of the clay-size fraction shows prevailing kaolinite and hematite in the most altered samples, complemented by amorphous Fe-Al (hydr)oxides. Serra Geral basalts-normalized spidergrams and mass balance calculations confirmed almost complete losses of all major oxides (i.e., ~50 g of material was removed by weathering from each 100 g of the original basalt) and depletions of some trace elements (e.g., Sc, V, Sr, Cr, Ni, Rb and U) in the uppermost and intermediate layers of the lateritic profile, reflecting the weathering of feldspars, clinopyroxenes, volcanic glass and apatite. In contrast, some elements are enriched in the topmost and intermediate layers, due to intrinsic immobility during weathering (e.g., Zr, Hf, Ta, Th) or adsorption onto clays (e.g., Cs). Rare earth elements (REEs) are depleted in the top layers and enriched in the middle section of the profile. The preferential leaching of REEs from the uppermost levels during weathering and its accumulation in the middle section can be caused by a pH increase in this level, the decomposition of organic matter and the consequent precipitation of REEs which exhibit an affinity to form aqueous organic complexes, or the presence of Fe and Mn (hydr)oxides in the intermediate level. Weathering intensity was appraised by means of different alteration indices, which showed the extreme leaching endured by the basaltic bedrock. The index of lateritization (IOL), which ranges between 35 and 55, and the accompanying SAF ternary plot (SiO2-Al2O3-Fe2O3), indicate an increasing weathering trend towards the profiles' top, reflecting the modest loss of SiO2 (relative to Al2O3 and Fe2O3) during kaolinitization. The geochemical approach used to constrain the origin of the lateritic mantle that partially covers Misiones province, clearly relates the analyzed laterites to the underlying tholeiitic basalts, supporting the autochthonous origin theory.

Mid-infrared Optics Using Dielectrics with Refractive Indices Below Unity

Conventional transparent materials at optical frequencies have refractive index values (n) greater than unity -- most commonly between about 1 and 4. This paper explores optical phenomena made possible by using materials with refractive indices less than unity. We focus primarily on fused silica (SiO2), a polar dielectric with strong phonon resonances in the mid infrared that result in a spectral region in which n < 1 with modest optical loss. Using this ubiquitous easy-to-deposit material, we demonstrate infrared-frequency external reflection, frustrated external reflection, and direct coupling to surface plasmon polaritons from free space. Our work suggests that materials with refractive indices below unity can bring significant new functionality to optical devices.

Porous silicon-poly(ε-caprolactone) film composites: evaluation of drug release and degradation behavior

This work focuses on an evaluation of novel composites of porous silicon (pSi) with the biocompatible polymer ε-polycaprolactone (PCL) for drug delivery and tissue engineering applications. The degradation behavior of the composites in terms of their morphology along with the effect of pSi on polymer degradation was monitored. PSi particles loaded with the drug camptothecin (CPT) were physically embedded into PCL films formed from electrospun PCL fiber sheets. PSi/PCL composites revealed a release profile of CPT (monitored via fluorescence spectroscopy) in accordance with the Higuchi release model, with significantly lower burst release percentage compared to pSi microparticles alone. Degradation studies of the composites, using gravimetric analysis, differential scanning calorimetry (DSC), and field emission scanning electron microscopy (FESEM), carried out in phosphate-buffered saline (PBS) under simulated physiological conditions, indicated a modest mass loss (15%) over 5weeks due to pSi dissolution and minor polymer hydrolysis. DSC results showed that, relative to PCL-only controls, pSi suppressed crystallization of the polymer film during PBS exposure. This suppression affects the evolution of surface morphology during this exposure that, in turn, influences the degradation behavior of the polymer. The implications of the above properties of these composites as a possible therapeutic device are discussed.

Long-term monitoring of the ANTARES optical module efficiencies using ^{40}mathrm{{K}} decays in sea water

Cherenkov light induced by radioactive decay products is one of the major sources of background light for deep-sea neutrino telescopes such as ANTARES. These decays are at the same time a powerful calibration source. Using data collected by the ANTARES neutrino telescope from mid 2008 to 2017, the time evolution of the photon detection efficiency of optical modules is studied. A modest loss of only 20% in 9 years is observed. The relative time calibration between adjacent modules is derived as well.

Threaded Fastener Locking With Safety Wire and Cotter Pins

This paper presents test results and analyses of safety lock wire and cotter pins with castellated nuts used as locking features in threaded fasteners. These mechanical components are used to secure hardware in aerospace and other applications as well as to assess whether a fastener has been tampered with. Tests are performed on aerospace threaded fasteners. Locking moments up to safety lock wire and cotter pin failure are measured. Calculations of locking moment to failure are provided and compared to measured results. For fasteners with safety lock wire, the angle of turn with applied moment is measured and computed. For fasteners with cotter pins and castellated nuts, the angles of turn from clearances and applied moment are computed. Since both safety lock wire and cotter pin with castellated nut applications result in some angle of turn, analysis for loss of preload with angle of turn is developed. Calculations show modest loss in preload for typical angles of turn for long bolts, but a significant loss of preload is found for short bolts.

Pro-inflammatory cytokines attenuate glucose-stimulated insulin secretion from INS-1E insulinoma cells by restricting mitochondrial pyruvate oxidation capacity - Novel mechanistic insight from real-time analysis of oxidative phosphorylation.

Pro-inflammatory cytokines cause pancreatic beta cell failure during the development of type 2 diabetes. This beta cell failure associates with mitochondrial dysfunction, but the precise effects of cytokines on mitochondrial respiration remain unclear. To test the hypothesis that pro-inflammatory cytokines impair glucose-stimulated insulin secretion (GSIS) by inhibiting oxidative ATP synthesis, we probed insulin release and real-time mitochondrial respiration in rat INS-1E insulinoma cells that were exposed to a combination of 2 ng/mL interleukin-1-beta and 50 ng/mL interferon-gamma. We show that 24-h exposure to these cytokines dampens both glucose- and pyruvate-stimulated insulin secretion (P < 0.0001 and P < 0.05, respectively), but does not affect KCl-induced insulin release. Mirroring secretory defects, glucose- and pyruvate-stimulated mitochondrial respiration are lowered after cytokine exposure (P < 0.01). Further analysis confirms that cytokine-induced mitochondrial respiratory defects occur irrespective of whether fuel oxidation is coupled to, or uncoupled from, ATP synthesis. These observations demonstrate that pro-inflammatory cytokines attenuate GSIS by restricting mitochondrial pyruvate oxidation capacity. Interleukin-1-beta and interferon-gamma also increase mitochondrial superoxide levels (P < 0.05), which may reinforce the inhibition of pyruvate oxidation, and cause a modest (20%) but significant (P < 0.01) loss of INS-1E cells. Cytokine-induced INS-1E cell failure is insensitive to palmitoleate and linoleate, which is at odds with the cytoprotection offered by unsaturated fatty acids against harm caused by nutrient excess. Our data disclose a mitochondrial mechanism for cytokine-impaired GSIS in INS-1E cells, and suggest that inflammatory and nutrient-related beta cell failure emerge, at least partly, through distinct paths.

Reduced modeling of porous media convection in a minimal flow unit at large Rayleigh number

Direct numerical simulations (DNS) indicate that at large values of the Rayleigh number (Ra) convection in porous media self-organizes into narrowly-spaced columnar flows, with more complex spatiotemporal features being confined to boundary layers near the top and bottom walls. In this investigation of high-Ra porous media convection in a minimal flow unit, two reduced modeling strategies are proposed that exploit these specific flow characteristics. Both approaches utilize the idea of decomposition since the flow exhibits different dynamics in different regions of the domain: small-scale cellular motions generally are localized within the thermal and vorticity boundary layers near the upper and lower walls, while in the interior, the flow exhibits persistent large-scale structures and only a few low (horizontal) wavenumber Fourier modes are active. Accordingly, in the first strategy, the domain is decomposed into two near-wall regions and one interior region. Our results confirm that suppressing the interior high-wavenumber modes has negligible impact on the essential structural features and transport properties of the flow. In the second strategy, a hybrid reduced model is constructed by using Galerkin projection onto a fully a priori eigenbasis drawn from energy stability and upper bound theory, thereby extending the model reduction strategy developed by Chini et al. (2011) [45] to large Ra. The results indicate that the near-wall upper-bound eigenmodes can economically represent the small-scale rolls within the exquisitely-thin thermal boundary layers. Relative to DNS, the hybrid algorithm enables over an order-of-magnitude increase in computational efficiency with only a modest loss of accuracy.

Expansion planning of the North Sea offshore grid: Simulation of integrated governance constraints

The development of offshore transmission and wind power generation in the North Sea of Europe is advancing fast, but there are significant barriers to an integrated offshore grid in the region. This offshore grid is a multi-level, multi-actor system requiring a governance decision-making approach, but there is currently no proven governance framework for it, or for the expansion planning of the European power system in general. In addition, existing offshore expansion planning models do not endogenously include governance considerations, such as country vetoes to integrated lines. We develop a myopic Mixed-Integer Linear Programming model of offshore generation and transmission expansion planning to study the effect of integrated governance constraints. These constraints limit investments in integrated lines: non-conventional lines linking offshore wind farms to other countries or to other farms. Each constraint affects the system (including the main transmission corridors), transmission technologies and welfare distribution differently. We apply our model to a long-term case study of the 2030–2050 offshore expansion pathways using data from the e-Highway2050 project. Results confirm that the offshore grid is beneficial to society. Integrated governance constraints induce a modest loss of social welfare, but do not change significantly the existing welfare distribution asymmetry between countries and actor groups. They do strongly affect the interaction of line technologies and types (conventional or integrated), so the impact of the integrated governance constraints is more visible on the grid topology than on welfare levels and distribution. We highlight the need to consider technology and type interactions in expansion planning, especially between multiterminal HVDC and integrated transmission lines. Also, an offshore governance framework should address the use of multiterminal HVDC in a non-integrated grid, but this is a second-best option compared to an integrated grid.

Quantitative measurement of cartilage volume is possible using two-dimensional magnetic resonance imaging data sets

3D Magnetic resonance imaging (MRI) scans are generally used for quantitative cartilage measurements in knee osteoarthritis. However, a great deal of MRI data is from 2D scans, often thought to be unsuitable for quantitative cartilage assessment. The goal of our study was to demonstrate that mLACS, a modified version of the Local Area Cartilage Segmentation (LACS) method, could be used to measure cartilage volume on 2D MRI images. We studied 301 randomly selected subjects from the OA Biomarkers Consortium FNIH Study, a nested case-control study within the Osteoarthritis Initiative (OAI). The study comprised four subgroups based on radiographic and pain progression. We compared mLACS applied to 2D TSE scans to LACS on 3D DESS data. The Pearson's correlation coefficient was used to establish agreement between LACS and mLACS, standardized response means (SRMs) for responsiveness, and intra-class correlation coefficients (ICCs) to measure reader precision. Logistic regression in a case/control analysis was used to compare the clinical validity between the two methods. We found R2=0.76 for the correlation between LACS and mLACs. For LACS, the responsiveness was SRM=0.49 compared to 0.39 for mLACS. The odds ratios (OR) for the primary case/control analyses were 1.62 for LACS and 1.78 for mLACS. The intra and inter reader reproducibility values for mLACS were ICC=0.90 and 0.86, respectively. This study has demonstrated that a reproducible, responsive, and clinically valid quantitative measurement of cartilage volume can be made using 2D TSE scans with a modest loss of responsiveness compared to 3D scans.

Rapid Disinhibition by Adjustment of PV Intrinsic Excitability during Whisker Map Plasticity in Mouse S1.

Rapid plasticity of layer (L) 2/3 inhibitory circuits is an early step in sensory cortical map plasticity, but its cellular basis is unclear. We show that, in mice of either sex, 1 d whisker deprivation drives the rapid loss of L4-evoked feedforward inhibition and more modest loss of feedforward excitation in L2/3 pyramidal (PYR) cells, increasing the excitation-inhibition conductance ratio. Rapid disinhibition was due to reduced L4-evoked spiking by L2/3 parvalbumin (PV) interneurons, caused by reduced PV intrinsic excitability. This included elevated PV spike threshold, which is associated with an increase in low-threshold, voltage-activated delayed rectifier (presumed Kv1) and A-type potassium currents. Excitatory synaptic input and unitary inhibitory output of PV cells were unaffected. Functionally, the loss of feedforward inhibition and excitation was precisely coordinated in L2/3 PYR cells, so that peak feedforward synaptic depolarization remained stable. Thus, the rapid plasticity of PV intrinsic excitability offsets early weakening of excitatory circuits to homeostatically stabilize synaptic potentials in PYR cells of sensory cortex.SIGNIFICANCE STATEMENT Inhibitory circuits in cerebral cortex are highly plastic, but the cellular mechanisms and functional importance of this plasticity are incompletely understood. We show that brief (1 d) sensory deprivation rapidly weakens parvalbumin (PV) inhibitory circuits by reducing the intrinsic excitability of PV neurons. This involved a rapid increase in voltage-gated potassium conductances that control near-threshold spiking excitability. Functionally, the loss of PV-mediated feedforward inhibition in L2/3 pyramidal cells was precisely balanced with the separate loss of feedforward excitation, resulting in a net homeostatic stabilization of synaptic potentials. Thus, rapid plasticity of PV intrinsic excitability implements network-level homeostasis to stabilize synaptic potentials in sensory cortex.

Excess homocysteine upregulates the NRF2-antioxidant pathway in retinal Müller glial cells

This study evaluated the effects of elevated homocysteine (Hcy) on the oxidative stress response in retinal Müller glial cells. Elevated Hcy has been implicated in retinal diseases including glaucoma and optic neuropathy, which are characterized by retinal ganglion cell (RGC) loss. To understand the mechanisms of Hcy-induced RGC loss, in vitro and in vivo models have been utilized. In vitro isolated RGCs are quite sensitive to elevated Hcy levels, while in vivo murine models of hyperhomocysteinemia (HHcy) demonstrate a more modest RGC loss (∼20%) over a period of many months. This differential response to Hcy between isolated cells and the intact retina suggests that the retinal milieu invokes mechanisms that buffer excess Hcy. Oxidative stress has been implicated as a mechanism of Hcy-induced neuron loss and NRF2 is a transcription factor that plays a major role in regulating cytoprotective responses to oxidative stress. In the present study we investigated whether HHcy upregulates NRF2-mediated stress responses in Müller cells, the chief retinal glial cell responsible for providing trophic support to retinal neurons. Primary Müller cells were exposed to L-Hcy-thiolactone [50μM–10mM] and assessed for viability, reactive oxygen species (ROS), and glutathione (GSH) levels. Gene/protein levels of Nrf2 and levels of NRF2-regulated antioxidants (NQO1, CAT, SOD2, HMOX1, GPX1) were assessed in Hcy-exposed Müller cells. Unlike isolated RGCs, isolated Müller cells are viable over a wide range of Hcy concentrations [50 μM – 1 mM]. Moreover, when exposed to elevated Hcy, Müller cells demonstrate decreased oxidative stress and decreased ROS levels. GSH levels increased by ∼20% within 24 h exposure to Hcy. Molecular analyses revealed 2-fold increase in Nrf2 expression. Expression of antioxidant genes Nqo1, Cat, Sod2, Hmox1, Gpx1 increased significantly. The consequences of Hcy exposure were evaluated also in Müller cells harvested from Nrf2−/− mice. In contrast to WT Müller cells, in which oxidative stress decreased upon exposure to Hcy, the Nrf2−/− Müller cells showed a significant increase in oxidative stress. Our data suggest that at least during early stages of Hhcy, a cytoprotective response may be in place, mediated in part by NRF2 in Müller cells.

Loss in working years after a breast cancer diagnosis

Background:Breast cancer can negatively influence working life, but it is unclear how many working years women with breast cancer can expect to lose.Methods:Women diagnosed with breast cancer between 1997 and 2012 were identified in the Breast Cancer Data Base Sweden (N=19 661), together with breast cancer-free comparison women (N=81 303). Using flexible parametric survival modelling, the loss in working years was calculated as the difference in the remaining years in the work force between women with and without breast cancer.Results:Women aged 50 years at diagnosis with stage I disease lost on average 0.5 years (95% CI, 0.2–0.7) of their remaining working time; the corresponding estimates were 0.9 years (0.5–1.2) in stage II, 2.5 years (1.9–3.1) in stage III and 8.1 years (6.5–9.7) in stage IV. Women with in situ breast cancer did not lose any working years. The strongest treatment determinant was axillary lymph node dissection.Conclusions:We found a loss in working years not only in late but also in early-stage breast cancer. Although it is reassuring that some groups had no or only a modest work loss, the economic consequences for society are considerable given the large number of women annually diagnosed with breast cancer.

Unravelling the Carbohydrate-Binding Preferences of the Carbohydrate-Binding Modules of AMP-Activated Protein Kinase.

The β subunit of adenosine monophosphate (AMP)-activated protein kinase (AMPK), which exists as two isoforms (β1 and β2) in humans, has a carbohydrate-binding module (CBM) that interacts with glycogen. Although the β1- and β2-CBMs are structurally similar, with strictly conserved ligand-contact residues, they show different carbohydrate affinities. β2-CBM shows the strongest affinity for both branched and unbranched oligosaccharides and it has recently been shown that a Thr insertion into β2-CBM (Thr101) forms a pocket to accommodate branches. This insertion does not explain why β2-CBM binds all carbohydrates with stronger affinity. Herein, it is shown that residue 134 (Val for β2 and Thr for β1), which does not come into contact with a carbohydrate, appears to account for the affinity difference. Characterisation by NMR spectroscopy, however, suggests that mutant β2-Thr101Δ/Val134Thr differs from that of β1-CBM, and mutant β1-Thr101ins/Thr134Val differs from that of β2-CBM. Furthermore, these mutants are less stable to chemical denaturation, relative to that of wild-type β-CBMs, which confounds the affinity analyses. To support the importance of Thr101 and Val134, the ancestral CBM has been constructed. This CBM retains Thr101 and Val134, which suggests that the extant β1-CBM has a modest loss of function in carbohydrate binding. Because the ancestor bound carbohydrate with equal affinity to that of β2-CBM, it is concluded that residue 134 plays an indirect role in carbohydrate binding.

One for my baby (and one more for the road): incentives, default waterfalls and central counterparty skin-in-the-game

In this paper, we argue that both for-profit central counterparties (CCPs) and their clearing members should contribute to the default waterfall, with a CCP’s two contributions coming directly before and directly after the tranche of clearing member contributions. This arrangement encourages the CCP and its clearing members to follow through on their responsibilities while balancing the interests of the CCP, its clearing members and the public. We argue that, in addition to affecting the incentives of a CCP’s shareholders, the inclusion of CCP capital in the default waterfall affects the incentives of its clearing members, as do the CCP contribution’s place- ment and size. CCPs and their regulators should determine the appropriate size of a CCP’s waterfall contributions, taking into account the problems that could arise from contributions that are too small or too large. We conclude with a brief examination of default waterfalls at mutualized CCPs, arguing that, in most cases, they do not need a CCP capital contribution to align incentives, though it could still serve to reduce the inconvenience of replenishing a waterfall contribution after a modest default loss

Prdm13 is required for Ebf3+ amacrine cell formation in the retina

Amacrine interneurons play a critical role in the processing of visual signals within the retina. They are highly diverse, representing 30 or more distinct subtypes. Little is known about how amacrine subtypes acquire their unique gene expression and morphological features. We characterized the gene expression pattern of the zinc-finger transcription factor Prdm13 in the mouse. Consistent with a developmental role, Prdm13 was expressed by Ptf1a+ amacrine and horizontal precursors. Over time, Prdm13 expression diverged from the transiently expressed Ptf1a and marked just a subset of amacrine cells in the adult retina. While heterogeneous, we show that most of these Prdm13+ amacrine cells express the transcription factor Ebf3 and the calcium binding protein calretinin. Loss of Prdm13 did not affect the number of amacrine cells formed during development. However, we observed a modest loss of amacrine cells and increased apoptosis that correlated with the onset timing of Ebf3 expression. Adult Prdm13 loss-of-function mice had 25% fewer amacrine cells, altered calretinin expression, and a lack of Ebf3+ amacrines. Forcing Prdm13 expression in retinal progenitor cells did not significantly increase amacrine cell formation, Ebf3 or calretinin expression, and appeared detrimental to the survival of photoreceptors. Our data show that Prdm13 is not required for amacrine fate as a class, but is essential for the formation of Ebf3+ amacrine cell subtypes. Rather than driving subtype identity, Prdm13 may act by restricting competing fate programs to maintain identity and survival.

Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced by Nigrostriatal \u03b1-Synuclein Overexpression

Subthalamic nucleus deep brain stimulation (STN DBS) protects dopaminergic neurons of the substantia nigra pars compacta (SNpc) against 6-OHDA and MPTP. We evaluated STN DBS in a parkinsonian model that displays α-synuclein pathology using unilateral, intranigral injections of recombinant adeno-associated virus pseudotype 2/5 to overexpress wildtype human α-synuclein (rAAV2/5 α-syn). A low titer of rAAV2/5 α-syn results in progressive forelimb asymmetry, loss of striatal dopaminergic terminal density and modest loss of SNpc dopamine neurons after eight weeks, corresponding to robust human-Snca expression and no effect on rat-Snca, Th, Bdnf or Trk2. α-syn overexpression increased phosphorylation of ribosomal protein S6 (p-rpS6) in SNpc neurons, a readout of trkB activation. Rats received intranigral injections of rAAV2/5 α-syn and three weeks later received four weeks of STN DBS or electrode implantation that remained inactive. STN DBS did not protect against α-syn-mediated deficits in forelimb akinesia, striatal denervation or loss of SNpc neuron, nor did STN DBS elevate p-rpS6 levels further. ON stimulation, forelimb asymmetry was exacerbated, indicating α-syn overexpression-mediated neurotransmission deficits. These results demonstrate that STN DBS does not protect the nigrostriatal system against α-syn overexpression-mediated toxicity. Whether STN DBS can be protective in other models of synucleinopathy is unknown.