Peri-nuclear Clustering of Mitochondria is Triggered during Aluminum Maltolate Induced Apoptosis

Synapse loss and neuronal death are key features of Alzheimer’s disease pathology. Disrupted axonal transport of mitochondria is a potential mechanism that could contribute to both. As the major producer of ATP in the cell, transport of mitochondria to the synapse is required for synapse maintenance. However, mitochondria also play an important role in the regulation of apoptosis. Investigation of aluminum (Al) maltolate induced apoptosis in human NT2 cells led us to explore the relationship between apoptosis related changes and the disruption of mitochondrial transport. Similar to that observed with tau over expression, NT2 cells exhibit peri-nuclear clustering of mitochondria following treatment with Al maltolate. Neuritic processes largely lacked mitochondria, except in axonal swellings. Similar, but more rapid results were observed following staurosporine administration, indicating that the clustering effect was not specific to Al maltolate. Organelle clustering and transport disruption preceded apoptosis. Incubation with the caspase inhibitor zVAD-FMK effectively blocked apoptosis, however failed to prevent organelle clustering. Thus, transport disruption is associated with the initiation, but not necessarily the completion of apoptosis. These results, together with observed transport defects and apoptosis related changes in Alzheimer disease brain suggest that mitochondrial transport disruption may play a significant role in synapse loss and thus the pathogenesis or Alzheimer’s disease

Hybrid Organic-Inorganic Coordination Complexes as Tunable Optical Response Materials.

Novel lead and bismuth dipyrido complexes have been synthesized and characterized by single-crystal X-ray diffraction, which shows their structures to be directed by highly oriented π-stacking of planar fully conjugated organic ligands. Optical band gaps are influenced by the identity of both the organic and inorganic component. Density functional theory calculations show optical excitation leads to exciton separation between inorganic and organic components. Using UV-vis, photoluminescence, and X-ray photoemission spectroscopies, we have determined the materials' frontier energy levels and show their suitability for photovoltaic device fabrication by use of electron- and hole-transport materials such as TiO2 and spiro-OMeTAD respectively. Such organic/inorganic hybrid materials promise greater electronic tunability than the inflexible methylammonium lead iodide structure through variation of both the metal and organic components

Choice of activity-intensity classification thresholds impacts upon accelerometer-assessed physical activity-health relationships in children

It is unknown whether using different published thresholds (PTs) for classifying physical activity (PA) impacts upon activity-health relationships. This study explored whether relationships between PA (sedentary [SED], light PA [LPA], moderate PA [MPA], moderate-to-vigorous PA, vigorous PA [VPA]) and health markers differed in children when classified using three different PTs

Sex differences in basal hypothalamic anorectic and orexigenic gene expression and the effect of quantitative and qualitative food restriction

Abstract Background Research into energy balance and growth has infrequently considered genetic sex, yet there is sexual dimorphism for growth across the animal kingdom. We test the hypothesis that in the chicken, there is a sex difference in arcuate nucleus neuropeptide gene expression, since previous research indicates hypothalamic AGRP expression is correlated with growth potential and that males grow faster than females. Because growth has been heavily selected in some chicken lines, food restriction is necessary to improve reproductive performance and welfare, but this increases hunger. Dietary dilution has been proposed to ameliorate this undesirable effect. We aimed to distinguish the effects of gut fullness from nutritional feedback on hypothalamic gene expression and its interaction with sex. Methods Twelve-week-old male and female fast-growing chickens were either released from restriction and fed ad libitum or a restricted diet plus 15% w/w ispaghula husk, a non-nutritive bulking agent, for 2 days. A control group remained on quantitative restriction. Hypothalamic arcuate nucleus neuropeptides were measured using real-time PCR. To confirm observed sex differences, the experiment was repeated using only ad libitum and restricted fed fast-growing chickens and in a genetically distinct breed of ad libitum fed male and female chickens. Linear mixed models (Genstat 18) were used for statistical analysis with transformation where appropriate. Results There were pronounced sex differences: expression of the orexigenic genes AGRP (P < 0.001) and NPY (P < 0.002) was higher in males of the fast-growing strain. In genetically distinct chickens, males had higher AGRP mRNA (P = 0.002) expression than females, suggesting sex difference was not restricted to a fast-growing strain. AGRP (P < 0.001) expression was significantly decreased in ad libitum fed birds but was high and indistinguishable between birds on a quantitative versus qualitative restricted diet. Inversely, gene expression of the anorectic genes POMC and CART was significantly higher in ad libitum fed birds but no consistent sex differences were observed. Conclusion Expression of orexigenic peptides in the avian hypothalamus are significantly different between sexes. This could be useful starting point of investigating further if AGRP is an indicator of growth potential. Results also demonstrate that gut fill alone does not reduce orexigenic gene expression

Optical network physical layer parameter optimization for digital backpropagation using Gaussian processes

We present a novel methodology for optimizing fiber optic network performance by determining the ideal values for attenuation, nonlinearity, and dispersion parameters in terms of achieved signal-to-noise ratio (SNR) gain from digital backpropagation (DBP). Our approach uses Gaussian process regression, a probabilistic machine learning technique, to create a computationally efficient model for mapping these parameters to the resulting SNR after applying DBP. We then use simplicial homology global optimization to find the parameter values that yield maximum SNR for the Gaussian process model within a set of a priori bounds. This approach optimizes the parameters in terms of the DBP gain at the receiver. We demonstrate the effectiveness of our method through simulation and experimental testing, achieving optimal estimates of the dispersion, nonlinearity, and attenuation parameters. Our approach also highlights the limitations of traditional one-at-a-time grid search methods and emphasizes the interpretability of the technique. This methodology has broad applications in engineering and can be used to optimize performance in various systems beyond optical networks

Cdx ParaHox genes acquired distinct developmental roles after gene duplication in vertebrate evolution

BACKGROUND: The functional consequences of whole genome duplications in vertebrate evolution are not fully understood. It remains unclear, for instance, why paralogues were retained in some gene families but extensively lost in others. Cdx homeobox genes encode conserved transcription factors controlling posterior development across diverse bilaterians. These genes are part of the ParaHox gene cluster. Multiple Cdx copies were retained after genome duplication, raising questions about how functional divergence, overlap, and redundancy respectively contributed to their retention and evolutionary fate. RESULTS: We examined the degree of regulatory and functional overlap between the three vertebrate Cdx genes using single and triple morpholino knock-down in Xenopus tropicalis followed by RNA-seq. We found that one paralogue, Cdx4, has a much stronger effect on gene expression than the others, including a strong regulatory effect on FGF and Wnt genes. Functional annotation revealed distinct and overlapping roles and subtly different temporal windows of action for each gene. The data also reveal a colinear-like effect of Cdx genes on Hox genes, with repression of Hox paralogy groups 1 and 2, and activation increasing from Hox group 5 to 11. We also highlight cases in which duplicated genes regulate distinct paralogous targets revealing pathway elaboration after whole genome duplication. CONCLUSIONS: Despite shared core pathways, Cdx paralogues have acquired distinct regulatory roles during development. This implies that the degree of functional overlap between paralogues is relatively low and that gene expression pattern alone should be used with caution when investigating the functional evolution of duplicated genes. We therefore suggest that developmental programmes were extensively rewired after whole genome duplication in the early evolution of vertebrates

Digital backpropagation accounting for polarization-mode dispersion

. Digital backpropagation (DBP) is a promising digital-domain technique to mitigate Kerr-induced nonlinear interference. While it successfully removes deterministic signal-signal interactions, the performance of ideal DBP is limited by stochastic effects, such as polarizationmode dispersion (PMD). In this paper, we consider an ideal full-field DBP implementation and modify it to additionally account for PMD; reversing the PMD effects in the backward propagation by passing the reverse propagated signal also through PMD sections, which concatenated equal the inverse of the PMD in the forward propagation. These PMD sections are calculated analytically at the receiver based on the total accumulated PMD of the link estimated from channel equalizers. Numerical simulations show that, accounting for nonlinear polarization-related interactions in the modified DBP algorithm, additional signal-to-noise ratio gains of 1.1 dB are obtained for transmission over 1000 km.Swedish Research Council (VR) (2012-5280); UK Engineering and Physical Sciences Research Council (EPSRC) (EP/J017582/1, UNLOC)

UK best practice recommendations for children and young people &lt;18 years with pre‐stage 3 type 1 diabetes, on behalf of the British Society for Paediatric Endocrinology and Diabetes ( BSPED )

Screening for childhood type 1 diabetes (T1D) is increasing worldwide. Historically, screening has been undertaken through research programmes, but increasingly in the UK, children and young people are also being tested in clinical care. This identifies children before the onset of clinical disease through measurement of four islet autoantibodies (IAb): anti‐glutamic acid decarboxylase; anti‐insulin; anti‐IA2 tyrosine phosphatase; and anti‐zinc transporter‐8. Otherwise well individuals confirmed to have ≥2 IAb have early‐stage T1D, meaning that they are in the pre‐symptomatic phase of the disease. This is categorised into stages, where stage 1 indicates ≥2 IAb and normoglycaemia, and stage 2 the presence of ≥2 IAb and dysglycaemia. Stage 3 T1D indicates that the diagnostic threshold for T1D has been reached, which may occur with or without symptoms of diabetes. The goal of screening and monitoring programmes is to reduce the adverse clinical consequences of diabetic ketoacidosis at diagnosis and to identify children who may benefit from disease‐modifying therapies to delay or reverse progression to insulin requirement. Additional benefits include avoiding hospitalisation and preparation for the 'softer landing' into T1D. To seek these benefits, children should be monitored; yet many individuals decline follow‐up in a research context. We therefore describe a pathway suitable for children identified from both screening programmes and clinical care settings. The pathway consists of 5 themes (IAb confirmation, monitoring of individuals in early‐stage T1D, starting insulin, monitoring in single IAb positivity, and audit standards against which the pathway can be assessed during implementation)

Polarizable Anionic Sublattices Can Screen Molecular Dipoles in Noncentrosymmetric Inorganic-Organic Hybrids

We report the growth and photophysical characterization of two polar hybrid lead halide phases, methylenedianiline lead iodide and bromide, (MDA)Pb2I6 and (MDA)Pb2Br6, respectively. The phases crystallize in noncentrosymmetric space group Fdd2, which produces a highly oriented molecular dipole moment that gives rise to second harmonic generation (SHG) upon excitation at 1064 nm. While both compositions are isostructural, the size dependence of the SHG signal suggests that the bromide exhibits a stronger phase-matching response whereas the iodide exhibits a significantly weaker non-phase-matching signal. Similarly, fluorescence from (MDA)Pb2Br6 is observed around 630 nm below 75 K whereas only very weak luminescence from (MDA)Pb2I6 can be seen. We attribute the contrasting optical properties to differences in the character of the halide sublattice and postulate that the increased polarizability of the iodide ions acts to screen the local dipole moment, effectively reducing the local electric field in the crystals