Deficient progranulin levels cause dose-dependent neurological syndromes: haploinsufficiency leads to frontotemporal lobar degeneration (FTLD) and nullizygosity produces adult-onset neuronal ceroid ...lipofuscinosis. Mechanisms controlling progranulin levels are largely unknown. To better understand progranulin regulation, we performed a genome-wide RNAi screen using an ELISA-based platform to discover genes that regulate progranulin levels in neurons. We identified 830 genes that raise or lower progranulin levels by at least 1.5-fold in Neuro2a cells. When inhibited by siRNA or some by submicromolar concentrations of small-molecule inhibitors, 33 genes of the druggable genome increased progranulin levels in mouse primary cortical neurons; several of these also raised progranulin levels in FTLD model mouse neurons. "Hit" genes regulated progranulin by transcriptional or posttranscriptional mechanisms. Pathway analysis revealed enrichment of hit genes from the autophagy-lysosome pathway (ALP), suggesting a key role for this pathway in regulating progranulin levels. Progranulin itself regulates lysosome function. We found progranulin deficiency in neurons increased autophagy and caused abnormally enlarged lysosomes and boosting progranulin levels restored autophagy and lysosome size to control levels. Our data link the ALP to neuronal progranulin: progranulin levels are regulated by autophagy and, in turn, progranulin regulates the ALP. Restoring progranulin levels by targeting genetic modifiers reversed FTLD functional deficits, opening up potential opportunities for future therapeutics development.
Progranulin regulates neuron and immune functions and is implicated in aging. Loss of one functional allele causes haploinsufficiency and leads to frontotemporal lobar degeneration (FTLD), the second leading cause of dementia. Progranulin gene polymorphisms are linked to Alzheimer's disease (AD) and complete loss of function causes neuronal ceroid lipofuscinosis. Despite the critical role of progranulin levels in neurodegenerative disease risk, almost nothing is known about their regulation. We performed an unbiased screen and identified specific pathways controlling progranulin levels in neurons. Modulation of these pathways restored levels in progranulin-deficient neurons and reversed FTLD phenotypes. We provide a new comprehensive understanding of the genetic regulation of progranulin levels and identify potential targets to treat FTLD and other neurodegenerative diseases, including AD.
Salt stress is a major abiotic factor that affects the growth and yield of crops. The present study was carried out to assess the salt tolerance among the Arka Samrat, Arka Rakshak, YVU-1, S-22, ...YVU-2, and PKM-OP tomato germplasms using principal component analysis (PCA). Different salt (NaCl) concentrations like control, 0.04 M, 0.12 M, and 0.20 M were selected in order to classify them into sensitive and tolerant tomato germplasms based on 13 parameters. A significant variation was observed among the selected tomato germplasms towards salinity tolerance at the seedling stage. Shoot length, root length, fresh weight, and dry weight parameters of the seedlings were decreased linearly with an increase in the external NaCl concentration. Salinization of plants has shown to reduce K
+
content and increase in the Na
+
accumulation, Ca
2+
, and Catalase activity. Salt stress also increased electrolyte leakage and reduced relative water content of all germplasms. The maximum parameters were less affected in Arka Rakshak and Arka Samrat compared to the remaining germplasms at higher salt stress. The PCA analysis of 13 morphological and physiological variables indicated that Arka Rakshak and Arka Samrat germplasms were salt-tolerant and PKM-OP was susceptible. Thus PCA analysis results are useful for the identification of resistance and sensitive germplasms at the seedling stage.
The detection efficiency of a broad-energy germanium detector was determined empirically and compared to predictions by the Monte-Carlo software GEANT4 and FLUKA . The considered source geometries ...were point-like, filter paper and a water beaker. Calculations were performed in the photon energy range of 30–1836 keV . Simulated detection efficiencies obtained from both Monte-Carlo software were found to be in a good agreement (typically <5%) with experimental results for the considered source geometries. A comparison between the detection efficiencies obtained with GEANT4 and FLUKA codes exhibited a good agreement with a robust average of approximately 1%.
Both the cadherin-catenin complex and Rho-family GTPases have been shown to regulate dendrite development. We show here a role for p120 catenin (p120ctn) in regulating spine and synapse formation in ...the developing mouse brain.
p120catenin gene deletion in hippocampal pyramidal neurons in vivo resulted in reduced spine and synapse densities along dendrites. In addition, p120 catenin loss resulted in reduced cadherin levels and misregulation of Rho-family GTPases, with decreased Rac1 and increased RhoA activity. Analyses in vitro indicate that the reduced spine density reflects aberrant Rho-family GTPase signaling, whereas the effects on spine maturation appear to result from reduced cadherin levels and possibly aberrant Rho-family GTPase signaling. Thus, p120ctn acts as a signal coordinator between cadherins and Rho-family GTPases to regulate cytoskeletal changes required during spine and synapse development.
We studied changes in the expression of growth‐associated protein 43 (GAP43), glial fibrillary acidic protein (GFAP), and calcium‐binding proteins (calbindin Cb and parvalbumin Pv) in the dorsal ...lateral geniculate nucleus (dLGN) of four capuchin monkeys with laser‐induced retinal lesions. The lesions were generated with the aid of a neodymium‐YAG dual‐frequency laser with shots of different intensity and at different survival time in each animal. The expression of these proteins in the layers of the dLGN was evaluated by performing histodensitometry of coronal sections throughout the nucleus. High‐power laser shots administered at the border of the optic disc (OD)‐injured fibers resulted in large scotomas. These lesions produced a devastating effect on fibers in this passage, resulting in large deafferentation of the dLGN. The time course of plasticity expressed in this nucleus varied with the degree of the retinal lesion. Topographically, corresponding portions of the dLGN were inferred by the extent of the ocular dominance column revealed by cytochrome oxidase histochemistry in flattened preparations of V1. In the region representing the retinal lesion, the expression of GFAP, GAP43, Pv, and Cb increased and decreased in the corresponding dLGN layers shortly after lesion induction and returned to their original values with different time courses. Synaptogenesis (indicated by GAP43 expression) appeared to be increased in all layers, while “cleansing” of the glial‐damaged region (indicated by GFAP expression) was markedly greater in the parvocellular layers, followed by the magnocellular layers.
Schematic drawings of optic discs laser lesions and of series of coronal sections of the dLGN, in three monkeys, depicting the areas of the nucleus deafferented by the lesions.
Schematic drawings of optic discs laser lesions and of series of coronal sections of the dLGN, in three monkeys, depicting the areas of the nucleus deafferented by the lesions.
A recent result of Zheng and Tse states that over a quasi-static channel, there exists a fundamental tradeoff, referred to as the diversity-multiplexing gain (D-MG) tradeoff, between the spatial ...multiplexing gain and the diversity gain that can be simultaneously achieved by a space-time (ST) code. This tradeoff is precisely known in the case of independent and identically distributed (i.i.d.) Rayleigh fading, for Tgesn t +n r -1 where T is the number of time slots over which coding takes place and n t ,n r are the number of transmit and receive antennas, respectively. For T<n t +n r -1, only upper and lower bounds on the D-MG tradeoff are available. In this paper, we present a complete solution to the problem of explicitly constructing D-MG optimal ST codes, i.e., codes that achieve the D-MG tradeoff for any number of receive antennas. We do this by showing that for the square minimum-delay case when T=n t =n, cyclic-division-algebra (CDA)-based ST codes having the nonvanishing determinant property are D-MG optimal. While constructions of such codes were previously known for restricted values of n, we provide here a construction for such codes that is valid for all n. For the rectangular, T>n t case, we present two general techniques for building D-MG-optimal rectangular ST codes from their square counterparts. A byproduct of our results establishes that the D-MG tradeoff for all Tgesn t is the same as that previously known to hold for Tgesn t +n r -1
In a recent paper, perfect ( n times n ) space-time codes were introduced as the class of linear dispersion space-time (ST) codes having full rate, nonvanishing determinant, a signal constellation ...isomorphic to either the rectangular or hexagonal lattices in 2 n 2 dimensions, and uniform average transmitted energy per antenna. Consequence of these conditions include optimality of perfect codes with respect to the Zheng-Tse diversity-multiplexing gain tradeoff (DMT), as well as excellent low signal-to-noise ratio (SNR) performance. Yet perfect space-time codes have been constructed only for two, three, four, and six transmit antennas. In this paper, we construct perfect codes for all channel dimensions, present some additional attributes of this class of ST codes, and extend the notion of a perfect code to the rectangular case.
We quantified the capacity for reorganization of the topographic representation of area V1 in adult monkeys. Bias-free automated mapping methods were used to delineate receptive fields (RFs) of an ...array of neuronal clusters prior to, and up to 6 h following retinal lesions. Monocular lesions caused a significant reorganization of the topographic map in this area, both inside and outside the cortical lesion projection zone (LPZ). Small flashed stimuli revealed responses up to 0.85 mm inside the boundaries of the LPZ, with RFs representing regions of undamaged retina immediately surrounding the lesion. In contrast, long moving bars that spanned the scotoma resulting from the lesion revealed responsive units up to 1.87 mm inside the LPZ, with RFs representing interpolated responses in this region. This reorganization is present immediately after monocular retinal lesioning. Both stimuli showed a similar and significant (5-fold) increase of the RF scatter in the LPZ, 0.56 mm (median), compared with the undamaged retina, 0.12 mm. Our results reveal an array of preexisting subthreshold functional connections of up to 2 mm in V1, which can be rapidly mobilized independently from the differential qualitative reorganization elicited by each stimulus.
Nine new two-dimensional Optical Orthogonal Codes (2-D OOCs) are presented here, all sharing the common feature of a code size that is much larger in relation to the number of time slots than those ...of constructions appearing previously in the literature. Each of these constructions is either optimal or asymptotically optimal with respect to either the original Johnson bound or else a nonbinary version of the Johnson bound introduced in this paper. The first five codes are constructed using polynomials over finite fields-the first construction is optimal while the remaining four are asymptotically optimal. The next two codes are constructed using rational functions in place of polynomials and these are asymptotically optimal. The last two codes, also asymptotically optimal, are constructed by composing two of the above codes with a constant weight binary code. Also presented is a three-dimensional Optical Orthogonal Code (3-D OOC) that exploits the polarization dimension. Finally, phase-encoded optical CDMA is considered and construction of two efficient codes are provided.
This study identifies the first lattice decoding solution that achieves, in the general outage-limited multiple-input multiple-output (MIMO) setting and in the high-rate and high-signal-to-noise ...ratio limit, both a vanishing gap to the error performance of the exact solution of regularized lattice decoding, as well as a computational complexity that is subexponential in the number of codeword bits and in the rate. The proposed solution employs Lenstra-Lenstra-Lovász-based lattice reduction (LR)-aided regularized (lattice) sphere decoding and proper timeout policies. These performance and complexity guarantees hold for most MIMO scenarios, most fading statistics, all channel dimensions, and all full-rate lattice codes. In sharp contrast to the aforementioned very manageable complexity, the complexity of other standard preprocessed lattice decoding solutions is revealed here to be extremely high. Specifically, this study has quantified the complexity of regularized lattice (sphere) decoding and has proved that the computational resources required by this decoder to achieve a good rate-reliability performance are exponential in the lattice dimensionality and in the number of codeword bits, and it in fact matches, in common scenarios, the complexity of ML-based sphere decoders. Through this sharp contrast, this study was able to, for the first time, rigorously demonstrate and quantify the pivotal role of LR as a special complexity reducing ingredient.
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