Structural and functional underpinnings of precentral abnormalities in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons. Studies using various magnetic resonance imaging (MRI) analytical approaches have consistently identified significant precentral abnormalities in ALS, whereas their structural and functional underpinnings remain poorly understood. METHODS: Using cortical thickness, fractional anisotropy (FA), and effective connectivity, we performed a multimodal MRI study to examine the structural and functional alterations associated with precentral abnormalities in patients with ALS (n = 60) compared with healthy controls (n = 60). RESULTS: Cortical thickness analysis revealed significant cortical thinning in the right precentral gyrus (PCG), superior frontal gyrus, and superior temporal gyrus in patients with ALS. Tractwise white matter microstructure analyses revealed decreased FA in the tracts connected to the PCG cluster in patients with ALS involving the right corticospinal tract and the middle posterior body of the corpus callosum. Additionally, the cortical thickness of the PCG cluster was found to be positively correlated with FA of the tracts connected to the PCG cluster, suggesting that these two structural features are tightly coupled. Using spectral dynamic causal modelling, effective connectivity analysis among the three regions with cortical thinning revealed decreased self-inhibitory influence in the PCG cluster in patients with ALS, which might be an endophenotypic manifestation of an imbalance in inhibitory and excitatory neurotransmitters in this region. CONCLUSIONS: The present data shed new light on the structural and functional underpinnings of precentral abnormalities in ALS.

Precentral degeneration and cerebellar compensation in amyotrophic lateral sclerosis: A multimodal MRI analysis.

Amyotrophic lateral sclerosis (ALS) is a progressive and intractable neurodegenerative disease of human motor system characterized by progressive muscular weakness and atrophy. A considerable body of research has demonstrated significant structural and functional abnormalities of the primary motor cortex in patients with ALS. In contrast, much less attention has been paid to the abnormalities of cerebellum in this disease. Using multimodal magnetic resonance imagining data of 60 patients with ALS and 60 healthy controls, we examined changes in gray matter volume (GMV), white matter (WM) fractional anisotropy (FA), and functional connectivity (FC) in patients with ALS. Compared with healthy controls, patients with ALS showed decreased GMV in the left precentral gyrus and increased GMV in bilateral cerebellum, decreased FA in the left corticospinal tract and body of corpus callosum, and decreased FC in multiple brain regions, involving bilateral postcentral gyrus, precentral gyrus and cerebellum anterior lobe, among others. Meanwhile, we found significant intermodal correlations among GMV of left precentral gyrus, FA of altered WM tracts, and FC of left precentral gyrus, and that WM microstructural alterations seem to play important roles in mediating the relationship between GMV and FC of the precentral gyrus, as well as the relationship between GMVs of the precentral gyrus and cerebellum. These findings provided evidence for the precentral degeneration and cerebellar compensation in ALS, and the involvement of WM alterations in mediating the relationship between pathologies of the primary motor cortex and cerebellum, which may contribute to a better understanding of the pathophysiology of ALS.

Association rule mining of aircraft event causes based on the Apriori algorithm.

To reveal complex causes of aircraft events, this paper aims to mine association rules between the trigger probability and relative strength via a modified Apriori algorithm. Clustering is adopted for data preprocessing and TF-IDF value calculation. Causative item sets of aircraft events are obtained based on the accident causation 2-4 model and are coded to establish code indicators. By avoiding the use of statistical methodologies to resolve not-a-number (NaN) values for altering the interrelations among causes, an enhancement in the Apriori algorithm is proposed by considering frequent items. By extracting frequent patterns, in this paper, all the association rules that satisfy three perspectives (support, confidence and lift) are determined by constantly generating and pruning candidate item sets. A network graph is used to visualize the association rules between different unsafe events and all types of causes. Finally, 9835 representative pieces of data, including general unsafe events, general incidents and serious incidents from the Southwest Air Traffic Management Bureau, are selected for analysis. The results show that improper energy allocation, poor conflict resolution ability, inadequate onsite management duties, adoption of a luck mentality, and occurrence of controller oversight are highly correlated with general unsafe events, and failure to rectify incorrect recitation is notably correlated with general incidents, while inadequate manual promotion, lack of conflict judgement and insufficient safety management are strongly correlated with serious incidents. This study quantitatively reveals the potential patterns and characteristics of mutual interactions among various types of historical aircraft events and highlights directions for controllable prevention and prediction of aircraft events.

Classification of Reservoirs and Fluids in Tight Sandstone Based on the NMR Logging Technique-A Case Study of the Upper Paleozoic in the Ordos Basin.

The Upper Paleozoic strata in the Ordos Basin are dominated by tight sandstone gas reservoirs characterized by strong heterogeneity and widely distributed aquifers. Laterally, there is no evidently continuous distribution of water and gas, and longitudinally, the gas and aquifers are mostly in isolated intersections without uniform gas-water contact, rendering difficulties for effectively identifying the reservoir and fluid properties by using traditional mud logging technology. To solve these problems mentioned, the reservoirs were classified by integrating the T2 spectra of cores obtained through nuclear magnetic resonance (NMR) logging, regional geological characteristics, and gas test results. It is indicated in the result that the "three-division" method can reflect the type of storage space, and the structural movement and sedimentary thickness in the basin are primary factors for the formation of reservoirs of various types. The "nine-division" method is closely related to characteristics of "initial tightening and subsequent accumulation" of the basin and the gas test results, which can give insights into natural gas charging status in the tight sandstone samples, thereby effectively identifying fluid properties.

Location decision of low-altitude service station for transfer flight based on modified immune algorithm.

The location of Low-Altitude Flight Service Station (LAFSS) is a comprehensive decision work, and it is also a multi-objective optimization problem (MOOP) with constraints. As a swarm intelligence search algorithm for solving constrained MOOP, the Immune Algorithm (IA) retains the excellent characteristics of genetic algorithm. Using some characteristic information or knowledge of the problem selectively and purposefully, the degradation phenomenon in the optimization process can be suppressed and the global optimum can be achieved. However, due to the large range involved in the low-altitude transition flight, the geographical characteristics, economic level and service requirements among the candidate stations in the corridor are quite different, and the operational safety and service efficiency are interrelated and conflict with each other. And all objectives cannot be optimal. Therefore, this article proposes a Modified Immune Algorithm (MIA) with two-layer response to solve the constrained multi-objective location mathematical model of LAFSS. The first layer uses the demand track as the cell membrane positioning pattern recognition service response distance to trigger the innate immunity to achieve the basic requirements of security service coverage. In the second layer, the expansion and upgrading of adjacent candidate sites are compared to the pathogen's effector, and the adaptive immunity is directly or indirectly triggered again through the cloning, mutation and reproduction between candidate sites to realize the multi-objective equilibrium of the scheme. Taking 486,000 km2 of Sichuan Province as an example, MIA for LAFSS is simulated by the MATLAB platform. Based on the Spring open source application framework of Java platform, the cesiumjs map data is called through easyui, and the visualization of site selection scheme is presented with the terrain data of Map World as the background. The experimental results show that, compared with dynamic programming and ordinary immunization, the immune trigger mode of double response and the improved algorithm of operation parameter combination designed by the Taguchi experiment, the total economic cost of location selection is reduced by 26.4%, the service response time is reduced by 25%, the repeat coverage rate is reduced by 29.5% and the effective service area is increased by 17.5%. The security risk, service efficiency and location cost are balanced. The present work is to provide an effective location method for the layout number and location of local transfer flight service stations. For complex scenes with larger scale of low-altitude flight supply and demand and larger terrain changes in the region, the above research methods can be used to effectively split and reduce the dimension.

Marker reconstitution mutagenesis: a simple and efficient reverse genetic approach.

A novel reverse genetic approach termed 'marker reconstitution mutagenesis' was designed to generate mutational allelic series in genes of interest. This approach consists of two simple steps which utilize two selective markers. First, using one selective marker, a partial fragment of another selective marker gene is inserted adjacently to a gene of interest by homologous recombination. Second, random mutations are introduced precisely into the gene of interest, together with the reconstitution of the latter selective marker by homologous recombination. This approach was successfully tested for several genes in the fission yeast Schizosaccharomyces pombe. It circumvents the problems encountered with other methods and should be adaptable to any organism that incorporates exogenous DNA by homologous recombination.

Bqt2p is essential for initiating telomere clustering upon pheromone sensing in fission yeast.

The telomere bouquet, i.e., telomere clustering on the nuclear envelope (NE) during meiotic prophase, is thought to promote homologous chromosome pairing. Using a visual screen, we identified bqt2/im295, a mutant that disrupts telomere clustering in fission yeast. Bqt2p is required for linking telomeres to the meiotic spindle pole body (SPB) but not for attachment of telomeres or the SPB to the NE. Bqt2p is expressed upon pheromone sensing and colocalizes thereafter to Sad1p, an SPB protein. This localization only depends on Bqt1p, not on other identified proteins required for telomere clustering. Upon pheromone sensing, generation of Sad1p foci next to telomeres depends on Bqt2p. However, depletion of Bqt2p from the SPB is dispensable for dissolving the telomere bouquet at the end of meiotic prophase. Therefore, telomere bouquet formation requires Bqt2p as a linking component and is finely regulated during meiotic progression.

Association of Gyrification Pattern, White Matter Changes, and Phenotypic Profile in Patients With Parkinson Disease.

OBJECTIVE: To investigate the cortical gyrification changes as well as their relationships with white matter (WM) microstructural abnormalities in the akinetic-rigid (AR) and tremor-dominant (TD) subtypes of Parkinson disease (PD). METHODS: Sixty-four patients with the AR subtype, 26 patients with the TD subtype, and 56 healthy controls (HCs) were included in this study. High-resolution T1-weighted and diffusion-weighted images were acquired for each participant. We computed local gyrification index (LGI) and fractional anisotropy (FA) to identify the cortical gyrification and WM microstructural changes in the AR and TD subtypes. RESULTS: Compared with HCs, patients with the AR subtype showed decreased LGI in the precentral, postcentral, inferior and superior parietal, middle and superior frontal/temporal, anterior and posterior cingulate, orbitofrontal, supramarginal, precuneus, and some visual cortices, and decreased FA in the corticospinal tract, inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, forceps minor/major, and anterior thalamic radiation. Decreases in LGI and FA of the AR subtype were found to be tightly coupled. LGIs of the left inferior and middle frontal gyrus correlated with Mini-Mental State Examination and Hoehn & Yahr scores of patients with the AR subtype. Patients with the TD subtype showed no significant change in the LGI and FA compared with patients with the AR subtype and HCs. CONCLUSIONS: Our results suggest that cortical gyrification changes in PD are motor phenotype-specific and are possibly mediated by the microstructural abnormalities of the underlying WM tracts.

Fiber-specific white matter reductions in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons. Studies using metrics derived from the diffusion tensor model have documented decreased fractional anisotropy (FA) and increased mean diffusivity in the corticospinal tract (CST) and the corpus callosum (CC) in ALS. These studies, however, only focused on microstructural white matter (WM) changes, while the macrostructural alterations of WM tracts in ALS remain unknown. Moreover, studies conducted based on the diffusion tensor model cannot provide information related to specific fiber bundles and fail to clarify which biological characteristics are changing. Using a novel fixel-based analytical method that can characterize the fiber density (FD) and the fiber-bundle cross-section (FC), this study investigated both microstructural and macrostructural changes in the WM in a large cohort of patients with ALS (N = 60) compared with demographically matched healthy controls (N = 60). Compared with healthy controls, we found decreased FD, FC and fiber density and cross-section (FDC, a combined measure of the FD and FC) values in the bilateral CST and the middle posterior body of the CC in patients with ALS, suggesting not only microstructural but also macrostructural abnormalities in these fiber bundles. Additionally, we found that the mean FD and FDC values in the bilateral CST were positively correlated with the revised ALS Functional Rating Scale, indicating that these two indices may serve as potential markers for assessing the clinical severity of ALS. Thus, these findings provide initial evidence for the existence of microstructural and macrostructural abnormalities of the fiber bundles in ALS.

Two novel proteins, dos1 and dos2, interact with rik1 to regulate heterochromatic RNA interference and histone modification.

BACKGROUND: Chromosomal behavior during mitosis and meiosis depends in part on heterochromatic modifications such as histone H3 lysine-9 methylation (H3K9me). In fission yeast, the Heterochromatin Protein 1 homolog Swi6 recognizes H3K9me, silences transcription, and retains cohesin at pericentromeric repeats. Heterochromatin formation also depends on processing of transcripts derived from centromeric repeats by the RNAi machinery. The DDB1 homolog, Rik1, and histone methyltransferase, Clr4, act in a complex to promote H3K9me. However, the mechanism underlying this interaction is poorly understood. RESULTS: Using a cytological screen, we have identified two novel genes, dos1(+) and dos2(+), which are required for localization of Swi6. Deletion of either of these genes results in mitotic and meiotic chromosome missegregation, defects in mitotic centromeric cohesion and meiotic telomere clustering, and loss of heterochromatic silencing. Dos1 is predominantly located in the nucleus in a Dos2-dependent manner and directly interacts with Rik1. Each of these genes is required for the association of H3K9me with centromeric repeats, as well as for the production of small interfering RNAs. CONCLUSIONS: Dos1 and Dos2 are required for the formation of heterochromatin in fission yeast. We hypothesize that the physical interaction between Dos1 and Rik1 represents a role in regulating activity of the Rik1/Clr4 complex. Dos2 contributes to this role by regulating Dos1 localization. Our findings suggest a mechanism for recruitment of Clr4 in the RNAi-dependent heterochromatin pathway, in which Dos1 and Dos2 are essential.

The localization of the integral membrane protein Cps1p to the cell division site is dependent on the actomyosin ring and the septation-inducing network in Schizosaccharomyces pombe.

Schizosaccharomyces pombe cells divide by medial fission through the use of an actomyosin-based contractile ring. Constriction of the actomyosin ring is accompanied by the centripetal addition of new membranes and cell wall material. In this article, we characterize the mechanism responsible for the localization of Cps1p, a septum-synthesizing 1,3-beta-glucan synthase, to the division site during cytokinesis. We show that Cps1p is an integral membrane protein that localizes to the cell division site late in anaphase. Neither F-actin nor microtubules are essential for the initial assembly of Cps1p to the medial division site. F-actin, but not microtubules, is however important for the eventual incorporation of Cps1p into the actomyosin ring. Assembly of Cps1p into the cell division ring is also dependent on the septation-inducing network (SIN) proteins that regulate division septum formation after assembly of the actomyosin ring. Fluorescence-recovery after-photobleaching experiments reveal that Cps1p does not diffuse appreciably within the plasma membrane and is retained at the division site by a mechanism that does not depend on an intact F-actin cytoskeleton. We conclude that the actomyosin ring serves as a spatial cue for Cps1p localization, whereas the maintenance of Cps1p at the division site occurs by a novel F-actin- and microtubule-independent mechanism. Furthermore, we propose that the SIN proteins ensure localization of Cps1p at the appropriate point in the cell cycle.

The multiprotein exocyst complex is essential for cell separation in Schizosaccharomyces pombe.

Schizosaccharomyces pombe cells divide by medial fission through the use of an actomyosin-based contractile ring. A mulitlayered division septum is assembled in concert with ring constriction. Finally, cleavage of the inner layer of the division septum results in the liberation of daughter cells. Although numerous studies have focused on actomyosin ring and division septum assembly, little information is available on the mechanism of cell separation. Here we describe a mutant, sec8-1, that is defective in cell separation but not in other aspects of cytokinesis. sec8-1 mutants accumulate about 100-nm vesicles and have reduced secretion of acid phosphatase, suggesting that they are defective in exocytosis. Sec8p is a component of the exocyst complex. Using biochemical methods, we show that Sec8p physically interacts with other members of the exocyst complex, including Sec6p, Sec10p, and Exo70p. These exocyst proteins localize to regions of active exocytosis-at the growing ends of interphase cells and in the medial region of cells undergoing cytokinesis-in an F-actin-dependent and exocytosis-independent manner. Analysis of a number of mutations in various exocyst components has established that these components are essential for cell viability. Interestingly, all exocyst mutants analyzed appear to be able to elongate and to assemble division septa but are defective for cell separation. We therefore propose that the fission yeast exocyst is involved in targeting of enzymes responsible for septum cleavage. We further propose that cell elongation and division septum assembly can continue with minimal levels of exocyst function.

Rho3p regulates cell separation by modulating exocyst function in Schizosaccharomyces pombe.

Cytokinesis is the final stage of the cell division cycle in which the mother cell is physically divided into two daughters. In recent years the fission yeast Schizosaccharomyces pombe has emerged as an attractive model organism for the study of cytokinesis, since it divides using an actomyosin ring whose constriction is coordinated with the centripetal deposition of new membranes and a division septum. The final step of cytokinesis in S. pombe requires the digestion of the primary septum to liberate two daughters. We have previously shown that the multiprotein exocyst complex is essential for this process. Here we report the isolation of rho3(+), encoding a Rho family GTPase, as a high-copy suppressor of an exocyst mutant, sec8-1. Overproduction of Rho3p also suppressed the temperature-sensitive growth phenotype observed in cells lacking Exo70p, another conserved component of the S. pombe exocyst complex. Cells deleted for rho3 arrest at higher growth temperatures with two or more nuclei and uncleaved division septa between pairs of nuclei. rho3Delta cells accumulate approximately 100-nm vesicle-like structures. These phenotypes are all similar to those observed in exocyst component mutants, consistent with a role for Rho3p in modulation of exocyst function. Taken together, our results suggest the possibility that S. pombe Rho3p regulates cell separation by modulation of exocyst function.

Insight into actin organization and function in cytokinesis from analysis of fission yeast mutants.

Actin is a key cytoskeletal protein with multiple roles in cellular processes such as polarized growth, cytokinesis, endocytosis, and cell migration. Actin is present in all eukaryotes as highly dynamic filamentous structures, such as linear cables and branched filaments. Detailed investigation of the molecular role of actin in various processes has been hampered due to the multifunctionality of the protein and the lack of alleles defective in specific processes. The actin cytoskeleton of the fission yeast, Schizosaccharomyces pombe, has been extensively characterized and contains structures analogous to those in other cell types. In this study, primarily with the view to uncover actin function in cytokinesis, we generated a large bank of fission yeast actin mutants that affect the organization of distinct actin structures and/or discrete physiological functions of actin. Our screen identified 17 mutants with specific defects in cytokinesis. Some of these cytokinesis mutants helped in dissecting the function of specific actin structures during ring assembly. Further genetic analysis of some of these actin mutants revealed multiple genetic interactions with mutants previously known to affect the actomyosin ring assembly. We also characterize a mutant allele of actin that is suppressed upon overexpression of Cdc8p-tropomyosin, underscoring the utility of this mutant bank. Another 22 mutant alleles, defective in polarized growth and/or other functions of actin obtained from this screen, are also described in this article. This mutant bank should be a valuable resource to study the physiological and biochemical functions of actin.

Nonmedially assembled F-actin cables incorporate into the actomyosin ring in fission yeast.

In many eukaryotes, cytokinesis requires the assembly and constriction of an actomyosin-based contractile ring. Despite the central role of this ring in cytokinesis, the mechanism of F-actin assembly and accumulation in the ring is not fully understood. In this paper, we investigate the mechanism of F-actin assembly during cytokinesis in Schizosaccharomyces pombe using lifeact as a probe to monitor actin dynamics. Previous work has shown that F-actin in the actomyosin ring is assembled de novo at the division site. Surprisingly, we find that a significant fraction of F-actin in the ring was recruited from formin-Cdc12p nucleated long actin cables that were generated at multiple nonmedial locations and incorporated into the ring by a combination of myosin II and myosin V activities. Our results, together with findings in animal cells, suggest that de novo F-actin assembly at the division site and directed transport of F-actin cables assembled elsewhere can contribute to ring assembly.

IQGAP-related Rng2p organizes cortical nodes and ensures position of cell division in fission yeast.

Correct positioning of the cell division machinery is crucial for genomic stability and cell fate determination. The fission yeast Schizosaccharomyces pombe, like animal cells, divides using an actomyosin ring and is an attractive model to study eukaryotic cytokinesis. In S. pombe, positioning of the actomyosin ring depends on the anillin-related protein Mid1p. Mid1p arrives first at the medial cortex and recruits actomyosin ring components to node-like structures, although how this is achieved is unknown. Here we show that the IQGAP-related protein Rng2p, an essential component of the actomyosin ring, is a key element downstream of Mid1p. Rng2p physically interacts with Mid1p and is required for the organization of other actomyosin ring components into cortical nodes. Failure of localization of Rng2p to the nodes prevents medial retention of Mid1p and leads to actomyosin ring assembly in a node-independent manner at nonmedial locations. We conclude that Mid1p recruits Rng2p to cortical nodes at the division site and that Rng2p, in turn, recruits other components of the actomyosin ring to cortical nodes, thereby ensuring correct placement of the division site.

SIN-inhibitory phosphatase complex promotes Cdc11p dephosphorylation and propagates SIN asymmetry in fission yeast.

BACKGROUND: Cytokinesis in many eukaryotes involves the function of an actomyosin-based contractile ring. In fission yeast, actomyosin ring maturation and stability require a conserved signaling pathway termed the SIN (septation initiation network). The SIN consists of a GTPase (Spg1p) and three protein kinases, all of which localize to the mitotic spindle pole bodies (SPBs). Two of the SIN kinases, Cdc7p and Sid1p, localize asymmetrically to the newly duplicated SPB in late anaphase. How this asymmetry is achieved is not understood, although it is known that their symmetric localization impairs cytokinesis. RESULTS: Here we characterize a new Forkhead-domain-associated protein, Csc1p, and identify SIN-inhibitory PP2A complex (SIP), which is crucial for the establishment of SIN asymmetry. Csc1p localizes to both SPBs early in mitosis, is lost from the SPB that accumulates Cdc7p, and instead accumulates at the SPB lacking Cdc7p. Csc1p is required for the dephosphorylation of the SIN scaffolding protein Cdc11p and is thereby required for the recruitment of Byr4p, a component of the GTPase-activating subunit for Spg1p, to the SPB. CONCLUSIONS: Because Cdc7p does not bind to GDP-Spg1p, we propose that the SIP-mediated Cdc11p dephosphorylation and the resulting recruitment of Byr4p are among the earliest steps in the establishment of SIN asymmetry.