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A comparison of neuroanatomical features of the brain between humans and our evolutionary relatives, nonhuman primates, is key to understanding the human brain system and the neural basis of mental and neurological disorders. Although most comparative MRI studies of human and nonhuman primate brains have been based on brains of primates that had been used as subjects in experiments, it is essential to investigate various species of nonhuman primates in order to elucidate and interpret the diversity of neuroanatomy features among humans and nonhuman primates. To develop a research platform for this purpose, it is necessary to harmonize the scientific contributions of studies with the standards of animal ethics, animal welfare, and the conservation of brain information for long-term continuation of the field. In previous research, we first developed a gated data-repository of anatomical images obtained using 9.4-T ex vivo MRI of postmortem brain samples from 12 nonhuman primate species, and which are stored at the Japan Monkey Centre. In the present study, as a second phase, we released a collection of T2-weighted images and diffusion tensor images obtained in nine species: white-throated capuchin, Bolivian squirrel monkey, stump-tailed macaque, Tibet monkey, Sykes' monkey, Assamese macaque, pig-tailed macaque, crested macaque, and chimpanzee. Our image repository should facilitate scientific discoveries in the field of comparative neuroscience. This repository can also promote animal ethics and animal welfare in experiments with nonhuman primate models by optimizing methods for in vivo and ex vivo MRI scanning of brains and supporting veterinary neuroradiological education. In addition, the repository is expected to contribute to conservation, preserving information about the brains of various primates, including endangered species, in a permanent digital form., Competing Interests: Declaration of Competing Interest The authors have no affiliation with any organization with a direct or indirectfinancial interest in the subject matter discussed in the manuscript., (Copyright © 2023. Published by Elsevier Inc.)

The neonatal period is a critical window for the development of the human brain and may hold implications for the long-term development of cognition and disorders. Multi-modal connectome studies have revealed many important findings underlying the adult brain but related studies were rare in the early human brain. One potential challenge is the lack of an appropriate and unbiased parcellation that combines structural and functional information in this population. Using 348 multi-modal MRI datasets from the developing human connectome project, we found that the information fused from the structural, diffusion, and functional MRI was relatively stable across MRI features and showed high reproducibility at the group level. Therefore, we generated automated multi-resolution parcellations (300 - 500 parcels) based on the similarity across multi-modal features using a gradient-based parcellation algorithm. In addition, to acquire a parcellation with high interpretability, we provided a manually delineated parcellation (210 parcels), which was approximately symmetric, and the adjacent areas around each boundary were statistically different in terms of the integrated similarity metric and at least one kind of original features. Overall, the present study provided multi-resolution and neonate-specific parcellations of the cerebral cortex based on multi-modal MRI properties, which may facilitate future studies of the human connectome in the early development period., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

The infant brain undergoes drastic morphological and functional development during the first year of life. Three-dimensional T1-weighted Magnetic Resonance Imaging (3D T1w-MRI) is a major tool to characterize the brain anatomy, which however, manifests inherently low and rapidly changing contrast between white matter (WM) and gray matter (GM) in the infant brains (0-12 month-old). Despite the prior efforts made to maximize tissue contrast in the neonatal brains (≤1 months), optimization of imaging methods in the rest of the infancy (1-12 months) is not fully addressed, while brains in the latter period exhibit even more challenging contrast. Here, we performed a systematic investigation to improve the contrast between cortical GM and subcortical WM throughout the infancy. We first performed simultaneous T1 and proton density mapping in a normally developing infant cohort at 3T (n = 57). Based on the evolution of T1 relaxation times, we defined three age groups and simulated the relative tissue contrast between WM and GM in each group. Age-specific imaging strategies were proposed according to the Bloch simulation: inversion time (TI) around 800 ms for the 0-3 month-old group, dual TI at 500 ms and 700 ms for the 3-7 month-old group, and TI around 700 ms for 7-12 month-old group, using a centrically encoded 3D-MPRAGE sequence at 3T. Experimental results with varying TIs in each group confirmed improved contrast at the proposed optimal TIs, even in 3-7 month-old infants who had nearly isointense contrast. We further demonstrated the advantage of improved relative contrast in segmenting the neonatal brains using a multi-atlas segmentation method. The proposed age-specific optimization strategies can be easily adapted to routine clinical examinations, and the improved image contrast would facilitate quantitative analysis of the infant brain development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The baby brain is constantly changing due to its active neurodevelopment, and research into the baby brain is one of the frontiers in neuroscience. To help guide neuroscientists and clinicians in their investigation of this frontier, maps of the baby brain, which contain a priori knowledge about neurodevelopment and anatomy, are essential. "Brain atlas" in this review refers to a 3D-brain image with a set of reference labels, such as a parcellation map, as the anatomical reference that guides the mapping of the brain. Recent advancements in scanners, sequences, and motion control methodologies enable the creation of various types of high-resolution baby brain atlases. What is becoming clear is that one atlas is not sufficient to characterize the existing knowledge about the anatomical variations, disease-related anatomical alterations, and the variations in time-dependent changes. In this review, the types and roles of the human baby brain MRI atlases that are currently available are described and discussed, and future directions in the field of developmental neuroscience and its clinical applications are proposed. The potential use of disease-based atlases to characterize clinically relevant information, such as clinical labels, in addition to conventional anatomical labels, is also discussed., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

During the 3rd trimester, dramatic structural changes take place in the human brain, underlying the neural circuit formation. The survival rate of premature infants has increased significantly in recent years. The large morphological differences of the preterm brain at 33 or 36 postmenstrual weeks (PMW) from the brain at 40PMW (full term) make it necessary to establish age-specific atlases for preterm brains. In this study, with high quality (1.5 × 1.5 × 1.6 mm 3 imaging resolution) diffusion tensor imaging (DTI) data obtained from 84 healthy preterm and term-born neonates, we established age-specific preterm and term-born brain templates and atlases at 33, 36 and 39PMW. Age-specific DTI templates include a single-subject template, a population-averaged template with linear transformation and a population-averaged template with nonlinear transformation. Each of the age-specific DTI atlases includes comprehensive labeling of 126 major gray matter (GM) and white matter (WM) structures, specifically 52 cerebral cortical structures, 40 cerebral WM structures, 22 brainstem and cerebellar structures and 12 subcortical GM structures. From 33 to 39 PMW, dramatic morphological changes of delineated individual neural structures such as ganglionic eminence and uncinate fasciculus were revealed. The evaluation based on measurements of Dice ratio and L1 error suggested reliable and reproducible automated labels from the age-matched atlases compared to labels from manual delineation. Applying these atlases to automatically and effectively delineate microstructural changes of major WM tracts during the 3rd trimester was demonstrated. The established age-specific DTI templates and atlases of 33, 36 and 39 PMW brains may be used for not only understanding normal functional and structural maturational processes but also detecting biomarkers of neural disorders in the preterm brains., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Astrocyte-microglia communication influences the onset and progression of central nervous system (CNS) disorders. In this study, we determined how chronic inflammation by activated astrocytes affected and regulated CNS functions in Sandhoff disease (SD), a CNS lysosomal storage disorder. SD triggers intense CNS inflammation such as microglial activation and astrogliosis. It is caused by mutation of the HEXB gene, which reduces β-hexosaminidase (Hex) enzymatic activity in lysosomes, leading to accumulation of the substrate GM2 ganglioside in neuronal cells. Hexb -/- mice display a phenotype similar to human patients that suffer from chronic inflammation characterized by activation of astrocytes and microglia. In Hexb -/- mice, tremors and loss of muscle coordination begins at ~12 weeks. Interestingly, we found that reactive astrocytes expressed adenosine A 2A receptor in the cerebral cortices of Hexb -/- mice at the later inflammatory phase. In cultured astrocytes, expression of A 2A receptor could be induced by astrocyte defined medium, and then the activation of the A 2A receptor induced ccl2 expression. In Hexb -/- mice, inhibition of the A 2A receptor antagonized by istradefylline decreased the number of activated microglial cells and inflammatory cytokines/chemokines at 13 weeks. Thus, the astrocytic A 2A receptor is an important sensor that regulates microglial activation in the late phase of inflammation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The influenza A virus protein PA-X comprises an N-terminal PA region and a C-terminal PA-X-specific region. PA-X suppresses host gene expression, termed shutoff, via mRNA cleavage. Although the endonuclease active site in the N-terminal PA region of PA-X and basic amino acids in the C-terminal PA-X-specific region are known to be important for PA-X shutoff activity, other amino acids may also play a role. Here, we used yeast to identify novel amino acids of PA-X that are important for PA-X shutoff activity. Unlike wild-type PA-X, most PA-X mutants predominantly localized in the cytoplasm, indicating that these mutations decreased the shutoff activity of PA-X by affecting PA-X translocation to the nucleus. Mapping of the identified amino acids onto the N-terminal structure of PA revealed that some of them likely contribute to the formation of the endonuclease active site of PA., (Copyright © 2018. Published by Elsevier Inc.)

Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis is a popular method for the measurement of mRNA expression level and is a critical tool for basic research. The identification of suitable reference genes that are stable and not affected by experimental conditions is a critical step in the accurate normalization of RT-PCR. On the other hand, the levels of numerous transcripts exhibit circadian oscillation in various peripheral tissues and it is thought to be regulated by feeding rhythms in addition to the molecular circadian clock. Here, we investigated the effects of feeding schedule on the temporal expression profiles of 13 common housekeeping genes in metabolic tissues of mice fed during either the sleep or the active phase. The expression of most of these genes fluctuated dependently on feeding rhythms in the liver and WAT, but not in skeletal muscle. Two-way analyses of variance (ANOVA) identified 18S ribosomal RNA (Rn18s) as the only gene that was stably expressed throughout the day independently of feeding schedules in the liver and WAT, although RefFinder software showed that peptidylprolyl isomerase A (Ppia) was the most stably expressed housekeeping gene. Both ANOVA and RefFinder software determined that Actb was the preferred reference gene for skeletal muscle. Furthermore, NormFinder proposed that the optimal pairs of reference genes were beta-2 microglobulin (B2m)-Ppia in the liver, Ppia-TATA box binding protein (Tbp) in WAT, and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide (Ywhaz)-glyceraldehyde-3-phosphate dehydrogenase (Gapdh) in skeletal muscle, and that their stability value was better than that of a single stable gene. The appropriate reference gene pairs for normalizing genes of interest in mouse circadian studies are B2m-Ppia in the liver, Ppia-Tbp in WAT, and Ywhaz-Gapdh in skeletal muscle., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Preterm birth adversely affects postnatal brain development. In order to investigate the critical gestational age at birth (GAB) that alters the developmental trajectory of gray and white matter structures in the brain, we investigated diffusion tensor and quantitative T2 mapping data in 43 term-born and 43 preterm-born infants. A novel multivariate linear model-the change point model, was applied to detect change points in fractional anisotropy, mean diffusivity, and T2 relaxation time. Change points captured the "critical" GAB value associated with a change in the linear relation between GAB and MRI measures. The analysis was performed in 126 regions across the whole brain using an atlas-based image quantification approach to investigate the spatial pattern of the critical GAB. Our results demonstrate that the critical GABs are region- and modality-specific, generally following a central-to-peripheral and bottom-to-top order of structural development. This study may offer unique insights into the postnatal neurological development associated with differential degrees of preterm birth., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The aims of this study were to determine the outcomes of emergency abdominal surgery in patients aged ≥90 y and to analyze the role of Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) and modified POSSUM in predicting their morbidity and mortality., Materials and Methods: Patients aged ≥90 y who underwent emergency abdominal surgery from January 2011 to December 2014 were enrolled in this study., Results: A total of 36 patients satisfied the inclusion criteria. The mortality and morbidity rates in the study group were 8.3% and 61.1%, respectively. Overall observed-to-expected morbidity ratio calculated by POSSUM and modified POSSUM were 0.83 (χ 2  = 32.189, P = 0.6045) and 0.97 (χ 2  = 33.915, P = 0.7398), respectively. Both models demonstrated a good fit for prediction of morbidity. Overall observed-to-expected mortality ratios calculated by POSSUM and modified POSSUM were 0.26 (χ 2  = 12.217, P = 0.2013) and 0.20 (χ 2  = 12.217, P = 0.0936), respectively., Conclusions: Both POSSUM and modified POSSUM accurately predicted morbidity in the setting of emergency abdominal surgery in nonagenarians., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Diffusion tensor imaging (DTI) has been widely used to investigate the development of the neonatal and infant brain, and deviations related to various diseases or medical conditions like preterm birth. In this study, we created a probabilistic map of fiber pathways with known associated functions, on a published neonatal multimodal atlas. The pathways-of-interest include the superficial white matter (SWM) fibers just beneath the specific cytoarchitectonically defined cortical areas, which were difficult to evaluate with existing DTI analysis methods. The Jülich cytoarchitectonic atlas was applied to define cortical areas related to specific brain functions, and the Dynamic Programming (DP) method was applied to delineate the white matter pathways traversing through the SWM. Probabilistic maps were created for pathways related to motor, somatosensory, auditory, visual, and limbic functions, as well as major white matter tracts, such as the corpus callosum, the inferior fronto-occipital fasciculus, and the middle cerebellar peduncle, by delineating these structures in eleven healthy term-born neonates. In order to characterize maturation-related changes in diffusivity measures of these pathways, the probabilistic maps were then applied to DTIs of 49 healthy infants who were longitudinally scanned at three time-points, approximately five weeks apart. First, we investigated the normal developmental pattern based on 19 term-born infants. Next, we analyzed 30 preterm-born infants to identify developmental patterns related to preterm birth. Last, we investigated the difference in diffusion measures between these groups to evaluate the effects of preterm birth on the development of these functional pathways. Term-born and preterm-born infants both demonstrated a time-dependent decrease in diffusivity, indicating postnatal maturation in these pathways, with laterality seen in the corticospinal tract and the optic radiation. The comparison between term- and preterm-born infants indicated higher diffusivity in the preterm-born infants than in the term-born infants in three of these pathways: the body of the corpus callosum; the left inferior longitudinal fasciculus; and the pathway connecting the left primary/secondary visual cortices and the motion-sensitive area in the occipitotemporal visual cortex (V5/MT+). Probabilistic maps provided an opportunity to investigate developmental changes of each white matter pathway. Whether alterations in white matter pathways can predict functional outcomes will be further investigated in a follow-up study., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Edwardsiella tarda is one of the major pathogenic bacteria affecting both marine and freshwater fish species. Sialidase NanA expressed endogenously in E. tarda is glycosidase removing sialic acids from glycoconjugates. Recently, the relationship of NanA sialidase activity to E. tarda infection has been reported, however, the mechanism with which sialidase NanA aids the pathogenicity of E. tarda remained unclear. Here, we comprehensively determined the biochemical properties of NanA towards various substrates in vitro to provide novel insights on the potential NanA target molecule at the host cell. GAKS cell pretreated with recombinant NanA showed increased susceptibility to E. tarda infection. Moreover, sialidase inhibitor treated E. tarda showed a significantly reduced ability to infect GAKS cells. These results indicate that NanA-induced desialylation of cell surface glycoconjugates is essential for the initial step of E. tarda infection. Among the natural substrates, NanA exhibited the highest activity towards 3-sialyllactose, α2-3 linked sialic acid carrying sialoglycoconjugates. Supporting this finding, intact GAKS cell membrane exposed to recombinant NanA showed changes of glycoconjugates only in α2-3 sialo-linked glycoproteins, but not in glycolipids and α2-6 sialo-linked glycoproteins. Lectin staining of cell surface glycoprotein provided further evidence that α2-3 sialo-linkage of the N-linked glycoproteins was the most plausible target of NanA sialidase. To confirm the significance of α2-3 sialo-linkage desialylation for E. tarda infection, HeLa cells which possessed lower amount of α2-3 sialo-linkage glycoprotein were used for infection experiment along with GAKS cells. As a result, infection of HeLa cells by E. tarda was significantly reduced when compared to GAKS cells. Furthermore, E. tarda infection was significantly inhibited by mannose pretreatment suggesting that the bacterium potentially recognizes and binds to mannose or mannose containing chains following desialylation. Together, these results suggest that E. tarda may employ endogenous NanA to desialylate α2-3 glycoproteins on host cells, thus revealing one of the potential binding molecules during infection., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Voxel-based analysis is widely used for quantitative analysis of brain MRI. While this type of analysis provides the highest granularity level of spatial information (i.e., each voxel), the sheer number of voxels and noisy information from each voxel often lead to low sensitivity for detection of abnormalities. To ameliorate this issue, granularity reduction is commonly performed by applying isotropic spatial filtering. This study proposes a systematic reduction of the spatial information using ontology-based hierarchical structural relationships. The 254 brain structures were first defined in multiple (n=29) geriatric atlases. The multiple atlases were then applied to T1-weighted MR images of each subject's data for automated brain parcellation and five levels of ontological relationships were established, which further reduced the spatial dimension to as few as 11 structures. At each ontology level, the amount of atrophy was evaluated, providing a unique view of low-granularity analysis. This reduction of spatial information allowed us to investigate the anatomical features of each patient, demonstrated in an Alzheimer's disease group., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Atlas-based image analysis (ABA), in which an anatomical "parcellation map" is used for parcel-by-parcel image quantification, is widely used to analyze anatomical and functional changes related to brain development, aging, and various diseases. The parcellation maps are often created based on common MRI templates, which allow users to transform the template to target images, or vice versa, to perform parcel-by-parcel statistics, and report the scientific findings based on common anatomical parcels. The use of a study-specific template, which represents the anatomical features of the study population better than common templates, is preferable for accurate anatomical labeling; however, the creation of a parcellation map for a study-specific template is extremely labor intensive, and the definitions of anatomical boundaries are not necessarily compatible with those of the common template. In this study, we employed a volume-based template estimation (VTE) method to create a neonatal brain template customized to a study population, while keeping the anatomical parcellation identical to that of a common MRI atlas. The VTE was used to morph the standardized parcellation map of the JHU-neonate-SS atlas to capture the anatomical features of a study population. The resultant "study-customized" T1-weighted and diffusion tensor imaging (DTI) template, with three-dimensional anatomical parcellation that defined 122 brain regions, was compared with the JHU-neonate-SS atlas, in terms of the registration accuracy. A pronounced increase in the accuracy of cortical parcellation and superior tensor alignment were observed when the customized template was used. With the customized atlas-based analysis, the fractional anisotropy (FA) detected closely approximated the manual measurements. This tool provides a solution for achieving normalization-based measurements with increased accuracy, while reporting scientific findings in a consistent framework., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Human parainfluenza virus type 1 (hPIV1) and type 3 (hPIV3) initiate infection by sialic acid binding. Here, we investigated sialic acid linkage specificities for binding and infection of hPIV1 and hPIV3 by using sialic acid linkage-modified cells treated with sialidases or sialyltransferases. The hPIV1 is bound to only α2,3-linked sialic acid residues, whereas hPIV3 is bound to α2,6-linked sialic acid residues in addition to α2,3-linked sialic acid residues in human red blood cells. α2,3 linkage-specific sialidase treatment of LLC-MK2 cells and A549 cells decreased the infectivity of hPIV1 but not that of hPIV3. Treatment of A549 cells with α2,3 linkage-specific sialyltransferase increased infectivities of both hPIV1 and hPIV3, whereas α2,6 linkage-specific sialyltransferase treatment increased only hPIV3 infectivity. Clinical isolates also showed similar sialic acid linkage specificities. We concluded that hPIV1 utilizes only α2,3 sialic acid linkages and that hPIV3 makes use of α2,6 sialic acid linkages in addition to α2,3 sialic acid linkages as viral receptors., (Copyright © 2014. Published by Elsevier Inc.)

MRI-based human brain atlases, which serve as a common coordinate system for image analysis, play an increasingly important role in our understanding of brain anatomy, image registration, and segmentation. Study-specific brain atlases are often obtained from one of the subjects in a study or by averaging the images of all participants after linear or non-linear registration. The latter approach has the advantage of providing an unbiased anatomical representation of the study population. But, the image contrast is influenced by both inherent MR contrasts and residual anatomical variability after the registration; in addition, the topology of the brain structures cannot reliably be preserved. In this study, we demonstrated a population-based template-creation approach, which is based on Bayesian template estimation on a diffeomorphic random orbit model. This approach attempts to define a population-representative template without the cross-subject intensity averaging; thus, the topology of the brain structures is preserved. It has been tested for segmented brain structures, such as the hippocampus, but its validity on whole-brain MR images has not been examined. This paper validates and evaluates this atlas generation approach, i.e., Volume-based Template Estimation (VTE). Using datasets from normal subjects and Alzheimer's patients, quantitative measurements of sub-cortical structural volumes, metric distance, displacement vector, and Jacobian were examined to validate the group-averaged shape features of the VTE. In addition to the volume-based quantitative analysis, the preserved brain topology of the VTE allows surface-based analysis within the same atlas framework. This property was demonstrated by analyzing the registration accuracy of the pre- and post-central gyri. The proposed method achieved registration accuracy within 1mm for these population-preserved cortical structures in an elderly population., (Published by Elsevier Inc.)

Streptococcus suis is an emerging zoonotic agent. This study aimed to investigate whether S. suis is likely to translocate across the intestines of human hosts who have liver disease and/or consume alcohol. Both the alcoholism and cirrhosis models exhibited high mRNA expression of TGF and collagen1, but only the cirrhosis model had fibrosis in the liver. After both models were infected with S. suis, significantly different concentrations of S. suis were detected in the blood and brains of the alcoholism model (Blood: 36.4%; Brain: 31.8%) and the cirrhosis model (Blood: 62.5%; Brain: 62.5%) compared to the concentrations in the healthy mice (Blood: 15.4%; Brain: 0%). Trans-epithelial electrical resistance (TER) was used to examine the Caco-2 cells in the in vitro that had an S. suis infection combined with 1% ethanol. Although the ethanol did not influence the Caco-2 cells' barriers, it did rapidly decrease the barriers' TER value and then their E-cadherin compared to the infected Caco-2 cells without the ethanol treatment. Immunofluorescence also indicated that the barriers of the Caco-2 cells treated with ethanol were disrupted and that S. suis translocated from the apical to the basolateral side. This study demonstrated that alcohol consumption helped S. suis to translocate., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Resting state functional connectivity MRI (rsfc-MRI) reveals a wealth of information about the functional organization of the brain, but poses unique challenges for quantitative image analysis, mostly related to the large number of voxels with low signal-to-noise ratios. In this study, we tested the idea of using a prior spatial parcellation of the entire brain into various structural units, to perform an analysis on a structure-by-structure, rather than voxel-by-voxel, basis. This analysis, based upon atlas parcels, potentially offers enhanced SNR and reproducibility, and can be used as a common anatomical framework for cross-modality and cross-subject quantitative analysis. We used Large Deformation Diffeomorphic Metric Mapping (LDDMM) and a deformable brain atlas to parcel each brain into 185 regions. To investigate the precision of the cross-subject analysis, we computed inter-parcel correlations in 20 participants, each of whom was scanned twice, as well as the consistency of the connectivity patterns inter- and intra-subject, and the intersession reproducibility. We report significant inter-parcel correlations consistent with previous findings, and high test-retest reliability, an important consideration when the goal is to compare clinical populations. As an example of the cross-modality analysis, correlation with anatomical connectivity is also examined., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: An important component of postoperative management includes alleviation of hepatic ischemia-reperfusion (I/R) injury, which commonly results from liver surgery. EPC-K1 is a hydroxyl radical scavenger reported to have mitigating effects on I/R injury in many organs. This study evaluates the effects of EPC-K1 on hepatic I/R injury., Materials and Methods: Rats were injected subcutaneously with either EPC-K1 (100 mg/kg) or saline. The hepatic artery and left branch of the portal vein were clamped for 45 min under general anesthesia. Indicators of liver function, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), and of liver tissue damage were evaluated after 6h and 24h of reperfusion. Serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and high-mobility group box 1 (HMGB1) protein were measured, and apoptosis was quantified via caspase 3/7 activity and TUNEL assay., Results: AST, ALT, and LDH levels increased significantly as a result of hepatic I/R injury, but were attenuated by EPC-K1 administration. Histologic findings revealed that normal structure of the hepatic parenchyma was maintained in rats pretreated with EPC-K1. TNF-α, IL-6, and HMGB1 levels rose significantly after reperfusion, together with activation of the inflammatory response. However, EPC-K1 administration suppressed levels of inflammatory markers and attenuated the inflammatory response. Moreover, EPC-K1 administration prevented apoptosis as determined by inhibition of caspase 3/7 activity and a decrease in apoptotic cells., Conclusions: Results demonstrate that EPC-K1 inhibits the inflammatory response and suppresses apoptosis during hepatic I/R injury. This suggests that EPC-K1 has hepatoprotective effects, and may be a valuable and novel therapeutic agent in the clinical setting., (Copyright © 2012 Elsevier Inc. All rights reserved.)

MRI is a sensitive method for detecting subtle anatomic abnormalities in the neonatal brain. To optimize the usefulness for neonatal and pediatric care, systematic research, based on quantitative image analysis and functional correlation, is required. Normalization-based image analysis is one of the most effective methods for image quantification and statistical comparison. However, the application of this methodology to neonatal brain MRI scans is rare. Some of the difficulties are the rapid changes in T1 and T2 contrasts and the lack of contrast between brain structures, which prohibits accurate cross-subject image registration. Diffusion tensor imaging (DTI), which provides rich and quantitative anatomical contrast in neonate brains, is an ideal technology for normalization-based neonatal brain analysis. In this paper, we report the development of neonatal brain atlases with detailed anatomic information derived from DTI and co-registered anatomical MRI. Combined with a diffeomorphic transformation, we were able to normalize neonatal brain images to the atlas space and three-dimensionally parcellate images into 122 regions. The accuracy of the normalization was comparable to the reliability of human raters. This method was then applied to babies of 37-53 post-conceptional weeks to characterize developmental changes of the white matter, which indicated a posterior-to-anterior and a central-to-peripheral direction of maturation. We expect that future applications of this atlas will include investigations of the effect of prenatal events and the effects of preterm birth or low birth weights, as well as clinical applications, such as determining imaging biomarkers for various neurological disorders., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Although a Streptococcus suis infection was recently expanded, the study of S. suis has not had enough attention. In this study, bacterial kinetics of S. suis were investigated for seven days of infection in a mouse model. Survival rates showed that 5.0 × 10(7) CFU ml(-1) of S. suis infection caused death in 30% of mice subjects. Streptococcal kinetics from 10(4) to 10(7) CFU ml(-1) were detected in the brain, kidney, lung, spleen and urine two days post-infection and still detected in both kidney and urine seven days post-infection. In addition, 5.0 × 10(6) CFU ml(-1) of low dose infection was conducted, showing that S. suis was detected in the kidney seven days post-infection. Expressions of virulence-associated genes (mrp, epf, sly and hyl) were evaluated and results showed that all virulence-associated genes were detected in both spleen and kidney, whereas no detectable bands in either lung and liver two days post-infection. Microscopy demonstrated that S. suis accumulated in the renal cortex side of blood vessels and renal tubules two days post-infection, while S. suis accumulated in the renal tubule seven days post-infection. This is the first report of accumulated S. suis in mice kidney during S. suis infection., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

We have developed a new method to provide a comprehensive quantitative analysis of brain anatomy in cerebral palsy patients, which makes use of two techniques: diffusion tensor imaging and automated 3D whole brain segmentation based on our brain atlas and a nonlinear normalization technique (large-deformation diffeomorphic metric mapping). This method was applied to 13 patients and normal controls. The reliability of the automated segmentation revealed close agreement with the manual segmentation. We illustrate some potential applications for individual characterization and group comparison. This technique also provides a framework for determining the impact of various neuroanatomic features on brain functions., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Tractography based on diffusion tensor imaging (DTI) is widely used to quantitatively analyze the status of the white matter anatomy in a tract-specific manner in many types of diseases. This approach, however, involves subjective judgment in the tract-editing process to extract only the tracts of interest. This process, usually performed by manual delineation of regions of interest, is also time-consuming, and certain tracts, especially the short cortico-cortical association fibers, are difficult to reconstruct. In this paper, we propose an automated approach for reconstruction of a large number of white matter tracts. In this approach, existing anatomical knowledge about tract trajectories (called the Template ROI Set or TRS) were stored in our DTI-based brain atlas with 130 three-dimensional anatomical segmentations, which were warped non-linearly to individual DTI data. We examined the degree of matching with manual results for selected fibers. We established 30 TRSs to reconstruct 30 prominent and previously well-described fibers. In addition, TRSs were developed to delineate 29 short association fibers that were found in all normal subjects examined in this paper (N=20). Probabilistic maps of the 59 tract trajectories were created from the normal subjects and were incorporated into our image analysis tool for automated tract-specific quantification., (Copyright 2010 Elsevier Inc. All rights reserved.)

Quantification of normal brain maturation is a crucial step in understanding developmental abnormalities in brain anatomy and function. The aim of this study was to develop atlas-based tools for time-dependent quantitative image analysis, and to characterize the anatomical changes that occur from 2years of age to adulthood. We used large deformation diffeomorphic metric mapping to register diffusion tensor images of normal participants into the common coordinates and used a pre-segmented atlas to segment the entire brain into 176 structures. Both voxel- and atlas-based analyses reported a structure that showed distinctive changes in terms of its volume and diffusivity measures. In the white matter, fractional anisotropy (FA) linearly increased with age in logarithmic scale, while diffusivity indices, such as apparent diffusion coefficient (ADC), and axial and radial diffusivity, decreased at a different rate in several regions. The average, variability, and the time course of each measured parameter are incorporated into the atlas, which can be used for automated detection of developmental abnormalities. As a demonstration of future application studies, the brainstem anatomy of cerebral palsy patients was evaluated and the altered anatomy was delineated., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Recently it has been reported that a cathepsin B inhibitor, CA-074Me, attenuates ecotropic murine leukemia virus (Eco-MLV) infection in NIH3T3 cells, suggesting that cathepsin B is required for the Eco-MLV infection. However, cathepsin B activity was negative or extremely low in NIH3T3 cells. How did CA-074Me attenuate the Eco-MLV infection? The CA-074Me treatment of NIH3T3 cells inhibited cathepsin L activity, and a cathepsin L specific inhibitor, CLIK148, attenuated the Eco-MLV vector infection. These results indicate that the suppression of cathepsin L activity by CA-074Me induces the inhibition of Eco-MLV infection, suggesting that cathepsin L is required for the Eco-MLV infection in NIH3T3 cells. The CA-074Me treatment inhibited the Eco-MLV infection in human cells expressing the exogenous mouse ecotropic receptor and endogenous cathepsins B and L, but the CLIK148 treatment did not, showing that only the cathepsin L suppression by CLIK148 is not enough to prevent the Eco-MLV infection in cells expressing both of cathepsins B and L, and CA-074Me inhibits the Eco-MLV infection by suppressing both of cathepsins B and L. These results suggest that either cathepsin B or L is sufficient for the Eco-MLV infection.

Diffusion tensor imaging (DTI) can reveal detailed white matter anatomy and has the potential to detect abnormalities in specific white matter structures. Such detection and quantification are, however, not straightforward. The voxel-based analysis after image normalization is one of the most widely used methods for quantitative image analyses. To apply this approach to DTI, it is important to examine if structures in the white matter are well registered among subjects, which would be highly dependent on employed algorithms for normalization. In this paper, we evaluate the accuracy of normalization of DTI data using a highly elastic transformation algorithm, called large deformation diffeomorphic metric mapping. After simulation-based validation of the algorithm, DTI data from normal subjects were used to measure the registration accuracy. To examine the impact of morphological abnormalities on the accuracy, the algorithm was also tested using data from Alzheimer's disease (AD) patients with severe brain atrophy. The accuracy level was measured by using manual landmark-based white matter matching and surface-based brain and ventricle matching as gold standard. To improve the accuracy level, cascading and multi-contrast approaches were developed. The accuracy level for the white matter was 1.88+/-0.55 and 2.19+/-0.84 mm for the measured locations in the controls and patients, respectively.

The purpose of this paper is to establish single-participant white matter atlases based on diffusion tensor imaging. As one of the applications of the atlas, automated brain segmentation was performed and the accuracy was measured using Large Deformation Diffeomorphic Metric Mapping (LDDMM). High-quality diffusion tensor imaging (DTI) data from a single-participant were B0-distortion-corrected and transformed to the ICBM-152 atlas or to Talairach coordinates. The deep white matter structures, which have been previously well documented and clearly identified by DTI, were manually segmented. The superficial white matter areas beneath the cortex were defined, based on a population-averaged white matter probability map. The white matter was parcellated into 176 regions based on the anatomical labeling in the ICBM-DTI-81 atlas. The automated parcellation was achieved by warping this parcellation map to normal controls and to Alzheimer's disease patients with severe anatomical atrophy. The parcellation accuracy was measured by a kappa analysis between the automated and manual parcellation at 11 anatomical regions. The kappa values were 0.70 for both normal controls and patients while the inter-rater reproducibility was 0.81 (controls) and 0.82 (patients), suggesting "almost perfect" agreement. A power analysis suggested that the proposed method is suitable for detecting FA and size abnormalities of the white matter in clinical studies.

An increased level of obesity-induced plasma plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular disease. To determine whether the circadian clock component PERIOD2 (PER2) is involved in the regulation of PAI-1 gene expression, we performed transient transfection assays in vitro, and generated transgenic (Tg) mice overexpressing PER2. We then compared PAI-1 expression in Tg and wild-type (WT) mice with or without obesity induced by a high-fat/high-sucrose diet. PER2 suppressed CLOCK:BMAL1- and CLOCK:BMAL2-dependent transactivation of the PAI-1 promoter in vitro. Furthermore, nuclear translocation is dispensable for PER2 to suppress CLOCK:BMAL1-dependent transactivation of the PAI-1 promoter, because functional loss of the nuclear localization domain did not affect either the interaction with BMAL1 or the suppressive role of PER2. The diurnal expression of clock and clock-controlled genes was disrupted in a gene-specific manner, whereas that of PAI-1 mRNA was significantly damped in the hearts of PER2 Tg mice fed with a normal diet. Obesity-induced plasma PAI-1 increase was significantly suppressed in Tg mice in accordance with cardiac PAI-1 mRNA levels, whereas body weight gain and changes in metabolic parameters were identical between WT and Tg mice. Endogenous PAI-1 gene expression induced by transforming growth factor-beta1 was significantly attenuated in embryonic fibroblasts derived from Tg mice compared with those from WT mice. Our results demonstrated that PER2 represses PAI-1 gene transcription in a BMAL1/2-dependent manner. The present findings also suggest that PER2 attenuates obesity-induced hypofibrinolysis by downregulating PAI-1 expression independently of metabolic disorders.

Structural delineation and assignment are the fundamental steps in understanding the anatomy of the human brain. The white matter has been structurally defined in the past only at its core regions (deep white matter). However, the most peripheral white matter areas, which are interleaved between the cortex and the deep white matter, have lacked clear anatomical definitions and parcellations. We used axonal fiber alignment information from diffusion tensor imaging (DTI) to delineate the peripheral white matter, and investigated its relationship with the cortex and the deep white matter. Using DTI data from 81 healthy subjects, we identified nine common, blade-like anatomical regions, which were further parcellated into 21 subregions based on the cortical anatomy. Four short association fiber tracts connecting adjacent gyri (U-fibers) were also identified reproducibly among the healthy population. We anticipate that this atlas will be useful resource for atlas-based white matter anatomical studies.

Brain registration to a stereotaxic atlas is an effective way to report anatomic locations of interest and to perform anatomic quantification. However, existing stereotaxic atlases lack comprehensive coordinate information about white matter structures. In this paper, white matter-specific atlases in stereotaxic coordinates are introduced. As a reference template, the widely used ICBM-152 was used. The atlas contains fiber orientation maps and hand-segmented white matter parcellation maps based on diffusion tensor imaging (DTI). Registration accuracy by linear and non-linear transformation was measured, and automated template-based white matter parcellation was tested. The results showed a high correlation between the manual ROI-based and the automated approaches for normal adult populations. The atlases are freely available and believed to be a useful resource as a target template and for automated parcellation methods.

Pericytes were isolated and cultured from mouse cerebroparenchymal microvessels. A single pericyte clone was three-dimensionally cultured in a collagen gel by adding tensile stress, resulting in the reconstruction of narrow stringy fibers. When the contractility of these fibers was evaluated isometrically, they contracted in response to acetylcholine (ACh)1 or noradrenaline; this was accompanied by an increase in intracellular calcium concentration ([Ca(2+)]i). The fibers that were pre-contracted by ACh were completely relaxed by papaverine, which is a smooth-muscle relaxant. Moreover, the muscarinic ACh receptor-antagonist atropine depressed the [Ca(2+)]i response that was induced by ACh. This study demonstrates for the first time the quantitative measurement of the contractions produced by cultured microvascular pericytes from mouse brain parenchyma.

Exercise or acute stress can exert significant effects on immune system as well as cardiovascular and respiratory systems through catecholamines. In this study, we investigated effects of norepinephrine (NE), a catecholamine neurotransmitter on human immunodeficiency virus type-1 (HIV-1) infection. NE inhibited in vitro HIV-1 infection of peripheral blood mononuclear cells (PBMC) from healthy donors and ex vivo HIV-1 replication in patients' PBMC. In transient expression assays, NE downregulated HIV-1 long terminal repeat, but site-directed mutagenesis on NF-kappaB-binding sites or cotreatment with H89 (a protein kinase A inhibitor) abrogated the NE-mediated effect. Gel-shift assays showed suppression of NF-kappaB activity in NE-treated cells. NE increased cytoplasmic levels of IkappaB-alpha, a natural inhibitor of NF-kappaB. Thus, NE apparently inhibits HIV-1 infection, at least in part through NF-kappaB inactivation.

The issue of whether acid aspiration facilitates bacterial pneumonia caused by Pseudomonas aeruginosa by enhanced bacterial adherence was examined in mice. Survival or the number of bacteria in lung tissues was evaluated after an intratracheal challenge of hydrochloric acid (HCl), a sublethal dose of P. aeruginosa, or both in mice. Bacterial adherence to the tracheal epithelium after acid aspiration was also examined by scanning electron microscopy. A simultaneous intratracheal challenge of 50 microl of 10(-1) N HCl, but not 10(-2) to 10(-4) N HCl, combined with a sublethal dose of P. aeruginosa significantly increased the number of bacteria in the lung tissues and decreased survival, while all mice that received either HCl or P. aeruginosa survived. Significantly higher numbers of adherent bacteria on the tracheal epithelium were found in mice that received 10(-1)N HCl, compared with mice that received HCl (10(-2) to 10(-4) N) or saline. These data indicate that acid aspiration induced airway epithelial injury and enhanced P. aeruginosa adherence to the epithelium, and led to the subsequent development of bacterial pneumonia in mice. Enhanced bacterial adherence on the acid-injured epithelium may explain fatal bacterial pneumonias in patients with respiratory aspiration of gastric contents.

Recently, our group and others cloned the TRMA disease gene, SLC19A2, which encodes a thiamin transporter. Here, we report the cloning and characterization of the full-length cDNA and genomic sequences of mouse Slc19a2. The Slc19a2 cDNA contained a 1494-bp open-reading frame, and had 5'- and 3'-untranslated regions of 189 and 1857 bp, respectively. A putative GC-rich, TATA-less promoter was identified in genomic sequence directly upstream of the identified 5' end. The Slc19a2 gene spanned 16.3 kb and was organized into six exons, a gene structure conserved with the human orthologue. The predicted Slc19a2 protein, like SLC19A2, was predicted to have 12 transmembrane domains and shared a number of other conserved sequence motifs with the human orthologue, including one potential N-glycosylation site (N(63)) and several potential phosphorylation sites. Comparison of the Slc19a2 amino acid sequence with those of the other known SLC19A solute carriers highlighted interesting patterns of conservation and divergence in various domains, allowing insight into potential structure-function relationships. The identification of the mouse Slc19a2 cDNA and genomic sequences will facilitate the generation of an animal model of TRMA, permitting future studies of disease pathogenesis., (Copyright 2001 Academic Press.)

Monocyte chemoattractant protein-1 (MCP-1), a chemoattractant for monocytes, is presumed to play a pivotal role in the recruitment and accumulation of monocytes in various diseases including pulmonary infections. We examined here whether or not Pseudomonas nitrite reductase (PNR), a recently identified IL-8 inducer in various respiratory cells, could stimulate human pulmonary type II epithelial-like cells (A549) to induce MCP-1 production. A time- and dose-dependent induction of MCP-1 protein synthesis associated with an increase of MCP-1 mRNA expression by A549 cells was observed in response to PNR. New protein translation was not required for PNR-mediated MCP-1 mRNA expression in the same cells. When anti-human MCP-1 monoclonal antibody was used for neutralizing of monocyte chemotactic factor (MCF) activities in the culture supernatants of these cells stimulated with PNR, significant reductions of MCF activities (the mean reduction rate; 49-59%, P<0. 05) were observed. These data suggest that PNR may contribute to monocyte migration, through inducing pulmonary epithelial cell-derived MCP-1 production in the airway of patients with pneumonia due to P. aeruginosa., (Copyright 2000 Academic Press.)

Neuronal ceroid lipofuscinosis (NCL) is one of the most common inherited neurological diseases in childhood. It occurs every 12,500 births in northern-European populations. Mental retardation, visual impairment, and seizures are common symptoms. The prevalence of NCL is variable depending upon the races or countries. Although a wealth information is available in Caucasian populations, there is little information about NCL in Asian people. Because a nationwide survey in Japanese patients with NCL has never been performed, we pursued an epidemiological survey. We identified 36 NCL patients in Japan. Patients with infantile, late infantile, juvenile, and adult type accounted for 2, 15, 15, and 4 cases, respectively. Seizures were a major initial symptom in the late infantile type. In the juvenile type, visual failure was present in 73% at onset. Recently, the juvenile NCL (Batten disease) gene has been isolated. Studies of the mutations in this gene demonstrated that a 1.02-kb deletion was the most prevalent mutation among Caucasian patients, accounting for 81% of total alleles. To determine the prevalence of this 1.02-kb deletion in Japanese patients, we performed a rapid allele-specific polymerase chain reaction test. No 1.02-kb major deletion was detected in 5 Japanese juvenile NCL cases. These data suggest that the distribution of NCL and clinical findings are similar to those of Caucasian subjects; however, prevalence of mutations in Japanese patients with NCL would be distinct from that observed in Caucasians., (Copyright 1999 Academic Press.)