ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway.

Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.

Correlation between blood albumin and hospital death and long-term death in ICU patients with heart failure: data from the medical information mart for intensive care III database.

BACKGROUND: Elevated circulating levels of albumin (ALB) are often associated with improved prognosis in patients with heart failure (HF). However, investigations of its association with hospital death and long-term death in HF patients in the intensive care unit (ICU) are limited. AIM: We examined whether increased blood ALB levels (first value at admission and maximum and minimum values in the ICU) were related to a greater risk of hospital death and long-term death in ICU patients with HF. METHODS: For the first time, we analyzed 4084 ICU patients with HF admitted to the ICU in The Medical Information Mart for Intensive Care III (MIMIC-III) database. RESULTS: Among 4084 HF patients, 774 (18.95%), 1056 (25.86%) and 1720 (42.12%) died in the hospital, within 30 days and 1 year, respectively. We conducted a logistic regression analysis and found significant inverse associations between blood ALB concentration and risk of hospital death, 30-day death and 1-year death when the covariates including age, sex, myocardial infarction (MI), hypertension, diabetes, valvular diseases, atrial fibrillation, stroke and chronic kidney disease (CKD) were adjusted. We additionally used a smooth curve for univariate analysis to establish an association between blood ALB concentration and death risk. Surprisingly, we observed U-shaped correlations between blood ALB concentration and hospital mortality, 30-day mortality and 1-year mortality. We found that the "inflection point" for the blood ALB concentration at the lowest risk of death was 3.5 g/dL. We further observed that a higher blood ALB concentration (albumin-max) did not contribute to a reduced risk of death (hospital death, 30-day death and 1-year death) in HF patients with an albumin concentration >3.5 g/dL. CONCLUSIONS: A lower blood ALB concentration contributed to a greater risk of hospital death and long-term death in HF patients admitted to the ICU, further suggesting that nutritional support in the ICU is highly important for improving the short-term and long-term mortality of HF patients. However, in HF patients without hypoproteinaemia (>3.5 g/dL), the impact of increased serum ALB on patient prognosis still needs to be demonstrated.

Effects of anesthesia exposure on postnatal maturation of white matter in rhesus monkeys.

There is increasing concern about the potential effects of anesthesia exposure on the developing brain. The effects of relatively brief anesthesia exposures used repeatedly to acquire serial magnetic resonance imaging scans could be examined prospectively in rhesus macaques. We analyzed magnetic resonance diffusion tensor imaging (DTI) of 32 rhesus macaques (14 females, 18 males) aged 2 weeks to 36 months to assess postnatal white matter (WM) maturation. We investigated the longitudinal relationships between each DTI property and anesthesia exposure, taking age, sex, and weight of the monkeys into consideration. Quantification of anesthesia exposure was normalized to account for variation in exposures. Segmented linear regression with two knots provided the best model for quantifying WM DTI properties across brain development as well as the summative effect of anesthesia exposure. The resulting model revealed statistically significant age and anesthesia effects in most WM tracts. Our analysis indicated there were major effects on WM associated with low levels of anesthesia even when repeated as few as three times. Fractional anisotropy values were reduced across several WM tracts in the brain, indicating that anesthesia exposure may delay WM maturation, and highlight the potential clinical concerns with even a few exposures in young children.

Effects of social rank and pubertal delay on brain structure in female rhesus macaques.

Adverse social experience during childhood and adolescence leads to developmental alterations in emotional and stress regulation and underlying neurocircuits. We examined the consequences of social subordination (low social rank) in juvenile female rhesus monkeys, as an ethologically valid model of chronic social stressor exposure, on brain structural and behavioral development through the pubertal transition. Adolescence is a developmental period of extensive brain remodeling and increased emotional and stress reactivity. Puberty-induced increases in gonadal hormones, particularly estradiol (E2), are likely involved due to its organizational effects on the brain and behavior. Thus, we also examined how experimentally delaying pubertal onset with Lupron (gonadotropin releasing hormone -GnRH- agonist used clinically to delay early puberty) interacted with social rank (dominant vs. subordinate) to affect brain and behavioral outcomes. Using a longitudinal experimental design, structural MRI (sMRI) scans were collected on socially housed juvenile female rhesus monkeys living in indoor-outdoor enclosures prior to the onset of puberty (18-25 months), defined as menarche or the initial occurrence of perineal swelling and coloration, and again at 29-36 months, when all control animals had reached puberty but none of the Lupron-treated had. We examined the effects of both social rank and pubertal delay on overall structural brain volume (i.e. intracranial, grey matter (GM) and white matter (WM) volumes), as well as on cortico-limbic regions involved in emotion and stress regulation: amygdala (AMYG), hippocampus (HC), and prefrontal cortex (PFC). Measures of stress physiology, social behavior, and emotional reactivity were collected to examine functional correlates of the brain structural effects. Apart from expected developmental effects, subordinates had bigger AMYG volumes than dominant animals, most notably in the right hemisphere, but pubertal delay with Lupron-treatment abolished those differences, suggesting a role of gonadal hormones potentiating the brain structural impact of social stress. Subordinates also had elevated baseline cortisol, indicating activation of stress systems. In general, Lupron-treated subjects had smaller AMYG and HC volume than controls, but larger total PFC (driven by bigger GM volumes), and different, region-specific, developmental patterns dependent on age and social rank. These findings highlight a region-specific effect of E2 on structural development during female adolescence, independent of those due to chronological age. Pubertal delay and AMYG volume, in turn, predicted differences in emotional reactivity and social behavior. These findings suggest that exposure to developmental increases in E2 modifies the consequences of adverse social experience on the volume of cortico-limbic regions involved in emotional and stress regulation during maturation. But, even more importantly, they indicate different brain structural effects of chronological age and pubertal developmental stage in females, which are very difficult to disentangle in human studies. These findings have additional relevance for young girls who experience prolonged pubertal delays or for those whose puberty is clinically arrested by pharmacological administration of Lupron.

AQP9 transports lactate in tumor-associated macrophages to stimulate an M2-like polarization that promotes colon cancer progression.

Macrophages play a major role in the immune defense against pathogenic factors; however, they can lead to tumor exacerbation and metastasis, as the tumor microenvironment (TME) polarizes tumor-associated macrophages (TAMs) into the M2 subtype. Lactate, a metabolite produced by carcinoma cells at high concentrations in the TME, induces an M2-polarization in macrophages, which ultimately leads to the secretion of factors, such as vascular endothelial growth factor (VEGF), and promotes tumor progression. However, the effect of TAM lactate import on tumor progression has not been fully elucidated. Aquaporin 9 (AQP9) is a transporter of water and glycerol expressed in macrophages. Here, we used a tumor allograft mouse model to show that AQP9 knockout (AQP9-/-) mice were more resistant against tumor cell growth and exhibited a suppressive M2-like polarization in tumor tissue than wild-type mice. Moreover, we discovered that the primary bone marrow-derived macrophages from AQP9-/- mice were less sensitive to lactate stimulation and exhibited reduced M2-like polarization as well as decreased VEGF production. To further investigate the role of AQP9 in macrophage polarization, we overexpressed AQP9 in Chinese hamster ovary cells and found that AQP9 functioned in lactate import. In contrast, primary AQP9-/- macrophages and AQP9 knockdown RAW264.7 cells exhibited a reduced lactate transport rate, suggesting the involvement of AQP9 in lactate transport in macrophages. Together, our results reveal the mechanism by which the TME modifies the polarization and function of tumor-infiltrating macrophages via AQP9 transport function.

The association between blood albumin level and cardiovascular complications and mortality risk in ICU patients with CKD.

BACKGROUND: Studies involving the association of blood albumin with prognosis in patients with chronic kidney disease (CKD) during intensive care unit (ICU) were scarce. AIM: We investigated whether reduced blood albumin level independently associated with an increased risk of cardiovascular (CV) complications and 1-year mortality risk in ICU patients with CKD. METHODS: The Medical Information Mart for Intensive Care III (MIMIC-III) database was used. Disease diagnosis and death information among a number of 925 ICU patients with CKD, who have been measured for blood biochemistry, were recorded. Here, multivariable logistic regression Models were structured to evaluate the associations between blood albumin levels (first value on admission, maximum and minimum value during ICU) and risks for CV complications and 1-year mortality among these CKD patients. RESULTS: In 925 CKD patients, the number of CV complication with heart failure (HF), myocardial infarction (MI) or stroke was 470 (50.8%). 406 (43.9%) patients were dead during the follow-up of 1 year after patients were discharged. Our smooth curve results suggested a curvilinear relation on association between blood albumin level and risk of CV complications. The "inflection point" of blood albumin level that patients were at highest risk of CV complications was 3.4 g/dL. The almost linear relationship with a downward trend was observed on the association between blood albumin level and 1-year mortality risk. We found that reduced blood albumin level contributed to lower risk for CV complications and higher risk for 1-year mortality respectively when blood albumin levels in CKD patients were below 3.4 g/dL. Additionally, albumin therapy had an obvious modifying effect on the independent association, suggesting a possible improved effect of albumin therapy on risk of CV complications and 1-year mortality risk in these CKD patients. CONCLUSIONS: Our study reported that reduced blood albumin levels in CKD patients during ICU were related to lower risk for CV complications and increased risk of 1-year mortality.

Emodin prevents renal ischemia-reperfusion injury via suppression of CAMKII/DRP1-mediated mitochondrial fission.

Acute kidney injury (AKI) is a serious threat to human health. Clinically, ischemia-reperfusion (I/R) injury is considered one of the most common contributors to AKI. Emodin has been reported to alleviate I/R injury in the heart, brain, and small intestine in rats and mice through its anti-inflammatory effects. The present study investigated whether emodin improved AKI induced by I/R and elucidated the molecular mechanisms. We used a mouse model of renal I/R injury and human renal tubular epithelial cell model of hypoxia/reoxygenation (H/R) injury. Ischemia/reperfusion resulted in renal dysfunction. Pretreatment with emodin ameliorated renal injury in mice following I/R injury. Emodin reduced mitochondrial-mediated apoptosis, suppressed the overproduction of mitochondrial reactive oxygen species and accelerated the recovery of adenosine triphosphate both in vivo and in vitro. Emodin prevented mitochondrial fission and restored the balance of mitochondrial dynamics. The phosphorylation of dynamin-related protein 1 (DRP1) at Ser616, a master regulator of mitochondrial fission, was upregulated in both models of I/R and H/R injury, and this upregulation was blocked by emodin. Using computational cognate protein kinase prediction and specific kinase inhibitors, we found that emodin inhibited the phosphorylation of calcium/calmodulin-dependent protein kinase II (https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1554), thereby inhibiting its kinase activity and reducing the phosphorylation of DRP1 at Ser616. The results demonstrated that emodin pretreatment could protect renal function by improving mitochondrial dysfunction induced by I/R.

Neutrophil Gelatinase-Associated Lipocalin Contributes to Increased Risk of Cardiovascular Death After Acute Coronary Syndrome.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) has been suggested to reflect early renal dysfunction. We investigated the predictive significance of serum NGAL in predicting cardiovascular (CV) death in an old-age population with coronary heart disease (CHD). METHODS: In total, 633 CHD patients with a stable clinical condition were enrolled. The measurements of serum NGAL and other laboratory indices were performed within 24 hours after admission. Adjusted analysis was used to assess relationships between serum NGAL and CV death during the 10-year follow-up period. RESULTS: Multivariate logistic regression analysis demonstrated that elevated NGAL levels were related to a higher prevalence of CV disease history [quartile 4, 2.41 (1.60-4.59), P-trend <0.001]. The Kaplan-Meier curve indicated that patients with high NGAL levels tended to have a higher rate of CV death than patients with low NGAL levels. A multivariate Cox model suggested that increased levels of NGAL were independently linked with elevated risk of CV death (HR=2.62, 95% CI 1.51-4.96, P<0.001) during the 10-year follow-up period, after adjusting for related confounding factors using sensitivity analysis. Furthermore, the receiver operating characteristics (ROC) curve demonstrated that serum NGAL (AUC=0.917, 95% CI 0.895-0.940, P<0.001) had an ideal predictive value in predicting CV death. CONCLUSION: Serum levels of NGAL were elevated in patients with CHD and may be a new parameter that could independently predict CV death in these patients, which may strengthen its potential application in clinical practice.

General anaesthesia during infancy reduces white matter micro-organisation in developing rhesus monkeys.

BACKGROUND: Non-human primates are commonly used in neuroimaging research for which general anaesthesia or sedation is typically required for data acquisition. In this analysis, the cumulative effects of exposure to ketamine, Telazol® (tiletamine and zolazepam), and the inhaled anaesthetic isoflurane on early brain development were evaluated in two independent cohorts of typically developing rhesus macaques. METHODS: Diffusion MRI scans were analysed from 43 rhesus macaques (20 females and 23 males) at either 12 or 18 months of age from two separate primate colonies. RESULTS: Significant, widespread reductions in fractional anisotropy with corresponding increased axial, mean, and radial diffusivity were observed across the brain as a result of repeated anaesthesia exposures. These effects were dose dependent and remained after accounting for age and sex at time of exposure in a generalised linear model. Decreases of up to 40% in fractional anisotropy were detected in some brain regions. CONCLUSIONS: Multiple exposures to commonly used anaesthetics were associated with marked changes in white matter microstructure. This study is amongst the first to examine clinically relevant anaesthesia exposures on the developing primate brain. It will be important to examine if, or to what degree, the maturing brain can recover from these white matter changes.

FOXO1 inhibition prevents renal ischemia-reperfusion injury via cAMP-response element binding protein/PPAR-γ coactivator-1α-mediated mitochondrial biogenesis.

BACKGROUND AND PURPOSE: Growing evidence indicates targeting mitochondrial dynamics and biogenesis could accelerate recovery from renal ischemia-reperfusion (I/R) injury, but the underlying mechanisms remain elusive. Transcription factor forkhead box O1 (FOXO1) is a key regulator of mitochondrial homeostasis and plays a pathological role in the progression of renal disease. EXPERIMENTAL APPROACH: A mouse model of renal I/R injury and a hypoxia/reoxygenation (H/R) injury model for human renal tubular epithelial cells were used. KEY RESULTS: I/R injury up-regulated renal expression of FOXO1 and treatment with FOXO1-selective inhibitor AS1842856 prior to I/R injury decreased serum urea nitrogen, serum creatinine and the tubular damage score after injury. Post-I/R injury AS1842856 treatment could also ameliorate renal function and improve the survival rate of mice following injury. AS1842856 administration reduced mitochondrial-mediated apoptosis, suppressed the overproduction of mitochondrial ROS and accelerated recovery of ATP both in vivo and in vitro. Additionally, FOXO1 inhibition improved mitochondrial biogenesis and suppressed mitophagy. Expression of PPAR-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis, was down-regulated in both I/R and H/R injury, which could be abrogated by FOXO1 inhibition. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that FOXO1 inhibited PGC-1α transcription by competing with cAMP-response element binding protein (CREB) for its binding to transcriptional coactivators CREBBP/EP300 (CBP/P300). CONCLUSION AND IMPLICATIONS: These findings suggested that FOXO1 was critical to maintain mitochondrial function in renal tubular epithelial cells and FOXO1 may serve as a therapeutic target for pharmacological intervention in renal I/R injury.

Disentangling the effects of early caregiving experience and heritable factors on brain white matter development in rhesus monkeys.

Early social experiences, particularly maternal care, shape behavioral and physiological development in primates. Thus, it is not surprising that adverse caregiving, such as child maltreatment leads to a vast array of poor developmental outcomes, including increased risk for psychopathology across the lifespan. Studies of the underlying neurobiology of this risk have identified structural and functional alterations in cortico-limbic brain circuits that seem particularly sensitive to these early adverse experiences and are associated with anxiety and affective disorders. However, it is not understood how these neurobiological alterations unfold during development as it is very difficult to study these early phases in humans, where the effects of maltreatment experience cannot be disentangled from heritable traits. The current study examined the specific effects of experience ("nurture") versus heritable factors ("nature") on the development of brain white matter (WM) tracts with putative roles in socioemotional behavior in primates from birth through the juvenile period. For this we used a randomized crossfostering experimental design in a naturalistic rhesus monkey model of infant maltreatment, where infant monkeys were randomly assigned at birth to either a mother with a history of maltreating her infants, or a competent mother. Using a longitudinal diffusion tensor imaging (DTI) atlas-based tract-profile approach we identified widespread, but also specific, maturational changes on major brain tracts, as well as alterations in a measure of WM integrity (fractional anisotropy, FA) in the middle longitudinal fasciculus (MdLF) and the inferior longitudinal fasciculus (ILF), of maltreated animals, suggesting decreased structural integrity in these tracts due to early adverse experience. Exploratory voxelwise analyses confirmed the tract-based approach, finding additional effects of early adversity, biological mother, social dominance rank, and sex in other WM tracts. These results suggest tract-specific effects of postnatal maternal care experience versus heritable or biological factors on primate WM microstructural development. Further studies are needed to determine the specific behavioral outcomes and biological mechanisms associated with these alterations in WM integrity.

Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development.

Brain size and cognitive skills are the most dramatically changed traits in humans during evolution and yet the genetic mechanisms underlying these human-specific changes remain elusive. Here, we successfully generated 11 transgenic rhesus monkeys (8 first-generation and 3 second-generation) carrying human copies of MCPH1, an important gene for brain development and brain evolution. Brain-image and tissue-section analyses indicated an altered pattern of neural-cell differentiation, resulting in a delayed neuronal maturation and neural-fiber myelination of the transgenic monkeys, similar to the known evolutionary change of developmental delay (neoteny) in humans. Further brain-transcriptome and tissue-section analyses of major developmental stages showed a marked human-like expression delay of neuron differentiation and synaptic-signaling genes, providing a molecular explanation for the observed brain-developmental delay of the transgenic monkeys. More importantly, the transgenic monkeys exhibited better short-term memory and shorter reaction time compared with the wild-type controls in the delayed-matching-to-sample task. The presented data represent the first attempt to experimentally interrogate the genetic basis of human brain origin using a transgenic monkey model and it values the use of non-human primates in understanding unique human traits.

FOXO1 inhibition potentiates endothelial angiogenic functions in diabetes via suppression of ROCK1/Drp1-mediated mitochondrial fission.

Diabetes-induced endothelial cell (EC) dysfunction and neovascularization impairment constitute vascular complications with limited treatment regimens. Transcription factor FOXO1 is a key angiogenic regulator and plays a pathologic role in progression of diabetes. The present study was designed to determine the involvement of FOXO1 in impaired EC function and post-ischemic neovascularization in diabetes and investigate underlying mechanisms. We found that FOXO1-selective inhibitor AS1842856 improved blood flow recovery and capillary density in ischemic hindlimb, and rescued the delay of wound closure with a concomitant augmentation of mean perfusion rate in diabetic mice. In vitro, treatment with AS1842856 or FOXO1 siRNA abrogated high glucose-induced apoptosis and ameliorated capillary tube formation in human umbilical vein endothelial cells (HUVECs). FOXO1 inhibition relieved alterations in mitochondrial networks and significantly suppressed the overproduction of mitochondrial reactive oxygen species (mtROS) induced by high glucose in ECs. Expression of dynamin-related protein-1 (Drp1) and phosphorylation at Ser616, a protein required for mitochondrial fission, were enhanced by hyperglycemia, which could be neutralized by FOXO1 inhibition. Moreover, the transcription of Rho-associated coiled-coil containing protein kinase 1 (ROCK1), which phosphorylates Drp1 at Ser616, was shown by luciferase assay to be directly regulated by FOXO1. These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and function in ECs, and FOXO1 may serve as a therapeutic target for microvascular complications of diabetes.

Fatty acid-binding protein 4 predicts gestational hypertension and preeclampsia in women with gestational diabetes mellitus.

OBJECTIVE: Fatty acid-binding protein 4 (FABP4) has been proposed to be a potential predictive factor of gestational hypertension or preeclampsia (GH/PE) because of its integrating metabolic and inflammatory responses. Women with gestational diabetes mellitus (GDM) are more likely to develop both GH/PE, than the normal population. The aim of our study was to examine the relationship between plasma FABP4 in the second trimester of pregnancy and the risk of GH/PE in women with GDM. METHODS: This was a nested case-control study conducted within a large on-going prospective cohort study conducted at Peking University First Hospital. A total of 1344 women, who were diagnosed with GDM, according to a 75 g oral glucose tolerance test, participated in the GDM One-Day Clinic at Peking University First Hospital from February 24, 2016 to February 9, 2017. Of the 748 GDM women who agreed to the blood sample collection, 637 were followed until their delivery. The cases included GDM patients who developed gestational hypertension or preeclampsia (GDM-GH/PE group, n = 41). Another 41 matched GDM women without major complications were selected as the control group (GDM group). RESULTS: The incidence of GH/PE was 6.44% and 3.30% for preeclampsia. The level of the second trimester plasma FABP4 in the GDM-GH/PE group was significantly higher than the GDM group (17.53±11.35 vs. 12.79±6.04 ng/ml, P = 0.020). The AUC ROC for the second trimester plasma FABP4 predicted GH/PE in the GDM patients alone was 0.647 (95%CI 0.529-0.766). Multivariate analysis showed that the elevated second trimester FABP4 level was independently associated with GH/PE in the GDM patients (OR 1.136 [95% CI 1.003-1.286], P = 0.045). CONCLUSIONS: Increased second trimester plasma FABP4 independently predicted GH/PE in GDM patients.

Aquaporins in Cardiovascular System.

Recent studies have shown that some aquaporins (AQPs ), including AQP1, AQP4, AQP7 and AQP9, are expressed in endothelial cells, vascular smooth muscle cells and heart of cardiovascular system. These AQPs are involved in the cardiovascular function and in pathological process of related diseases, such as cerebral ischemia , congestion heart failure , hypertension and angiogenesis. Therefore, it is important to understand the accurate association between AQPs and cardiovascular system, which may provide novel approaches to prevent and treat related diseases. Here we will discuss the expression and physiological function of AQPs in cardiovascular system and summarize recent researches on AQPs related cardiovascular diseases.

The UNC-Wisconsin Rhesus Macaque Neurodevelopment Database: A Structural MRI and DTI Database of Early Postnatal Development.

Rhesus macaques are commonly used as a translational animal model in neuroimaging and neurodevelopmental research. In this report, we present longitudinal data from both structural and diffusion MRI images generated on a cohort of 34 typically developing monkeys from 2 weeks to 36 months of age. All images have been manually skull stripped and are being made freely available via an online repository for use by the research community.

Maternal buffering beyond glucocorticoids: impact of early life stress on corticolimbic circuits that control infant responses to novelty.

Maternal presence has a potent buffering effect on infant fear and stress responses in primates. We previously reported that maternal presence is not effective in buffering the endocrine stress response in infant rhesus monkeys reared by maltreating mothers. We have also reported that maltreating mothers show low maternal responsiveness and permissiveness/secure-base behavior. Although still not understood, it is possible that this maternal buffering effect is mediated, at least partially, through deactivation of amygdala response circuits when mothers are present. Here, we studied rhesus monkey infants that differed in the quality of early maternal care to investigate how this early experience modulated maternal buffering effects on behavioral responses to novelty during the weaning period. We also examined the relationship between these behavioral responses and structural connectivity in one of the underlying regulatory neural circuits: amygdala-prefrontal pathways. Our findings suggest that infant exploration in a novel situation is predicted by maternal responsiveness and structural integrity of amygdala-prefrontal white matter depending on maternal presence (positive relationships when mother is absent). These results provide evidence that maternal buffering of infant behavioral inhibition is dependent on the quality of maternal care and structural connectivity of neural pathways that are sensitive to early life stress.

Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1.

Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer.

UNC-Emory Infant Atlases for Macaque Brain Image Analysis: Postnatal Brain Development through 12 Months.

Computational anatomical atlases have shown to be of immense value in neuroimaging as they provide age appropriate reference spaces alongside ancillary anatomical information for automated analysis such as subcortical structural definitions, cortical parcellations or white fiber tract regions. Standard workflows in neuroimaging necessitate such atlases to be appropriately selected for the subject population of interest. This is especially of importance in early postnatal brain development, where rapid changes in brain shape and appearance render neuroimaging workflows sensitive to the appropriate atlas choice. We present here a set of novel computation atlases for structural MRI and Diffusion Tensor Imaging as crucial resource for the analysis of MRI data from non-human primate rhesus monkey (Macaca mulatta) data in early postnatal brain development. Forty socially-housed infant macaques were scanned longitudinally at ages 2 weeks, 3, 6, and 12 months in order to create cross-sectional structural and DTI atlases via unbiased atlas building at each of these ages. Probabilistic spatial prior definitions for the major tissue classes were trained on each atlas with expert manual segmentations. In this article we present the development and use of these atlases with publicly available tools, as well as the atlases themselves, which are publicly disseminated to the scientific community.

The DTI Challenge: Toward Standardized Evaluation of Diffusion Tensor Imaging Tractography for Neurosurgery.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) tractography reconstruction of white matter pathways can help guide brain tumor resection. However, DTI tracts are complex mathematical objects and the validity of tractography-derived information in clinical settings has yet to be fully established. To address this issue, we initiated the DTI Challenge, an international working group of clinicians and scientists whose goal was to provide standardized evaluation of tractography methods for neurosurgery. The purpose of this empirical study was to evaluate different tractography techniques in the first DTI Challenge workshop. METHODS: Eight international teams from leading institutions reconstructed the pyramidal tract in four neurosurgical cases presenting with a glioma near the motor cortex. Tractography methods included deterministic, probabilistic, filtered, and global approaches. Standardized evaluation of the tracts consisted in the qualitative review of the pyramidal pathways by a panel of neurosurgeons and DTI experts and the quantitative evaluation of the degree of agreement among methods. RESULTS: The evaluation of tractography reconstructions showed a great interalgorithm variability. Although most methods found projections of the pyramidal tract from the medial portion of the motor strip, only a few algorithms could trace the lateral projections from the hand, face, and tongue area. In addition, the structure of disagreement among methods was similar across hemispheres despite the anatomical distortions caused by pathological tissues. CONCLUSIONS: The DTI Challenge provides a benchmark for the standardized evaluation of tractography methods on neurosurgical data. This study suggests that there are still limitations to the clinical use of tractography for neurosurgical decision making.