Two chemoattenuated PfSPZ malaria vaccines induce sterile hepatic immunity.

The global decline in malaria has stalled1, emphasizing the need for vaccines that induce durable sterilizing immunity. Here we optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))-which kill liver-stage and blood-stage parasites, respectively-and we assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization ( https://clinicaltrials.gov/ , NCT02511054 and NCT03083847). We report that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 × 104 to 2 × 105 PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with Vδ2 γδ T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of P. falciparum, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African P. falciparum strains.

[Analysis of molecular and clinical characteristics of carbapenem-resistant hypervirulent Klebsiella pneumoniae in the intensive care unit].

To investigate the carbapenemases distribution of carbapenem-resistant Klebsiella pneumoniae (CRKP) in the intensive care unit, and the clinical characteristics between carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) and carbapenem-resistant non-hypervirulent Klebsiella pneumoniae (CR-non-hvKP) were compared. A total of 53 non-repetitive CRKP strains isolated from 49 patients in the intensive care unit of the Second Affiliated Hospital of Xi'an Jiaotong University from May 2020 to March 2021 were retrospectively studied. The carbapenemase inhibitor enhancement test was used for screening carbapenemase-producing strains, and the string test was carried out to screen the hypermucoviscosity phenotype. Using PCR to detect five main carbapenemase genes (blaKPC-2, blaNDM, blaIMP , blaVIM and blaOXA-48-like), common serotype (K1 and K2) and virulence gene (rmpA and iutA). Treated the strains with both rmpA and iutA genes as hypervirulent Klebsiella pneumonia (hvKP), and the whole genome sequencing of CR-hvKP was completed. At the same time, the clinical data of 49 patients were sorted out, and the differences in clinical characteristics of CR-hvKP and CR-non-hvKP infected patients were compared using the independent sample t test, Mann-Whitney U test, chi-square test or Fisher's exact probability test. CRKP isolated from the intensive care unit were extensively drug resistance and still had a good sensitivity to polymyxin B and tigecycline. Producing carbapenemases were the main resistance mechanism of CRKP (52/53, 98.1%). Of the 53 CRKP strains, except for 1strain that did not detect carbapenemase, at least one carbapenemase resistance gene was detected in the remaining 52 CRKP strains, of which 45 strains carried an enzyme, including 36 blaKPC-2 (36/53, 67.9%), 8 blaNDM (8/53, 15.1%), 1 blaIMP (1/53, 1.9%), and 7 strains carried with both blaKPC-2 and blaNDM (7/53, 13.2%). String test and virulence gene showed that 7 CR-hvKP strains (13.2%) were detected in 53 CRKP strains, and two of which were hypermucoviscosity phenotype. Sequencing results revealed that CR-hvKP were mainly ST11 type. Almost all patients with CR-hvKP infection were over 60 years old (7/7), with invasive treatment (7/7), pulmonary infection with hypermucoviscosity phenotype (2/7) and high mortality (5/7); and the percentage of neutrophils in patients with CR-hvKP infection (86.44±4.70) % was higher than those patients with CR-non-hvKP infection (78.90±19.15) %, the difference was statistically significant (t=-2.225, P=0.032). The CR-hvKP strains in the intensive care unit mainly produced KPC-2 enzyme, with K2 capsular serotype and ST11 type. It is necessary to strengthen the monitoring and control of the CR-hvKP strain to prevent the co-evolution of drug-resistant and hypervirulent strains.

Bone metabolism markers are associated with neck circumference in adult Arab women.

The study aimed to determine whether neck circumference is associated with bone metabolism markers among adult Arab women and found modest but significant associations with bone resorption markers, suggesting that neck circumference, a surrogate measure of upper subcutaneous fat, influences bone turnover expression among adult females. INTRODUCTION: Body fat distribution is associated with decreased bone resorption and neck circumference (NC), a surrogate measure for upper body fat, has never been tested as a marker that can reflect bone turnover. This is the first study aimed to analyze the associations between NC and several bone biomarkers among adult Saudi women. METHODS: This cross-sectional study included a total of 265 middle-aged Saudi women [86 non-obese (mean age 52.7 ± 8.1; mean BMI 26.9 ± 2.3) and 179 obese (mean age 50.6 ± 7.5; mean BMI 35.7 ± 4.5)] recruited from primary care centers in Riyadh, Saudi Arabia. Anthropometrics included BMI, NC, waist and hip circumferences, total body fat percentage (%), and blood pressure. Biochemical parameters included glucose and lipid profile which were measured routinely. Serum levels of 25(OH) D, parathyroid hormone, RANKl, sclerostin, C-terminal telopeptide of collagen I (CTX-I), Dkk1, IL1ß, osteoprotegerin, osteopontin, and osteocalcin were measured using commercially available assays. RESULTS: In all groups, NC was inversely associated with PTH (R = - 0.22; p < 0.05) and positively associated with osteoprotegerin (R = 0.20; p < 0.05) even after adjustments for age and BMI. Using all anthropometric indices as independent variables showed that only NC explained the variance perceived in CTX-I (p = 0.049). In the non-obese, waist-hip ratio (WHR) was significantly associated with sclerostin (R = 0.40; p < 0.05) and body fat was significantly associated with osteopontin (R = 0.42; p < 0.05). CONCLUSION: NC is modestly but significantly associated with bone biomarkers, particularly the bone resorption markers, among adult Arab women. The present findings highlight the importance of NC as measure of upper body subcutaneous fat in influencing bone biomarker expression in adult females.

Epstein-Barr virus infection and type I interferon signature in patients with systemic lupus erythematosus.

Epstein-Barr (EB) virus infection has long been speculated to evoke systemic lupus erythematosus (SLE). Since a virus infection can induce interferon (IFN) system activation, we aimed to discover the relationship between the two in the progression of SLE in a Chinese inpatient cohort. Methods Peripheral blood mononuclear cells and sera were isolated from 116 SLE patients and 76 healthy controls. Antibodies against EBV-VCA (IgM and IgG) and EBNA (IgG) along with IFNα in patient sera were detected with enzyme-linked immunosorbent assays. The EB virus DNA load was detected by real-time quantitative polymerase chain reaction. Peripheral blood mononuclear cells both from patients and controls were isolated immediately. The mRNA from these samples was subjected to real-time PCR for the latent genes EBNA1, EBNA2 and LMP1 of EB virus, as well as four IFN-stimulated genes (ISGs) ( OASL, MX1, ISG15 and LY6E). The antibody results were used to determine the stage of EBV infection (lytic, latent, or previous). Results SLE patients had a higher rate of lytic infection defined as positive EBV-VCA IgM antibody (39.66% vs 10.53%, p = 0.027), but not the EB virus DNA load. Patients with lytic EB virus infection had higher SLEDAI scores than patients with non-lytic infection (15.24 ± 2.63 vs 13.79 ± 3.24, p = 0.012). LMP1 was the only EBV gene that had a higher expression level in SLE patients than in healthy controls (3.26 ± 2.95 vs 1.00 ± 2.89, p = 0.000). It was also positively correlated with SLEDAI scores ( r = 0.462, p = 0.000). Levels of IFNα and the four ISGs were all significantly higher in SLE patients than in healthy controls ( p < 0.05). LMP1 was positively correlated with the four ISGs ( r = 0.403 ∼ 0.494, p < 0.05) in SLE patients but not in healthy controls ( r = -0.153 ∼ 0.129, p > 0.05). Neither EBNA1 nor EBNA2 was correlated with the ISGs in SLE patients or in healthy controls. Conclusions The SLE patients had higher rates of lytic EB virus infection and higher latent gene LMP1 expression, which might be associated with the development and/or the progression of SLE via the type I IFN pathway. The underlying mechanism needs more study.

Increased carotid intima-media thickness in African American pediatric kidney transplant recipients.

Early signs of subclinical CV dysfunction can be detected by ultrasound for CIMT. Although A-A are at high risk for CV disease, CIMT of A-A kidney transplant recipients has not been previously investigated. The aim of this prospective, controlled, longitudinal study was to investigate determinants of CIMT in a multiracial pediatric kidney transplant population, with a focus on A-A. Transplant recipients (n = 42) had BMI, waist-to-height ratio, fasting glucose, lipid panel, HbA1c%, and CIMT measured at 1, 18, and 30 months post-transplant. Twenty-four healthy children (14 A-A) served as controls. CIMT of A-A transplant (0.49, 0.49, and 0.48 mm) was higher than non-AA transplant (0.43, 0.44, and 0.44 mm) at 1, 18, and 30 months and higher than A-A controls (0.47 mm). Hyperparathyroidism prior to transplant predicted high CIMT-for-race. A-A race was associated with 10% higher CIMT vs non-A-A transplant. Metabolic syndrome was associated with 0.03 ± 0.01 mm increase in CIMT among A-A transplant recipients only. In conclusion, A-A kidney transplant recipients have increased CIMT. Metabolic syndrome disproportionately affects CIMT of A-A children post-transplant. Identification of subclinical CV damage, detected by CIMT, may provide an opportunity for early detection of CV risk in this vulnerable population.

Effects of obesity and metabolic syndrome on cardiovascular outcomes in pediatric kidney transplant recipients: a longitudinal study.

BACKGROUND: Obesity and metabolic syndrome (MS) are common after kidney transplantation, but their contribution to adverse cardiovascular (CV) outcomes in children are not well known. A prospective, controlled, longitudinal cohort study was conducted to investigate the effects of obesity and MS on left ventricular hypertrophy (LVH) and myocardial strain in pediatric kidney transplant recipients. METHODS: Transplant recipients (n = 42) had anthropometrics [body mass index (BMI), waist circumference, waist-to-height ratio], biochemical parameters (fasting glucose, lipid panel, HbA1c%), and echocardiogram with speckle tracking analysis for strain measured at 1, 18, and 30 months post-transplant. Additionally, 35 pre-transplant echocardiograms were analyzed retrospectively. Healthy children (n = 24) served as controls. RESULTS: Waist-to-height ratio detected abdominal obesity in 46% of transplant patients, whereas only 8.1% were identified as obese by waist circumference. Ejection fraction and fractional shortening of the transplant group were normal. Prevalence of LVH was 35.2%, 17.1%, and 35.5% at 1, 18, and 30 months respectively. The longitudinal strain of transplant group was worse than controls at all time points (p < 0.001). Hemodialysis was independently associated with 21% worse longitudinal strain during the pre-transplant period (p = 0.04). After transplantation, obesity, MS, and systolic hypertension predicted increased odds of LVH (p < 0.04). Worse longitudinal strain was independently associated with obesity, MS, hypertension, and the combination of MS with elevated low density lipoprotein (LDL) cholesterol (p < 0.04), whereas higher estimated glomerular filtration rate (eGFR) conferred a protective effect (p < 0.001). CONCLUSION: Obesity and MS adversely affect CV outcomes after transplantation. Further studies are needed to investigate speckle tracking echocardiography as a tool for early detection of subclinical myocardial dysfunction in this population.

Correction to: Effects of obesity and metabolic syndrome on cardiovascular outcomes in pediatric kidney transplant recipients: a longitudinal study.

As originally published, this article contained errors owing to oversights in typesetting. The article has now been amended accordingly.

Community Socioeconomic Disadvantage in Midlife Relates to Cortical Morphology via Neuroendocrine and Cardiometabolic Pathways.

Residing in communities of socioeconomic disadvantage confers risk for chronic diseases and cognitive aging, as well as risk for biological factors that negatively affect brain morphology. The present study tested whether community disadvantage negatively associates with brain morphology via 2 biological factors encompassing cardiometabolic disease risk and neuroendocrine function. Participants were 448 midlife adults aged 30-54 years (236 women) who underwent structural neuroimaging to assess cortical and subcortical brain tissue morphology. Community disadvantage was indexed by US Census data geocoded to participants' residential addresses. Cardiometabolic risk was indexed by measurements of adiposity, blood pressure, glucose, insulin, and lipids. Neuroendocrine function was indexed from salivary cortisol measurements taken over 3 days, from which we computed the cortisol awakening response, area-under-the-curve, and diurnal cortisol decline. Community disadvantage was associated with reduced cortical tissue volume, cortical surface area, and cortical thickness, but not subcortical morphology. Moreover, increased cardiometabolic risk and a flatter (dysregulated) diurnal cortisol decline mediated the associations of community disadvantage and cortical gray matter volume. These effects were independent of age, sex, and individual-level socioeconomic position. The adverse risks of residing in a disadvantaged community may extend to the cerebral cortex via cardiometabolic and neuroendocrine pathways.

[A study of clinical and genetic characteristics of a Leber hereditary optic neuropathy family with the heteroplasmic m.14484T>C mutation].

Objective: To study clinical and genetic characteristics of a Leber hereditary optic neuropathy (LHON) family with the heteroplasmic m.14484T>C mutation. Methods: A cross-sectional study. The objects of the study included a 31-year-old male LHON patient with the heteroplasmic m.14484T>C mutation (the proband) who visited Department of Ophthalmology in the Affiliated Central Hospital of Qingdao University in March 2015 and other 36 matrilineal relatives in a four-generation family (12 males and 24 females aged 2-81 years, median 27 years). The visual acuity, intraocular pressure, fundus, color vision, visual field, visual evoked potential and optical coherence tomography were evaluated in maternal members. The mitochondrial DNA (mtDNA) sequence of fragments including m.14484 loci was detected by Sanger sequencing in 33 members. The sequencing peaks were analyzed by QSVanalyzer software to get the heteroplasmy levels of m.14484T>C mutation. The mtDNA of the proband was amplified by PCR and sequenced. Assembled sequence of mtDNA was compared with the updated consensus Cambridge sequence. The differences in visual evoked potential, optical coherence tomography and heteroplasmy levels were compared between two groups by the t-test, and among multiple groups by the single factor variance analysis. Results: Among the 33 maternal members of the family, 4 patients, 28 carriers and 1 person without a mutation were confirmed. The penetrance was 12.5% (4/32) . In addition to 4 patients with obvious abnormality on the ophthalmic examination, 5 carriers also appeared anomaly on the electrophysiological and visual function examinations. Compared to carriers, the amplitude of P100 was obviously decreased in the LHON patients[ (5.6±2.6) µV vs. (15.6±9.6) µV, t=2.880, P=0.006]. Significantly reduced values were seen in the average retinal nerve fiber layer thickness[ (71±17) µm vs. (99±11) µm, t=5.969, P< 0.001], in each side of the sub-area macular thickness, and in the nasal side of the lateral sub-area macular thickness [ (260±16) µm vs. (291±12) µm, t=5.593, P<0.001] between the LHON patients and carriers. The heteroplasmic levels were 80%±3% in the LHON patients, and 27%±18% in the unaffected members;the difference was significant (t=-8.395, P<0.001). The average degree of heteroplasmy had no difference between male and female members (48%±34% vs. 35%±28%, t=-1.147, P=0.258). The average mutation load was 29%±14% in the second generation members, 36%±29% in the third generation members, and 51%±36% in the fourth generation members;the differences were not statistically significant (F=1.152, P=0.330). The difference in the heteroplasmic levels was not statistically significant between mothers and their offspring (31%±25% vs. 42%±32%, t=1.165, P=0.251). Compared to Cambridge consensus sequence, 41 mutations was found in mtDNA of the proband, of which, 10 were missense mutations, including mutations m.4216T>C and m.3394T>C. According to the phylogenetic tree, the haplotype of the proband was M9a (M9a1a1c1a). Conclusions: In the family with the heteroplasmic m.14484T>C mutation, clinical manifestations of LHON appear in the individuals whose heteroplasmic level is more than 75%, and all of patients show typical chronic optic atrophy on the ophthalmic examination. The carriers with the m.14484T>C mutation also appear anomaly on the electrophysiological and visual function examinations. The heteroplasmic level of m.14484T>C mutation has a tendency to increase during the transmission in the family. The primary mutation m.14484T>C coordinate mutations m.4216T>C and m.3394T>C to increase the penetrance and incidence of abnormal visual function in carriers. (Chin J Ophthalmol, 2018, 54: 526-534).

Effects of pair bonding on parental behavior and dopamine activity in the nucleus accumbens in male prairie voles.

Male parental care is a vital behavior for the development as well as the physical and mental well-being of the young. However, little is known about the neurochemical regulation of male parental behavior, mainly due to the lack of appropriate animal models. In this study, we used the socially monogamous male prairie vole (Microtus ochrogaster) to investigate the effect of pair-bonding experience on paternal behavior and dopamine (DA) signaling in the nucleus accumbens (NAcc) in the brain. We compared sexually naïve males with males that were pair bonded with a female for two weeks. Our data showed that pair-bonded males displayed enhanced paternal behavior, particularly in pup licking/grooming, associated with increased DA type-1 receptor (D1R) protein expression in the NAcc, compared to sexually naïve males. Site-specific brain microdialysis revealed a significant, but transient, increase in DA release in the NAcc associated with pup exposure in both groups of the males. Further, pharmacological blockade of D1R in the NAcc decreased pup licking/grooming in the pair-bonded males. Together, our data demonstrate that pair-bonding experience with a female facilitated male parental behavior via NAcc D1R mediation in male prairie voles.

Systemic inflammation and resting state connectivity of the default mode network.

The default mode network (DMN) encompasses brain systems that exhibit coherent neural activity at rest. DMN brain systems have been implicated in diverse social, cognitive, and affective processes, as well as risk for forms of dementia and psychiatric disorders that associate with systemic inflammation. Areas of the anterior cingulate cortex (ACC) and surrounding medial prefrontal cortex (mPFC) within the DMN have been implicated specifically in regulating autonomic and neuroendocrine processes that relate to systemic inflammation via bidirectional signaling mechanisms. However, it is still unclear whether indicators of inflammation relate directly to coherent resting state activity of the ACC, mPFC, or other areas within the DMN. Accordingly, we tested whether plasma interleukin (IL)-6, an indicator of systemic inflammation, covaried with resting-state functional connectivity of the DMN among 98 adults aged 30-54 (39% male; 81% Caucasian). Independent component analyses were applied to resting state fMRI data to generate DMN connectivity maps. Voxel-wise regression analyses were then used to test for associations between IL-6 and DMN connectivity across individuals, controlling for age, sex, body mass index, and fMRI signal motion. Within the DMN, IL-6 covaried positively with connectivity of the sub-genual ACC and negatively with a region of the dorsal medial PFC at corrected statistical thresholds. These novel findings offer evidence for a unique association between a marker of systemic inflammation (IL-6) and ACC and mPFC functional connectivity within the DMN, a network that may be important for linking aspects of immune function to psychological and behavioral states in health and disease.

Childhood maltreatment moderates the effect of combat exposure on cingulum structural integrity.

Limbic white matter pathways link emotion, cognition, and behavior and are potentially malleable to the influences of traumatic events throughout development. However, the impact of interactions between childhood and later life trauma on limbic white matter pathways has yet to be examined. Here, we examined whether childhood maltreatment moderated the effect of combat exposure on diffusion tensor imaging measures within a sample of military veterans (N = 28). We examined five limbic tracts of interest: two components of the cingulum (cingulum, cingulate gyrus, and cingulum hippocampus [CGH]), the uncinate fasciculus, the fornix/stria terminalis, and the anterior limb of the internal capsule. Using effect sizes, clinically meaningful moderator effects were found only within the CGH. Greater combat exposure was associated with decreased CGH fractional anisotropy (overall structural integrity) and increased CGH radial diffusivity (perpendicular water diffusivity) among individuals with more severe childhood maltreatment. Our findings provide preliminary evidence of the moderating effect of childhood maltreatment on the relationship between combat exposure and CGH structural integrity. These differences in CGH structural integrity could have maladaptive implications for emotion and memory, as well as provide a potential mechanism by which childhood maltreatment induces vulnerability to later life trauma exposure.

The study of progesterone action in human myometrial explants.

STUDY HYPOTHESIS: Myometrial explants represent a superior model compared with cell culture models for the study of human myometrial progesterone (P4) signalling in parturition. STUDY FINDING: Gene expression analysis showed myometrial explants closely resemble the in vivo condition and the anti-inflammatory action of P4 is not lost with labour onset. WHAT IS KNOWN ALREADY: Circulating P4 levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is a functional withdrawal of P4 action at the myometrial level prior to labour onset. However, to date, no evidence of a loss of P4 function has been provided, with studies hampered by a lack of a physiologically relevant model. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Myometrial biopsies obtained at Caesarean section were dissected into explants after a portion was immediately snap frozen (t = 0). Microarray analysis was used to compare gene expression of t = 0 with paired (i) explants, (ii) passage 4 myometrial cell cultures or (iii) the hTERT myometrial cell line. Western blotting and chemokine/cytokine assays were used to study P4 signalling in myometrial explants. MAIN RESULTS AND THE ROLE OF CHANCE: Gene expression comparison of t = 0 to the three models demonstrated that explants more closely resemble the in vivo status. At the protein level, explants maintain both P4 receptor (PR) and glucocorticoid receptor (GR) levels versus t = 0 whereas cells only maintain GR levels. Additionally, treatment with 1 µM P4 led to a reduction in interleukin-1 (IL-1) ß-driven cyclooxygenase-2 in explants but not in cells. P4 signalling in explants was PR-mediated and associated with a repression of p65 and c-Jun phosphorylation. Furthermore, the anti-inflammatory action of P4 was maintained after labour onset. LIMITATIONS/REASONS FOR CAUTION: There is evidence of basal inflammation in the myometrial explant model. WIDER IMPLICATIONS OF THE FINDINGS: Myometrial explants constitute a novel model to study P4 signalling in the myometrium and can be used to further elucidate the mechanisms of P4 action in human labour. LARGE SCALE DATA: Data deposited at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=gvmpggkurbgxfqf&acc=GSE77830. STUDY FUNDING AND COMPETING INTEREST: This work was supported by grants from the Joint Research Committee of the Westminster Medical School Research Trust, Borne (No. 1067412-7; a sub-charity of the Chelsea and Westminster Health Charity) and the Imperial NIHR Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS or the Department of Health. The authors have no conflict of interest.

Methylation-sensitive amplified polymorphism analysis of Verticillium wilt-stressed cotton (Gossypium).

In this study, a methylation-sensitive amplification polymorphism analysis system was used to analyze DNA methylation level in three cotton accessions. Two disease-sensitive near-isogenic lines, PD94042 and IL41, and one disease-resistant Gossypium mustelinum accession were exposed to Verticillium wilt, to investigate molecular disease resistance mechanisms in cotton. We observed multiple different DNA methylation types across the three accessions following Verticillium wilt exposure. These included hypomethylation, hypermethylation, and other patterns. In general, the global DNA methylation level was significantly increased in the disease-resistant accession G. mustelinum following disease exposure. In contrast, there was no significant difference in the disease-sensitive accession PD94042, and a significant decrease was observed in IL41. Our results suggest that disease-resistant cotton might employ a mechanism to increase methylation level in response to disease stress. The differing methylation patterns, together with the increase in global DNA methylation level, might play important roles in tolerance to Verticillium wilt in cotton. Through cloning and analysis of differently methylated DNA sequences, we were also able to identify several genes that may contribute to disease resistance in cotton. Our results revealed the effect of DNA methylation on cotton disease resistance, and also identified genes that played important roles, which may shed light on the future cotton disease-resistant molecular breeding.

Brain morphology links systemic inflammation to cognitive function in midlife adults.

BACKGROUND: Inflammation is linked to cognitive decline in midlife, but the neural basis for this link is unclear. One possibility is that inflammation associates with adverse changes in brain morphology, which accelerates cognitive aging and later dementia risk. Clear evidence is lacking, however, regarding whether inflammation relates to cognition in midlife via changes in brain morphology. Accordingly, the current study examines whether associations of inflammation with cognitive function are mediated by variation in cortical gray matter volume among midlife adults. METHODS: Plasma levels of interleukin (IL)-6 and C-reactive protein (CRP), relatively stable markers of peripheral systemic inflammation, were assessed in 408 community volunteers aged 30-54 years. All participants underwent structural neuroimaging to assess global and regional brain morphology and completed neuropsychological tests sensitive to early changes in cognitive function. Measurements of brain morphology (regional tissue volumes and cortical thickness and surface area) were derived using Freesurfer. RESULTS: Higher peripheral inflammation was associated with poorer spatial reasoning, short term memory, verbal proficiency, learning and memory, and executive function, as well as lower cortical gray and white matter volumes, hippocampal volume and cortical surface area. Mediation models with age, sex and intracranial volume as covariates showed cortical gray matter volume to partially mediate the association of inflammation with cognitive performance. Exploratory analyses of body mass suggested that adiposity may be a source of the inflammation linking brain morphology to cognition. CONCLUSIONS: Inflammation and adiposity might relate to cognitive decline via influences on brain morphology.

Emotion reactivity and regulation in late-life generalized anxiety disorder: functional connectivity at baseline and post-treatment.

OBJECTIVES: Generalized anxiety disorder (GAD) is one of the most prevalent mental disorders in the elderly, but its functional neuroanatomy is not well understood. Given the role of emotion dysregulation in GAD, we sought to describe the neural bases of emotion regulation in late-life GAD by analyzing the functional connectivity (FC) in the Salience Network and the Executive Control Network during worry induction and worry reappraisal. METHODS: The study included 28 elderly GAD and 31 non-anxious comparison participants. Twelve elderly GAD completed a 12-week pharmacotherapy trial. We used an in-scanner worry script that alternates blocks of worry induction and reappraisal. We assessed network FC, using the following seeds: anterior insula (AI), dorsolateral prefrontal cortex (dlPFC), the bed nucleus of stria terminalis (BNST), and the paraventricular nucleus (PVN). RESULTS: GAD participants exhibited greater FC during worry induction between the left AI and the right orbitofrontal cortex, and between the BNST and the subgenual cingulate. During worry reappraisal, the non-anxious participants had greater FC between the left dlPFC and the medial PFC, as well as between the left AI and the medial PFC, and elderly GAD patients had greater FC between the PVN and the amygdala. Following 12 weeks of pharmacotherapy, GAD participants had greater connectivity between the dlPFC and several prefrontal regions during worry reappraisal. CONCLUSION: FC during worry induction and reappraisal points toward abnormalities in both worry generation and worry reappraisal. Following successful pharmacologic treatment, we observed greater connectivity in the prefrontal nodes of the Executive Control Network during reappraisal of worry.

The ages of anxiety--differences across the lifespan in the default mode network functional connectivity in generalized anxiety disorder.

OBJECTIVES: Generalized anxiety disorder (GAD) is one of the most prevalent anxiety disorders, but its neural basis is relatively understudied. This study aims to characterize the functional connectivity in the default mode network (DMN) in GAD across the lifespan. DESIGN AND SETTINGS: Functional and structural magnetic resonance imaging data were collected with subjects at rest. We analyzed the resting state functional connectivity patterns in the DMN for 27 GAD participants and 39 non-anxious comparison participants. Using a two-way analysis of variance, we explored the interaction between age and GAD status on functional connectivity. In GAD participants, we analyzed the correlation of functional connectivity indices with the duration of illness and worry severity. RESULTS: The age-by-anxiety interaction showed a greater anxiety effect on the functional connectivity between the posterior cingulate seed and the medial prefrontal cortex for the older group relative to the younger participants. Longer duration of illness was positively correlated with greater functional connectivity between the posterior cingulate cortex and the insula. Worry severity was inversely correlated with the functional connectivity between the posterior cingulate cortex seed and the medial prefrontal cortex. CONCLUSION: The presence of GAD, longer duration of illness, and more severe worry exacerbate the effects of age on the functional connectivity in the DMN. These results support the need for tailored research and interventions in late-life anxiety.

Inflammatory pathways link socioeconomic inequalities to white matter architecture.

Socioeconomic disadvantage confers risk for aspects of ill health that may be mediated by systemic inflammatory influences on the integrity of distributed brain networks. Following this hypothesis, we tested whether socioeconomic disadvantage related to the structural integrity of white matter tracts connecting brain regions of distributed networks, and whether such a relationship would be mediated by anthropometric, behavioral, and molecular risk factors associated with systemic inflammation. Otherwise healthy adults (N= 155, aged 30-50 years, 78 men) completed protocols assessing multilevel indicators of socioeconomic position (SEP), anthropometric and behavioral measures of adiposity and cigarette smoking, circulating levels of C-reactive protein (CRP), and white matter integrity by diffusion tensor imaging. Mediation modeling was used to test associations between SEP indicators and measures of white matter tract integrity, as well as indirect mediating paths. Measures of tract integrity followed a socioeconomic gradient: individuals completing more schooling, earning higher incomes, and residing in advantaged neighborhoods exhibited increases in white matter fractional anisotropy and decreases in radial diffusivity, relative to disadvantaged individuals. Moreover, analysis of indirect paths showed that adiposity, cigarette smoking, and CRP partially mediated these effects. Socioeconomic inequalities may relate to diverse health disparities via inflammatory pathways impacting the structural integrity of brain networks.

METTL3 Modulates Ctsk+ Lineage Supporting Cranial Osteogenesis via Hedgehog.

N6-methyladenosine (m6A) modification, a eukaryotic messenger RNA modification catalyzed by methyltransferase-like 3 (METTL3), plays a pivotal role in stem cell fate determination. Calvarial bone development and maintenance are orchestrated by the cranial sutures. Cathepsin K (CTSK)-positive calvarial stem cells (CSCs) contribute to mice calvarial ossification. However, the role of m6A modification in regulating Ctsk+ lineage cells during calvarial development remains elusive. Here, we showed that METTL3 was colocalized with cranial nonosteoclastic Ctsk+ lineage cells, which were also associated with GLI1 expression. During neonatal development, depletion of Mettl3 in the Ctsk+ lineage cells delayed suture formation and decreased mineralization. During adulthood maintenance, loss of Mettl3 in the Ctsk+ lineage cells impaired calvarial bone formation, which was featured by the increased bone porosity, enhanced bone marrow cavity, and decreased number of osteocytes with the less-developed cellular outline. The analysis of methylated RNA immunoprecipitation sequencing and RNA sequencing data indicated that loss of METTL3 reduced Hedgehog (Hh) signaling pathway. Restoration of Hh signaling pathway by crossing Sufufl/+ alleles or by local administration of SAG21 partially rescued the abnormity. Our data indicate that METTL3 modulates Ctsk+ lineage cells supporting calvarial bone formation by regulating the Hh signaling pathway, providing new insights for clinical treatment of skull vault osseous diseases.

Competing physiological pathways link individual differences in weight and abdominal adiposity to white matter microstructure.

Being overweight or obese is associated with reduced white matter integrity throughout the brain. It is not yet clear which physiological systems mediate the association between inter-individual variation in adiposity and white matter. We tested whether composite indicators of cardiovascular, lipid, glucose, and inflammatory factors would mediate the adiposity-related variation in white matter microstructure, measured with diffusion tensor imaging on a group of neurologically healthy adults (N=155). A composite factor representing adiposity (comprised of body mass index and waist circumference) was associated with smaller fractional anisotropy and greater radial diffusivity throughout the brain, a pattern previously linked to myelin structure changes in non-human animal models. A similar global negative association was found for factors representing inflammation and, to a lesser extent, glucose regulation. In contrast, factors for blood pressure and dyslipidemia had positive associations with white matter in isolated brain regions. Taken together, these competing influences on the diffusion signal were significant mediators linking adiposity to white matter and explained up to fifty-percent of the adiposity-white matter variance. These results provide the first evidence for contrasting physiological pathways, a globally distributed immunity-linked negative component and a more localized vascular-linked positive component, that associate adiposity to individual differences in the microstructure of white matter tracts in otherwise healthy adults.