Blocking Type I Interferon Production: A New Therapeutic Option to Reduce the HIV-1-Induced Immune Activation

Highly active antiretroviral therapy has dramatically improved the morbidity and mortality of HIV-1-infected individuals. A total of 25 licensed drugs provide the basis for an optimized virus-suppressive treatment of nearly each subject. The promises of immune reconstitution and normal life expectancy, however, fall short for a number of patients, either through inadequate recovery of CD4+ T-cell counts or the occurrence of non-AIDS defining malignancies. In this respect, the prevalence of Epstein-Barr virus-associated Hodgkin lymphoma and human papillomavirus-related anal neoplasia is rising in aging HIV-1-infected individuals despite antiretroviral therapy. An important cause appears to be the HIV-1-induced chronic immune activation, propagated by inappropriate release of proinflammatory cytokines and type I interferons. This immune dysregulation can be reduced in vitro by inhibitors blocking the endosomal acidification. Recent data suggest that this concept is also of relevance in vivo, which opens the door for adjuvant immunomodulatory therapies in HIV-1 infection

Internalisierung des Humanen Immundefizienz-Virus Typ 1 in plasmazytoide dendritische Zellen

Chronic immune activation plays an important role in the HIV-1 immunopathogenesis. Among other factors, it is characterized by a strong secretion of proinflammatory chemokines and cytokines, in particular the type 1 interferons (IFN). Although the type 1 IFN fulfill a protective function in HIV-1 infection, they also contribute to viral pathogenesis. The main producers of type 1 IFN are the plasmacytoid dendritic cells (PDCs), which can be stimulated by infectious and non-infectious HIV-1 and in particular virus-infected cells. Given the fact that the viral entry is essential for activation of PDCs, the aim of this study was to identify new cellular factors, which are involved in the HIV-1 uptake into PDCs and the virus-induced IFN-alpha induction. Using immuno-electron microscopy, the attachment and localization of HIV-1 in endosomes of PDCs was directly visualized for the first time. Cellular fractionation assays indicated that PDCs and CD4+ T cells internalized viral particles predominatly through endocytosis, with PDCs haboring significantly more HIV-1 particles in endosomal vesicles. Our data confirmed that the CD4 receptor was essentiell for the HIV-1 uptake in PDCs, leaving room for an additional attachment factor. Confocal imaging revealed that HIV-1 was located in intracellular compartments positive for Caveolin-1, the tetraspanin CD81, the early endosomal antigen 1 (EEA1), the Rab GTPases 5, 7 and 9 and the lysosomal-associated membrane protein 1 (LAMP-1). In functional assays it was demonstrated that a dynamin-dependent endocytosis, but not viral fusion or CD81, were involved in the IFN-alpha induction by HIV-1. Altogether the data of our study support the role of a CD4- and dynamin-dependent endocytosis for the entry and activation of HIV-1 in PDCs. This mechanism may become a new target for an adjuvant antiretroviral therapy to reduce the HIV-1 induced chronic immune activation.Die chronische Immunaktivierung spielt eine wichtige Rolle in der HIV-1 Pathogenese. Sie ist unter anderem durch eine stärkere Sekretion von proinflammatorischen Chemokinen und Zytokinen, wie den Typ I Interferonen (IFN) gekennzeichnet. Obwohl die Typ I IFN eine protektive Funktion in der HIV-1 Infektion erfüllen, tragen sie auch zur Immunpathogenese des Virus bei. Die Hauptproduzenten der Typ I IFN sind die plasmazytoiden dendritischen Zellen (PDCs), die durch infektiöses und nicht-infektiöses HIV-1 sowie durch Virus-infizierte Zellen stimuliert werden. Davon ausgehend, dass der Viruseintritt für die PDC-Aktivierung essentiell ist, war es das Ziel dieser Arbeit neue zelluläre Faktoren zu identifizieren, die an der Aufnahme von HIV-1 in die PDCs und an der Virus-bedingten IFN-alpha Induktion beteiligt sind. Über Immunelektronenmikroskopie konnten wir erstmals die Anheftung und Lokalisation von HIV-1 in Endosomen von PDCs direkt visualisieren. Die Ergebnisse der Zellfraktionierung deuteten darauf hin, dass PDCs und CD4+ T-Zellen einen großen Teil der Viruspartikel über Endozytose aufnehmen, wobei die PDCs HIV-1 effizienter in die endosomalen Vesikel internalisieren. Unsere Untersuchungen bestätigten, dass der CD4-Rezeptor essentiell für die HIV-1 Aufnahme in PDCs ist und lassen Raum für einen zusätzlichen Anheftungsfaktor. Die Kolokalisationsstudien zeigten, dass HIV-1 in intrazellulären Kompartimenten lokalisiert ist, die positiv für Caveolin-1, das Tetraspanin CD81, das frühe endosomale Antigen 1 (EEA1), die Rab GTPasen 5, 7 und 9 und das Lysosomen-assoziierte Membranprotein 1 (LAMP-1) sind. In funktionellen Untersuchungen konnte gezeigt werden, dass eine Dynamin-abhängige Endozytose, nicht aber die Fusion des Virus oder CD81, an der IFN-alpha Induktion durch HIV-1 beteiligt sind. Zusammenfassend unterstützen die Daten dieser Arbeit die Rolle einer CD4- und Dynamin-abhängigen Endozytose beim Eintritt und der Aktivierung von PDCs durch HIV-1. Dieser Mechanismus könnte neue Angriffspunkte für eine adjuvante antiretrovirale Therapie liefern, um die HIV-1-bedingte chronische Immunaktivierung zu dämpfen

Circadian Rhythms Tied to Changes in Brain Morphology in a Densely Sampled Male.

Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed 40 MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones

Exploring neuroendocrine influences on the sensorimotor-association axis in a female and a male individual

Human neuroimaging studies consistently show multimodal patterns of variabilityalong a key principle of macroscale cortical organization-thesensorimotor-association (S-A) axis. However, little is known about day-to-dayfluctuations in functional activity along this axis within an individual,including sex-specific neuroendocrine factors contributing to such transientchanges. We leveraged data from two densely sampled healthy young adults, onefemale and one male, to investigate intra-individual daily variability along theS-A axis, which we computed as our measure of functional cortical organizationby reducing the dimensionality of functional connectivity matrices. Dailyvariability was greatest in temporal limbic and ventral prefrontal regions inboth participants, and was more strongly pronounced in the male subject. Next,we probed local- and system-level effects of steroid hormones and self-reportedperceived stress on functional organization. Beyond shared patterns of effects,our findings revealed subtle and unique associations between neuroendocrinefluctuations and intra-individual variability along the S-A axis in the femaleand male participants. In sum, our study points to neuroendocrine factors aspossible modulators of intra-individual variability in functional brainorganization, highlighting the need for further research in larger samples toassess the sex specificity of these effects

The earth is flat (p < 0.05): significance thresholds and the crisis of unreplicable research

The widespread use of ‘statistical significance’ as a license for making a claim of a scientific finding leads to considerable distortion of the scientific process (according to the American Statistical Association). We review why degrading p -values into ‘significant’ and ‘nonsignificant’ contributes to making studies irreproducible, or to making them seem irreproducible. A major problem is that we tend to take small p -values at face value, but mistrust results with larger p -values. In either case, p -values tell little about reliability of research, because they are hardly replicable even if an alternative hypothesis is true. Also significance ( p ≤ 0.05) is hardly replicable: at a good statistical power of 80%, two studies will be ‘conflicting’, meaning that one is significant and the other is not, in one third of the cases if there is a true effect. A replication can therefore not be interpreted as having failed only because it is nonsignificant. Many apparent replication failures may thus reflect faulty judgment based on significance thresholds rather than a crisis of unreplicable research. Reliable conclusions on replicability and practical importance of a finding can only be drawn using cumulative evidence from multiple independent studies. However, applying significance thresholds makes cumulative knowledge unreliable. One reason is that with anything but ideal statistical power, significant effect sizes will be biased upwards. Interpreting inflated significant results while ignoring nonsignificant results will thus lead to wrong conclusions. But current incentives to hunt for significance lead to selective reporting and to publication bias against nonsignificant findings. Data dredging, p -hacking, and publication bias should be addressed by removing fixed significance thresholds. Consistent with the recommendations of the late Ronald Fisher, p -values should be interpreted as graded measures of the strength of evidence against the null hypothesis. Also larger p -values offer some evidence against the null hypothesis, and they cannot be interpreted as supporting the null hypothesis, falsely concluding that ‘there is no effect’. Information on possible true effect sizes that are compatible with the data must be obtained from the point estimate, e.g., from a sample average, and from the interval estimate, such as a confidence interval. We review how confusion about interpretation of larger p -values can be traced back to historical disputes among the founders of modern statistics. We further discuss potential arguments against removing significance thresholds, for example that decision rules should rather be more stringent, that sample sizes could decrease, or that p -values should better be completely abandoned. We conclude that whatever method of statistical inference we use, dichotomous threshold thinking must give way to non-automated informed judgment

Chronic Immune Activation in HIV-1 Infection Contributes to Reduced Interferon Alpha Production via Enhanced CD40:CD40 Ligand Interaction

Although a signature of increased interferon (IFN-)alpha production is observed in HIV-1 infection, the response of circulating plasmacytoid dendritic cells (PDC) to Toll-like receptor ligand stimulation is substantially impaired. This functional PDC deficit, which we specifically observed in HIV-1 infected individuals with less than 500 CD4+ T cells/µl, is not well understood. We provide evidence that the peripheral IFN-alpha production in HIV-1 infection is actively suppressed by the enhanced interaction of CD40 ligand (CD40L), a member of the tumor necrosis factor family, and its receptor CD40, which are both upregulated upon immune activation. Plasma levels of soluble CD40L were significantly higher in untreated HIV-1 infected individuals (n = 52) than in subjects on long-term antiretroviral therapy (n = 62, p<0.03) and in uninfected control donors (n = 16, p<0.001). Concomitantly, cell-associated CD40L and the expression of the receptor CD40 on the PDC were significantly upregulated in HIV-1 infection (p<0.05). Soluble and cell-associated CD40L inhibited the PDC-derived IFN-alpha production by CpG oligodeoxynucleotides dose-dependently. This suppressive effect was observed at much lower, physiological CD40L concentrations in peripheral blood mononuclear cells (PBMC) of HIV-1 infected individuals compared to controls (p<0.05). The CpG-induced IFN-alpha production in PBMC of HIV-1 infected donors was directly correlated with PDC and CD4+ T cell counts, and inversely correlated with the viral loads (p<0.001). In HIV-1 infected donors with less than 500 CD4+ T cells/µl, the CpG-induced IFN-alpha production was significantly correlated with the percentage of CD40-expressing PDC and the level of CD40 expression on these cells (p<0.05), whereas CD40L plasma levels played a minor role. In addition, low-dose CD40L contributed to the enhanced production of interleukin 6 and 8 in PBMC of HIV-1 infected donors compared to controls. Our data support the conclusion that the chronic immune activation in HIV-1 infection impairs peripheral PDC innate immune responses at least in part via enhanced CD40:CD40L interactions

Neuroanatomical changes observed over the course of a human pregnancy

Pregnancy is a period of profound hormonal and physiological change experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation have not been studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through two years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, which stand in contrast to increases in white matter microstructural integrity, ventricle volume, and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as the first comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to stimulate further exploration and discovery

Comparing thigh muscle cross-sectional area and squat strength among national class Olympic weightlifters, power lifters, and bodybuilders

Few studies have compared anthropometric characteristics among national class athletes from different resistance training disciplines, such as Olympic Weightlifting (OL), Power Lifting (PL), and Bodybuilding (BB). Objective: The purpose of the current study was to determine if significant differences exist in the relationship between thigh muscle cross-sectional area and back squat strength among national class athletes from the sports of OL, PL, and BB. Methods: Fifteen national class athletes were assessed for back squat strength, mid-thigh circumference, and mid-thigh skinfold from which total thigh cross-sectional was estimated. A series of One-Way ANOVAs and Pearson Product Moment Correlations were used to compare groups and assess the relationship between variables. Results: The OL (200.18 + 25.16kg) and PL (205.45 + 17.28kg) groups were significantly stronger than the BB (160 + 16.80 kg; p \u3c 0.05) group. However, mid-thigh skinfold thickness (p = 0.36), mid-thigh circumference (p = 0.87), and estimated thigh cross-sectional area (p = 0.34) were not significantly different between groups. Thigh muscle cross-sectional area was weakly correlated to back squat strength in the OL (r = .42) and PL (r = .12) groups, but moderately correlated in the BB (r = .70) group. Conclusion: Thigh cross-sectional area was of relatively minor importance in determining back squat strength for the OL and PL groups, despite these groups being significantly stronger than the BB group. Specific training protocols will elicit different outcomes with regard to muscular hypertrophy that may or may not contribute to a functional increase in back squat strength

The Menstrual Cycle Modulates Whole-Brain Turbulent Dynamics

Brain dynamics have recently been shown to be modulated by rhythmic changes in female sex hormone concentrations across an entire menstrual cycle. However, many questions remain regarding the specific differences in information processing across spacetime between the two main follicular and luteal phases in the menstrual cycle. Using a novel turbulent dynamic framework, we studied whole-brain information processing across spacetime scales (i.e., across long and short distances in the brain) in two open-source, dense-sampled resting-state datasets. A healthy naturally cycling woman in her early twenties was scanned over 30 consecutive days during a naturally occurring menstrual cycle and under a hormonal contraceptive regime. Our results indicated that the luteal phase is characterized by significantly higher information transmission across spatial scales than the follicular phase. Furthermore, we found significant differences in turbulence levels between the two phases in brain regions belonging to the default mode, salience/ventral attention, somatomotor, control, and dorsal attention networks. Finally, we found that changes in estradiol and progesterone concentrations modulate whole-brain turbulent dynamics in long distances. In contrast, we reported no significant differences in information processing measures between the active and placebo phases in the hormonal contraceptive study. Overall, the results demonstrate that the turbulence framework is able to capture differences in whole-brain turbulent dynamics related to ovarian hormones and menstrual cycle stages