Determinants of the essential one-carbon metabolism metabolites, homocysteine, S-adenosylmethionine, S-adenosylhomocysteine and folate, in cerebrospinal fluid

Background: Disturbances in the levels of one-carbon (1C) metabolism metabolites have been associated with a wide variety of neuropsychiatric diseases. Cerebrospinal fluid (CSF) levels of homocysteine (Hcy) and the other 1C metabolites, nor their interrelatedness and putative determinants, have been studied extensively in a healthy population. Methods: Plasma and CSF samples from 100 individuals free from neuropsychiatric diseases were analyzed (55 male, 45 female; age 50±17 years). In blood, we measured plasma Hcy, serum folate and serum vitamin B12. In CSF, we measured total Hcy, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and 5-methyltetrahydrofolate (5-methylTHF). Highly selective analytical methods like liquid chromatography combined with either mass spectrometry or fluorescence detection were used. Results: CSF Hcy was inversely correlated with CSF 5-methylTHF and positively with plasma Hcy, independent of serum folate status. CSF SAH correlated with age, lower CSF 5-methylTHF and higher CSF Hcy. CSF 5-methylTHF showed independent negative correlations with age and positive correlations with serum folate. CSF SAM did not correlate with any of the 1C metabolites. Conclusions: Aging is characterized by a reduction in CSF 5-methylTHF levels and increased CSF levels of the potentially neurotoxic transmethylation inhibitor SAH. CSF 5-methylTHF, which is itself determined in part by systemic folate status, is a powerful independent determinant of CSF levels of Hcy and SA

Home and epigenome: How DNA methylation could explain the association between housing quality and depression

Poor housing quality is a consistent risk factor for mental health problems. Despite the large body of evidence for housing’s relationship with mental health, housing quality as an environmental stressor has not yet been investigated with regards to the mediational process of DNA methylation. Previous investigations have provided little insight into the biological mechanisms through which this association may arise and been limited by insufficient control of socioeconomic status (SES) and baseline depression. By investigating the mediational role of DNA methylation in the association between housing and mental health, this research paper aimed to investigate housing’s potential as both a protectant and opportunity for intervention for mental health on a population-level. In a sample of up to 6,446 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC), we set out to investigate if housing quality (e.g. size, facilities, condensation/mould, decorations and feelings towards the home) associated with depressive symptoms (Crown Crisp Experiential Index depression scores) in early or middle adulthood (mean age 29 and 48, respectively). In these associations we controlled for neighbourhood quality, housing stability (the number of times the individual moved house in the previous 5 years), contextual risk (including socioeconomic factors such as experiences of losing a job, reduced income, homelessness) and familial history of depression (known history of persistent low mood or known diagnoses in parents). We then investigated whether this association was mediated by DNA methylation, measured at the same time points in a sub-sample of these mothers with blood sample data (n=786), whilst controlling for cell-type heterogeneity, total fat-mass, age and smoking. Housing quality predicted depression consistently over 3 years in early adulthood (beta range: .316 to 1.21, all p-values <.003), even after controlling for multiple SES risks, familial depression risk, 5-year housing stability, baseline depression at age 28 and neighbourhood quality. However, housing quality did not predict depression in middle adulthood (beta = 0.63, p value = .251). In an epigenome-wide association analysis (EWAS), housing quality was associated with DNA methylation at 4 CpG sites at age 29 with suggestive evidence for 391 CpGs, as defined in Smith et al. (2021). Following up on these 391 CpGs using high-dimensional mediational analysis, the largest indirect effect, mediating the association between housing and depression at age 29, was detected for a CpG linked to gene SLCO4A1 (beta = -.009, p-value = .052). The smallest indirect effect, mediating the association between housing and depression at age 48, was detected for a CpG linked to gene Mir_544 (beta = -.076, p-value = .037). These results demonstrate the importance of housing quality in depression’s aetiology, especially in early adulthood. However, our findings point towards limited evidence for single CpG sites mediating this association, suggesting a more complex relationship between housing quality, DNA methylation and depression. Moreover, our findings suggest the role of housing quality in the aetiology of depression may vary across the lifespan

A glassy contribution to the heat capacity of hcp 4^4He solids

We model the low-temperature specific heat of solid $^4$He in the hexagonal closed packed structure by invoking two-level tunneling states in addition to the usual phonon contribution of a Debye crystal for temperatures far below the Debye temperature, $T < \Theta_D/50$. By introducing a cutoff energy in the two-level tunneling density of states, we can describe the excess specific heat observed in solid hcp $^4$He, as well as the low-temperature linear term in the specific heat. Agreement is found with recent measurements of the temperature behavior of both specific heat and pressure. These results suggest the presence of a very small fraction, at the parts-per-million (ppm) level, of two-level tunneling systems in solid $^4$He, irrespective of the existence of supersolidity.Comment: 11 pages, 4 figure

Out-of-Sequence Signal 3 Paralyzes Primary CD4+ T-Cell-Dependent Immunity

SummaryPrimary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing “bystander” T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4+ T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4+ but not CD8+ T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4+ T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4+ T cells during inflammatory conditions

X-ray Survey Results on Active Galaxy Physics and Evolution

This "pedagogical" review describes the key Chandra and XMM-Newton extragalactic surveys to date and details some of their implications for AGN physics and evolution. We additionally highlight two topics of current widespread interest: (1) X-ray constraints on the AGN content of luminous submillimeter galaxies, and (2) the demography and physics of high-redshift (z > 4) AGN as revealed by X-ray observations. Finally, we discuss prospects for future X-ray surveys with Chandra, XMM-Newton, and upcoming missions.Comment: 26 pages, in Physics of Active Galactic Nuclei at All Scales, eds. Alloin D., Johnson R., Lira P. (Springer-Verlag, Berlin), version with all figures at http://www.astro.psu.edu/users/niel/papers/papers.htm

For science, love and money: the social worlds of poultry and rabbit breeding in Britain, 1900-1940

This paper traces the joint histories of poultry and rabbit breeding by fanciers, and for commercial and scientific purposes, in early 20th-century Britain. I show that the histories of the social worlds that bred for these different purposes are intertwined, as are the histories of poultry and rabbit breeding in general. To properly understand the history of scientific breeding we must therefore understand the general context of breeding in which this occurred. In the paper I show that as fancy poultry and rabbits were taken up for scientific research at the start of the 20th century they became scientific specimens and boundary objects between the social worlds. Their existence as boundary objects motivated the social worlds to coordinate their work through translators and trading zones. By the 1930s all three coordination methods were being used simultaneously

Star Formation and Dynamics in the Galactic Centre

The centre of our Galaxy is one of the most studied and yet enigmatic places in the Universe. At a distance of about 8 kpc from our Sun, the Galactic centre (GC) is the ideal environment to study the extreme processes that take place in the vicinity of a supermassive black hole (SMBH). Despite the hostile environment, several tens of early-type stars populate the central parsec of our Galaxy. A fraction of them lie in a thin ring with mild eccentricity and inner radius ~0.04 pc, while the S-stars, i.e. the ~30 stars closest to the SMBH (<0.04 pc), have randomly oriented and highly eccentric orbits. The formation of such early-type stars has been a puzzle for a long time: molecular clouds should be tidally disrupted by the SMBH before they can fragment into stars. We review the main scenarios proposed to explain the formation and the dynamical evolution of the early-type stars in the GC. In particular, we discuss the most popular in situ scenarios (accretion disc fragmentation and molecular cloud disruption) and migration scenarios (star cluster inspiral and Hills mechanism). We focus on the most pressing challenges that must be faced to shed light on the process of star formation in the vicinity of a SMBH.Comment: 68 pages, 35 figures; invited review chapter, to be published in expanded form in Haardt, F., Gorini, V., Moschella, U. and Treves, A., 'Astrophysical Black Holes'. Lecture Notes in Physics. Springer 201

A Measurement of Psi(2S) Resonance Parameters

Cross sections for e+e- to hadons, pi+pi- J/Psi, and mu+mu- have been measured in the vicinity of the Psi(2S) resonance using the BESII detector operated at the BEPC. The Psi(2S) total width; partial widths to hadrons, pi+pi- J/Psi, muons; and corresponding branching fractions have been determined to be Gamma(total)= (264+-27) keV; Gamma(hadron)= (258+-26) keV, Gamma(mu)= (2.44+-0.21) keV, and Gamma(pi+pi- J/Psi)= (85+-8.7) keV; and Br(hadron)= (97.79+-0.15)%, Br(pi+pi- J/Psi)= (32+-1.4)%, Br(mu)= (0.93+-0.08)%, respectively.Comment: 8 pages, 6 figure