Adult attachment style across individuals and role-relationships: Avoidance is relationship-specific, but anxiety shows greater generalizability

A generalisability study examined the hypotheses that avoidant attachment, reflecting the representation of others, should be more relationship-specific (vary across relationships more than across individuals), while attachment anxiety, reflecting self-representation, should be more generalisable across a person’s relationships. College students responded to 6-item questionnaire measures of these variables for 5 relationships (mother, father, best same-gender friend, romantic partner or best opposite-gender friend, other close person), on 3 (N = 120) or 2 (N = 77) occasions separated by a few weeks. Results supported the hypotheses, with the person variance component being larger than the relationship-specific component for anxiety, and the opposite happening for avoidance. Anxiety therefore seems not to be as relationship-specific as previous research suggested. Possible reasons for discrepancies between the current and previous studies are discussed

Interleukin-10 signaling blocks inhibitor of κB kinase activity and nuclear factor κB DNA binding

The transcription factor nuclear factor κB (NF-κB) coordinates the activation of numerous genes in response to pathogens and proinflammatory cytokines and is, therefore, pivotal in the development of acute and chronic inflammatory diseases. In its inactive state, NF-κB is constitutively present in the cytoplasm as a p50-p65 heterodimer bound to its inhibitory protein IκB. Proinflammatory cytokines, such as tumor necrosis factor (TNF), activate NF-κB by stimulating the activity of the IκB kinases (IKKs) which phosphorylate IκBα on serine residues 32 and 36, targeting it for rapid degradation by the 26 S proteasome. This enables the release and nuclear translocation of the NF-κB complex and activation of gene transcription. Interleukin-10 (IL-10) is a pleiotropic cytokine that controls inflammatory processes by suppressing the production of proinflammatory cytokines which are known to be transcriptionally controlled by NF-κB. Conflicting data exists on the effects of IL-10 on TNF- and LPS-induced NF-≃B activity in human monocytes and the molecular mechanisms involved have not been elucidated. In this study, we show that IL-10 functions to block NF-≃B activity at two levels: 1) through the suppression of IKK activity and 2) through the inhibition of NF-κB DNA binding activity. This is the first evidence of an anti-inflammatory protein inhibiting IKK activity and demonstrates that IKK is a logical target for blocking inflammatory diseases

VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma

Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC

Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss

von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC. © 2020 Elsevier Inc.The pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC

Developing an inverted Barrovian sequence; insights from monazite petrochronology

In the Himalayan region of Sikkim, the well-developed inverted metamorphic sequence of the Main Central Thrust (MCT) zone is folded, thus exposing several transects through the structure that reached similar metamorphic grades at different times. In-situ LA-ICP-MS U–Th–Pb monazite ages, linked to pressure–temperature conditions via trace-element reaction fingerprints, allow key aspects of the evolution of the thrust zone to be understood for the first time. The ages show that peak metamorphic conditions were reached earliest in the structurally highest part of the inverted metamorphic sequence, in the Greater Himalayan Sequence (GHS) in the hanging wall of the MCT. Monazite in this unit grew over a prolonged period between ~37 and 16 Ma in the southerly leading-edge of the thrust zone and between ~37 and 14.5 Ma in the northern rear-edge of the thrust zone, at peak metamorphic conditions of ~790 ◦C and 10 kbar. Monazite ages in Lesser Himalayan Sequence (LHS) footwall rocks show that identical metamorphic conditions were reached ~4–6 Ma apart along the ~60 km separating samples along the MCT transport direction. Upper LHS footwall rocks reached peak metamorphic conditions of ~655 ◦C and 9 kbar between ~21 and 16 Ma in the more southerly-exposed transect and ~14.5–12 Ma in the northern transect. Similarly, lower LHS footwall rocks reached peak metamorphic conditions of ~580 ◦C and 8.5 kbar at ~16 Ma in the south, and 9–10 Ma in the north. In the southern transect, the timing of partial melting in the GHS hanging wall (~23–19.5 Ma) overlaps with the timing of prograde metamorphism (~21 Ma) in the LHS footwall, confirming that the hanging wall may have provided the heat necessary for the metamorphism of the footwall. Overall, the data provide robust evidence for progressively downwards-penetrating deformation and accretion of original LHS footwall material to the GHS hanging wall over a period of ~5 Ma. These processes appear to have occurred several times during the prolonged ductile evolution of the thrust. The preserved inverted metamorphic sequence therefore documents the formation of sequential ‘paleothrusts’ through time, cutting down from the original locus of MCT movement at the LHS–GHS protolith boundary and forming at successively lower pressure and temperature conditions. The petrochronologic methods applied here constrain a complex temporal and thermal deformation history, and demonstrate that inverted metamorphic sequences can preserve a rich record of the duration of progressive ductile thrusting

Psychology and aggression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68264/2/10.1177_002200275900300301.pd