Real time dynamics and confinement in the Znschwinger-weyl lattice model for 1+1 QED

We study the out-of-equilibrium properties of 1 + 1 dimensional quantum electrodynamics (QED), discretized via the staggered-fermion Schwinger model with an Abelian Zngauge group. We look at two relevant phenomena: first, we analyze the stability of the Dirac vacuum with respect to particle/antiparticle pair production, both spontaneous and induced by an external electric field; then, we examine the string breaking mechanism. We observe a strong effect of confinement, which acts by suppressing both spontaneous pair production and string breaking into quark/antiquark pairs, indicating that the system dynamics displays a number of out-of-equilibrium features

Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy

The authors used 1H-MRS to investigate hypothalamic metabolism in 26 patients with cluster headache (CH) and 12 healthy subjects. Hypothalamic N-acetylaspartate/creatine was reduced in patients with CH vs controls (p < 0.01). Dividing the patients into episodic CH outside- and in-cluster periods and chronic CH, the hypothalamic N-acetylaspartate/creatine in all three subgroups of patients was reduced. The reduction of the neuronal marker N-acetylaspartate is consistent with hypothalamic neuronal dysfunction in patients with CH

Targeting the Interaction between the SH3 Domain of Grb2 and Gab2

Gab2 is a scaffolding protein, overexpressed in many types of cancers, that plays a key role in the formation of signaling complexes involved in cellular proliferation, migration, and differentiation. The interaction between Gab2 and the C-terminal SH3 domain of the protein Grb2 is crucial for the activation of the proliferation-signaling pathway Ras/Erk, thus representing a potential pharmacological target. In this study, we identified, by virtual screening, seven potential inhibitor molecules that were experimentally tested through kinetic and equilibrium binding experiments. One compound showed a remarkable effect in lowering the affinity of the C-SH3 domain for Gab2. This inhibitory effect was subsequently validated in cellula by using lung cancer cell lines A549 and H1299. Our results are discussed under the light of previous works on the C-SH3:Gab2 interaction

Histone Acetylation Defects in Brain Precursor Cells: A Potential Pathogenic Mechanism Causing Proliferation and Differentiation Dysfunctions in Mitochondrial Aspartate-Glutamate Carrier Isoform 1 Deficiency

Mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) deficiency is an ultra-rare genetic disease characterized by global hypomyelination and brain atrophy, caused by mutations in the SLC25A12 gene leading to a reduction in AGC1 activity. In both neuronal precursor cells and oligodendrocytes precursor cells (NPCs and OPCs), the AGC1 determines reduced proliferation with an accelerated differentiation of OPCs, both associated with gene expression dysregulation. Epigenetic regulation of gene expression through histone acetylation plays a crucial role in the proliferation/differentiation of both NPCs and OPCs and is modulated by mitochondrial metabolism. In AGC1 deficiency models, both OPCs and NPCs show an altered expression of transcription factors involved in the proliferation/differentiation of brain precursor cells (BPCs) as well as a reduction in histone acetylation with a parallel alteration in the expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, histone acetylation dysfunctions have been dissected in in vitro models of AGC1 deficiency OPCs (Oli-Neu cells) and NPCs (neurospheres), in physiological conditions and following pharmacological treatments. The inhibition of HATs by curcumin arrests the proliferation of OPCs leading to their differentiation, while the inhibition of HDACs by suberanilohydroxamic acid (SAHA) has only a limited effect on proliferation, but it significantly stimulates the differentiation of OPCs. In NPCs, both treatments determine an alteration in the commitment toward glial cells. These data contribute to clarifying the molecular and epigenetic mechanisms regulating the proliferation/differentiation of OPCs and NPCs. This will help to identify potential targets for new therapeutic approaches that are able to increase the OPCs pool and to sustain their differentiation toward oligodendrocytes and to myelination/remyelination processes in AGC1 deficiency, as well as in other white matter neuropathologies

The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism

Enzymes of intermediary metabolism are often reported to have moonlighting functions as RNA-binding proteins and have regulatory roles beyond their primary activities. Human serine hydroxymethyltransferase (SHMT) is essential for the one-carbon metabolism, which sustains growth and proliferation in normal and tumour cells. Here, we characterize the RNA-binding function of cytosolic SHMT (SHMT1) in vitro and using cancer cell models. We show that SHMT1 controls the expression of its mitochondrial counterpart (SHMT2) by binding to the 5'untranslated region of the SHMT2 transcript (UTR2). Importantly, binding to RNA is modulated by metabolites in vitro and the formation of the SHMT1-UTR2 complex inhibits the serine cleavage activity of the SHMT1, without affecting the reverse reaction. Transfection of UTR2 in cancer cells controls SHMT1 activity and reduces cell viability. We propose a novel mechanism of SHMT regulation, which interconnects RNA and metabolites levels to control the cross-talk between cytosolic and mitochondrial compartments of serine metabolism

Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment

Next Generation European Research Vessels: Current Status and Foreseeable Evolution

The European research vessel fleet plays a vital role in supporting scientific research and development not just in Europe but also across the globe. This document explores how the fleet has developed since the publication of the European Marine Board Position Paper 10 (EMB PP 10) "European Ocean Research Fleets – Towards a Common Strategy and Enhanced Use" (Binot et al., 2007). It looks at the current fleet and its equipment and capabilities (Chapter 2), the deep sea (Chapter 3) and Polar regions (Chapter 4) as study areas of ever- increasing importance for science and for the vessels that explore them, the role that research vessels play in the wider ocean observing landscape (Chapter 5), the importance of training personnel for research vessels (Chapter 6), and considers management of the European research vessel fleet (Chapter 7). This Position Paper considers what has changed since 2007, what the status is in 2019, and future directions for the European fleet, with a 10-year horizon to 2030. This Position Paper finds that the current European research vessel fleet is highly capable, and is able to provide excellent support to European marine science and wider scientific research and can lead on the world stage. However, with a typical life expectancy of a research vessel of 30 years, the fleet is ageing and urgently requires further investment and reinvestment to continue to be as efficient and capable as the scientific community expects and requires. The capabilities of the fleet have increased considerably since 2007, and vessels have kept up with fast-paced technological developments. The demand for complex and highly capable vessels will continue, and research vessel designs and the fleet as a whole will need to keep pace in order to remain fit-for-purpose and continue to be a key player globally. There is huge diversity in vessel types and designs in terms of capabilities and equipment, management structures and processes, and training possibilities. While it would not be possible or appropriate to highlight any one approach as the only one to use, a growing trend in collaboration through community groups, agreements, legal entities and funded projects now enables more strategic thinking in the development of these vital infrastructures. However, some issues remain in enabling equal access to research vessel time for all researchers across Europe regardless of country, and regardless of whether or not that country owns a suitable research vessel for their scientific needs

Phosphorylation of Kif26b Promotes Its Polyubiquitination and Subsequent Proteasomal Degradation during Kidney Development

Kif26b, a member of the kinesin superfamily proteins (KIFs), is essential for kidney development. Kif26b expression is restricted to the metanephric mesenchyme, and its transcription is regulated by a zinc finger transcriptional regulator Sall1. However, the mechanism(s) by which Kif26b protein is regulated remain unknown. Here, we demonstrate phosphorylation and subsequent polyubiquitination of Kif26b in the developing kidney. We find that Kif26b interacts with an E3 ubiquitin ligase, neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) in developing kidney. Phosphorylation of Kif26b at Thr-1859 and Ser-1962 by the cyclin-dependent kinases (CDKs) enhances the interaction of Kif26b with Nedd4. Nedd4 polyubiquitinates Kif26b and thereby promotes degradation of Kif26b via the ubiquitin-proteasome pathway. Furthermore, Kif26b lacks ATPase activity but does associate with microtubules. Nocodazole treatment not only disrupts the localization of Kif26b to microtubules but also promotes phosphorylation and polyubiquitination of Kif26b. These results suggest that the function of Kif26b is microtubule-based and that Kif26b degradation in the metanephric mesenchyme via the ubiquitin-proteasome pathway may be important for proper kidney development

HER2 Phosphorylation Is Maintained by a PKB Negative Feedback Loop in Response to Anti-HER2 Herceptin in Breast Cancer

A feedback loop maintains HER2 receptor signalling and cell survival in response to Herceptin treatment in HER2-positive breast cancers, but this Herceptin resistance may be bypassed by pan-HER inhibitors