A Branch-and-Bound Approach for Tautomer Enumeration.

Knowledge about tautomer forms of a structure is important since, e.g., a property prediction for a molecule can yield to different results which depend on the individual tautomer.

Inside-out Regulation of Ectodomain Cleavage of Cluster-of-Differentiation-44 (CD44) and of Neuregulin-1 Requires Substrate Dimerization.

Ectodomain shedding of transmembrane precursor proteins generates numerous life-essential molecules, such as epidermal growth factor receptor ligands. This cleavage not only releases the regulatory growth factor, but it is also the required first step for the subsequent processing by γ-secretase and the release of gene regulatory intracellular fragments. Signaling within the cell modifies the cytoplasmic tails of substrates, a step important in starting the specific and regulated cleavage of a large number of studied substrates.

High levels of TopBP1 induce ATR-dependent shut-down of rRNA transcription and nucleolar segregation.

Nucleoli are not only organelles that produce ribosomal subunits. They are also overarching sensors of different stress conditions and they control specific nucleolar stress pathways leading to stabilization of p53. During DNA replication, ATR and its activator TopBP1 initiate DNA damage response upon DNA damage and replication stress.

Interventions to Slow Aging in Humans: Are We Ready?

The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged.

Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways.

Wild-type p53-induced phosphatase 1 (Wip1) negatively regulates several tumour suppressor and DNA damage response pathways. However, the impact of Wip1 on haematopoietic stem cell (HSC) homeostasis and aging remains unknown. Here we show that Wip1 is highly expressed in HSCs but decreases with age.

Aluminum-induced kinesin inactivation as potential molecular cause of impairment of neuronal transport processes.

It is commonly accepted that aluminum ions may initiate the development of diverse diseases, including neurological disorders. So far, our knowledge of the molecular mechanisms of the interaction of aluminum with defined cellular structures has been still fragmentary. As functional key tasks of neuronal cells essentially depend on the activity of kinesin, we wanted to find out whether this motor protein represents a molecular target for aluminum.

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy.

The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases.

Mutants of metal binding site M1 in APP E2 show metal specific differences in binding of heparin but not of sorLA.

The amyloid precursor protein (APP) and its neurotoxic cleavage product Aβ are key players in the development of Alzheimer's disease (AD) and appear to be essential for neuronal development and cell homeostasis. Proteolytic processing of APP and its physiological function depend on its interaction with heparin and are influenced by the binding of metal ions and sorLA. We created various mutations of metal binding site M1 residing within the extracellular E2 domain of APP.

Measuring telomere length and telomere dynamics in evolutionary biology and ecology.

Telomeres play a fundamental role in the protection of chromosomal DNA and in the regulation of cellular senescence. Recent work in human epidemiology and evolutionary ecology suggests adult telomere length (TL) may reflect past physiological stress and predict subsequent morbidity and mortality, independent of chronological age.Several different methods have been developed to measure TL, each offering its own technical challenges.

VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis.

Background & Aims: Senescence prevents cellular transformation. We investigated whether vascular endothelial growth factor (VEGF) signaling via its receptor, VEGFR2, regulates senescence and proliferation of tumor cells in mice with colitis-associated cancer (CAC).

Methods: CAC was induced in VEGFR2(ΔIEC) mice, which do not express VEGFR2 in the intestinal epithelium, and VEGFR2(fl/fl) mice (controls) by administration of azoxymethane followed by dextran sodium sulfate.

Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay.

Nonsense-mediated mRNA decay (NMD) is a post-transcriptional mechanism that targets aberrant transcripts and regulates the cellular RNA reservoir. Genetic modulation in vertebrates suggests that NMD is critical for cellular and tissue homeostasis, although the underlying mechanism remains elusive. Here, we generate knockout mice lacking Smg6/Est1, a key nuclease in NMD and a telomerase cofactor.

Interaction of the amyloid precursor protein-like protein 1 (APLP1) E2 domain with heparan sulfate involves two distinct binding modes.

Beyond the pathology of Alzheimer's disease, the members of the amyloid precursor protein (APP) family are essential for neuronal development and cell homeostasis in mammals. APP and its paralogues APP-like protein 1 (APLP1) and APP-like protein 2 (APLP2) contain the highly conserved heparan sulfate (HS) binding domain E2, which effects various (patho)physiological functions. Here, two crystal structures of the E2 domain of APLP1 are presented in the apo form and in complex with a heparin dodecasaccharide at 2.

RHAMM deficiency disrupts folliculogenesis resulting in female hypofertility.

The postnatal mammalian ovary contains the primary follicles, each comprising an immature oocyte surrounded by a layer of somatic granulosa cells. Oocytes reach meiotic and developmental competence via folliculogenesis. During this process, the granulosa cells proliferate massively around the oocyte, form an extensive extracellular matrix (ECM) and differentiate into cumulus cells.

Merlin's wizardry guides cohesive migration.

Cells often migrate in tightly connected groups with coordinated movement and polarity. The collective migration of epithelial cell sheets is now shown to be mediated by a signalling axis that involves the merlin tumour-suppressor protein, the tight-junction-associated angiomotin-Rich1 complex and the Rac1 small GTPase.

MAS solid state NMR of proteins: simultaneous ¹⁵N- ¹³CA and ¹⁵N- ¹³CO dipolar recoupling via low-power symmetry-based RF pulse schemes.

The generation of efficient RN n (ν)s,(ν)k symmetry-based low-power RF pulse schemes for simultaneous (15)N-(13)CA and (15)N-(13)CO dipolar recoupling is demonstrated. The method involves mixing schemes employing phase and amplitude-modulated dual band-selective 180° pulses as basic "R" element and tailoring of the RF field-modulation profile of the 180° pulses so as to obtain efficient magnetisation transfer characteristics over the resonance offset range of the nuclei involved. Mixing schemes leading to simultaneous (15)N-(13)CA and (15)N-(13)CO dipolar recoupling would permit the one-shot acquisition of different chemical shift correlation spectra that are typically utilized for protein backbone resonance assignments and thereby save data acquisition time.

Structure and regulatory role of the C-terminal winged helix domain of the archaeal minichromosome maintenance complex.

The minichromosome maintenance complex (MCM) represents the replicative DNA helicase both in eukaryotes and archaea. Here, we describe the solution structure of the C-terminal domains of the archaeal MCMs of Sulfolobus solfataricus (Sso) and Methanothermobacter thermautotrophicus (Mth). Those domains consist of a structurally conserved truncated winged helix (WH) domain lacking the two typical 'wings' of canonical WH domains.

Sumoylation of HDAC2 promotes NF-κB-dependent gene expression.

The transcription factor nuclear factor-κB (NF-κB) is crucial for the maintenance of homeostasis. It is incompletely understood how nuclear NF-κB and the crosstalk of NF-κB with other transcription factors are controlled. Here, we demonstrate that the epigenetic regulator histone deacetylase 2 (HDAC2) activates NF-κB in transformed and primary cells.

Inhibition of wild-type p53-induced phosphatase 1 promotes liver regeneration in mice by direct activation of mammalian target of rapamycin.

Unlabelled: The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration (LR) is often impaired in disease conditions. Wild-type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation, mainly by deactivating antioncogenes.

Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity.

Mercury (Hg) is a bioaccumulating trace metal that globally circulates the atmosphere and waters in its elemental, inorganic and organic chemical forms. While Hg represents a notorious neurotoxicant, the underlying cellular pathways are insufficiently understood. We identify amyloid protein aggregation in the cell nucleus as a novel pathway of Hg-bio-interactions.

Genome instability of ageing stem cells--Induction and defence mechanisms.

The mammalian organism is comprised of tissue types with varying degrees of self-renewal and regenerative capacity. In most organs self-renewing tissue-specific stem and progenitor cells contribute to organ maintenance, and it is vital to maintain a functional stem cell pool to preserve organ homeostasis. Various conditions like tissue injury, stress responses, and regeneration challenge the stem cell pool to re-establish homeostasis (Fig.

An approach to NMR assignment of intrinsically disordered proteins.

An efficient approach to NMR assignments in intrinsically disordered proteins is presented, making use of the good dispersion of cross peaks observed in [(15) N,(13) C']- and [(13) C',(1) H(N) ]-correlation spectra. The method involves the simultaneous collection of {3D (H)NCO(CAN)H and 3D (HACA)CON(CA)HA} spectra for backbone assignments via sequential H(N) and H(α) correlations and {3D (H)NCO(CACS)HS and 3D (HS)CS(CA)CO(N)H} spectra for side-chain (1) H and (13) C assignments, employing sequential (1) H data acquisitions with direct detection of both the amide and aliphatic protons. The efficacy of the approach for obtaining resonance assignments with complete backbone and side-chain chemical shifts is demonstrated experimentally for the 61-residue [(13) C,(15) N]-labelled peptide of a voltage-gated potassium channel protein of the Kv1.

Cooperative development of logical modelling standards and tools with CoLoMoTo.

The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour and provide (testable) predictions by performing in silico experiments. In this context, qualitative, logical frameworks have emerged as relevant approaches, as demonstrated by a growing number of published models, along with new methodologies and software tools.

Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage.

Aging and carcinogenesis coincide with the accumulation of DNA damage and mutations in stem and progenitor cells. Molecular mechanisms that influence responses of stem and progenitor cells to DNA damage remain to be delineated. Here, we show that niche positioning and Wnt signaling activity modulate the sensitivity of intestinal stem and progenitor cells (ISPCs) to DNA damage.