Oligomerization mediated by the D2 domain of DTX3L is critical for DTX3L-PARP9 reading function of mono-ADP-ribosylated androgen receptor.

Deltex proteins are a family of E3 ubiquitin ligases that encode C-terminal RING and DTC domains that mediate interactions with E2 ubiquitin-conjugating enzymes and recognize ubiquitination substrates. DTX3L is unique among the Deltex proteins based on its N-terminal domain architecture. The N-terminal D1 and D2 domains of DTX3L mediate homo-oligomerization, and the D3 domain interacts with PARP9, a protein that contains tandem macrodomains with ADP-ribose reader function.

Oligomerisation mediated by the D2 domain of DTX3L is critical for DTX3L-PARP9 reading function of mono-ADP-ribosylated androgen receptor.

Deltex proteins are a family of E3 ubiquitin ligases that encode C-terminal RING and DTC domains that mediate interactions with E2 ubiquitin-conjugating enzymes and recognise ubiquitination substrates. DTX3L is unique among the Deltex proteins based on its N-terminal domain architecture. The N-terminal D1 and D2 domains of DTX3L mediate homo-oligomerisation, and the D3 domain interacts with PARP9, a protein that contains tandem macrodomains with ADP-ribose reader function.

Introduction of a More Glutaredoxin-like Active Site to PDI Results in Competition between Protein Substrate and Glutathione Binding.

Proteins in the thioredoxin superfamily share a similar fold, contain a -CXXC- active site, and catalyze oxidoreductase reactions by dithiol-disulfide exchange mechanisms. Protein disulfide isomerase (PDI) has two -CGHC- active sites. For in vitro studies, oxidation/reduction of PDI during the catalytic cycle is accomplished with glutathione.

Protein engineering approach to enhance activity assays of mono-ADP-ribosyltransferases through proximity.

Human mono-ADP-ribosylating PARP enzymes have been linked to several clinically relevant processes and many of these PARPs have been suggested as potential drug targets. Despite recent advances in the field, efforts to discover inhibitors have been hindered by the lack of tools to rapidly screen for high potency compounds and profile them against the different enzymes. We engineered mono-ART catalytic fragments to be incorporated into a cellulosome-based octavalent scaffold.

Preparation of screening assays for ADP-ribosyl readers and erasers using the GAP-tag as a binding probe.

Here, we describe a protocol to set up a screening assay for ADP-ribosyl binding proteins including proteins that possess O-glycosidase or N-glycosidase activities. The FRET-based assay measures the interaction of any ADP-ribosyl binding protein fused to CFP with a cysteine-ADP-ribosylated GAP-tag fused to YFP. Recombinant PtxS1 and PARP2 are used to mono-ADP-ribosylate and poly-ADP-ribosylate the GAP-tag.

Reconstitution of the DTX3L-PARP9 complex reveals determinants for high-affinity heterodimerization and multimeric assembly.

Ubiquitination and ADP-ribosylation are post-translational modifications that play major roles in pathways including the DNA damage response and viral infection. The enzymes responsible for these modifications are therefore potential targets for therapeutic intervention. DTX3L is an E3 Ubiquitin ligase that forms a heterodimer with PARP9.

A molecular toolbox for ADP-ribosyl binding proteins.

Proteins interacting with ADP-ribosyl groups are often involved in disease-related pathways or viral infections, making them attractive drug targets. We present a robust and accessible assay applicable to both hydrolyzing or non-hydrolyzing binders of mono- and poly-ADP-ribosyl groups. This technology relies on a C-terminal tag based on a G protein alpha subunit peptide (GAP), which allows for site-specific introduction of cysteine-linked mono- and poly-ADP-ribosyl groups or analogs.

Activity-Based Screening Assay for Mono-ADP-Ribosylhydrolases.

ADP-ribosylation is a post-translational modification involved in the regulation of many vital cellular processes. This posttranslational modification is carried out by ADP-ribosyltransferases converting β-NAD into nicotinamide and a protein-linked ADP-ribosyl group or a chain of PAR. The reverse reaction, release of ADP-ribose from the acceptor molecule, is catalyzed by ADP-ribosylhydrolases.

The crystal structure of human microsomal triglyceride transfer protein.

Microsomal triglyceride transfer protein (MTP) plays an essential role in lipid metabolism, especially in the biogenesis of very low-density lipoproteins and chylomicrons via the transfer of neutral lipids and the assembly of apoB-containing lipoproteins. Our understanding of the molecular mechanisms of MTP has been hindered by a lack of structural information of this heterodimeric complex comprising an MTPα subunit and a protein disulfide isomerase (PDI) β-subunit. The structure of MTP presented here gives important insights into the potential mechanisms of action of this essential lipid transfer molecule, structure-based rationale for previously reported disease-causing mutations, and a means for rational drug design against cardiovascular disease and obesity.

Implementing physical exercise and music interventions for patients suffering from dementia on an acute psychogeriatric inpatient ward.

Increasing attention is focusing on psychosocial interventions for treating patients with dementia. This observational intervention study investigated the impact of physical exercise and music interventions among patients with dementia on an acute psychogeriatric ward. The data were collected during February 2009-December 2010 ( = 89; treatment as usual) and during April 2011-March 2013 ( = 86; treatment as usual with physical exercise, e.

Outcome of neuropsychiatric symptoms and daily functioning of patients with dementia treated on an acute psychogeriatric ward.

Background: Dementia is associated with progressive deterioration in multiple cognitive domains, functional impairment and neuropsychiatric symptoms (NPS).

Aims: The aim of this study was to explore the factors associated with the outcome of NPS and daily functioning in patients with dementia during acute psychogeriatric hospitalization.

Materials And Method: The data (n = 175) were collected between 2009 and 2013 in naturalistic settings on one acute psychogeriatric ward at one university hospital in Finland.

Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease.

Coronary artery disease is the most common cause of death globally and is linked to a number of risk factors including serum low density lipoprotein, high density lipoprotein, triglycerides and lipoprotein(a). Recently two proteins, angiopoietin-like protein 3 and 4, have emerged from genetic studies as being factors that significantly modulate plasma triglyceride levels and coronary artery disease. The exact function and mechanism of action of both proteins remains to be elucidated, however, mutations in these proteins results in up to 34% reduction in coronary artery disease and inhibition of function results in reduced plasma triglyceride levels.

NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease.

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction.

Acute Psychogeriatric Inpatient Treatment Improves Neuropsychiatric Symptoms but Impairs the Level of Functioning in Patients with Dementia.

Aims: To explore the impact of hospitalization on neuropsychiatric symptoms (NPS) and the level of functioning in patients with dementia. Our aim was also to study the influence of psychotropic medications.

Methods: Behavioral disturbances, cognition and functional status of 89 patients were assessed using the Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, Barthel Index, and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCSADL).

Psychiatric hospital admission and long-term care in patients with very-late-onset schizophrenia-like psychosis.

Objective: In this register-based study the rates and durations of psychiatric hospitalizations were compared between patients with very-late-onset schizophrenia-like psychosis (VLOSLP, n = 918) and elderly patients with illness onset before 60 years (n = 6142). The proportion of patients ending up in long-term care (LTC) or long-lasting psychiatric hospital care (LLP) was also studied.

Methods: A sample of patients with schizophrenia aged 65 or over was collected from the Finnish Hospital Discharge Register.

Efficient export of human growth hormone, interferon α2b and antibody fragments to the periplasm by the Escherichia coli Tat pathway in the absence of prior disulfide bond formation.

Numerous therapeutic proteins are expressed in Escherichia coli and targeted to the periplasm in order to facilitate purification and enable disulfide bond formation. Export is normally achieved by the Sec pathway, which transports proteins through the plasma membrane in a reduced, unfolded state. The Tat pathway is a promising alternative means of export, because it preferentially exports correctly folded proteins; however, the reducing cytoplasm of standard strains has been predicted to preclude export by Tat of proteins that contain disulfide bonds in the native state because, in the reduced state, they are sensed as misfolded and rejected.

Patients with very-late-onset schizoprhenia-like psychosis have higher mortality rates than elderly patients with earlier onset schizophrenia.

Objective: In this register-based study of schizophrenia patients aged 65 years or above, mortality and causes of death diagnosed at age of 60+ (very-late-onset schizophrenia-like psychosis, VLOSLP) were studied in comparison with sex- and age-matched general Finnish population. Standardized Mortality Ratios (SMRs) of VLOSLP patients were also compared with those of earlier onset (below 60 years) schizophrenia patients, and hazard of death was calculated between these patient groups.

Methods: The data was obtained from Finnish nationwide registers and consisted of 918 VLOSLP patients and 6142 earlier onset patients who were at least 65 years on 1 January 1999.

Efficient export of prefolded, disulfide-bonded recombinant proteins to the periplasm by the Tat pathway in Escherichia coli CyDisCo strains.

Numerous high-value therapeutic proteins are produced in Escherichia coli and exported to the periplasm, as this approach simplifies downstream processing and enables disulfide bond formation. Most recombinant proteins are exported by the Sec pathway, which transports substrates across the plasma membrane in an unfolded state. The Tat system also exports proteins to the periplasm, but transports them in a folded state.

Change in antipsychotic usage pattern and risk of relapse in older patients with schizophrenia.

Objective: The aim of this study was to explore the use of first (FGAs) and second generation antipsychotics (SGAs) in older outpatients with schizophrenia and schizoaffective disorder. Factors associated with schizophrenic relapses were also studied.

Methods: The study sample consisting of 8792 patients aged 64 years or more was collected from Finnish nationwide registers.

One-year follow-up after discontinuing maintenance electroconvulsive therapy.

Objectives: Electroconvulsive therapy (ECT) has been established as an effective method in the treatment of severe depressive or psychotic disorders. Its efficacy is greatest in severe major depressive disorder (MDD) with or without psychotic symptoms. However, maintaining remission after a successful course of short-term ECT is often difficult owing to resistance to medication in these patients.

Mortality and causes of death in older patients with schizophrenia.

Objective: The aim of this study was to evaluate mortality and causes of death in older patients with schizophrenia in comparison with the general population. The mortality of patients experiencing relapse was also compared with those in remission.

Methods: The study sample consists of patients (n = 9461) over 65 years by the first of January 1999, with schizophrenia or schizoaffective disorder (ICD-8, ICD-9: 295, ICD-10: F20, F25) as the main register diagnosis during the period 1969-1998.

Beyond KDEL: the role of positions 5 and 6 in determining ER localization.

The C-terminal amino acid sequence of a protein plays an important role in determining the endoplasmic reticulum (ER) localization of many soluble proteins that enter the secretory pathway. While it is known that the four amino acids found at the extreme C-terminus of the protein (e.g.

[Hyponatremia due to psychoactive drugs is common in the elderly].

Hyponatremia due to psychoactive drugs commonly used in the treatment of elderly patients appears usually during the first weeks of treatment. Blood sodium level should be measured before the initiation of medication and checked after a few weeks. Symptoms suggesting hyponatremia in a patient under psychoactive medication are always an indication for checking the sodium level.

[Severe psychoses in the elderly--schizophrenia and delusional disorder].

The number of persons over 65 years of age with schizophrenia will increase in the future. Geriatric schizophrenia involves bizarre delusions and hallucinations similar to those occurring in younger schizophrenic patients. Delusions of an elderly delusional disorder patient focusing on the family and environment easily lead to social withdrawal.

Two endoplasmic reticulum PDI peroxidases increase the efficiency of the use of peroxide during disulfide bond formation.

Disulfide bond formation in the endoplasmic reticulum by the sulfhydryl oxidase Ero1 family is thought to be accompanied by the concomitant formation of hydrogen peroxide. Since secretory cells can make substantial amounts of proteins that contain disulfide bonds, the production of this reactive oxygen species could have potentially lethal consequences. Here, we show that two human proteins, GPx7 and GPx8, labeled as secreted glutathione peroxidases, are actually endoplasmic reticulum-resident protein disulfide isomerase peroxidases.