STIC2 selectively binds ribosome-nascent chain complexes in the cotranslational sorting of Arabidopsis thylakoid proteins.

Chloroplast-encoded multi-span thylakoid membrane proteins are crucial for photosynthetic complexes, yet the coordination of their biogenesis remains poorly understood. To identify factors that specifically support the cotranslational biogenesis of the reaction center protein D1 of photosystem (PS) II, we generated and affinity-purified stalled ribosome-nascent chain complexes (RNCs) bearing D1 nascent chains. Stalled RNCs translating the soluble ribosomal subunit uS2c were used for comparison.

CO-EXPRESSED WITH PSI ASSEMBLY1 (CEPA1) is a photosystem I assembly factor in Arabidopsis.

Photosystem I (PSI) forms a large macromolecular complex of ∼580 kDa that resides in the thylakoid membrane and mediates photosynthetic electron transfer. PSI is composed of 18 protein subunits and nearly 200 co-factors. The assembly of the complex in thylakoid membranes requires high spatial and temporal coordination, and is critically dependent on a sophisticated assembly machinery.

Eukaryote-specific assembly factor DEAP2 mediates an early step of photosystem II assembly in Arabidopsis.

The initial step of oxygenic photosynthesis is the thermodynamically challenging extraction of electrons from water and the release of molecular oxygen. This light-driven process, which is the basis for most life on Earth, is catalyzed by photosystem II (PSII) within the thylakoid membrane of photosynthetic organisms. The biogenesis of PSII requires a controlled step-wise assembly process of which the early steps are considered to be highly conserved between plants and their cyanobacterial progenitors.

Emergence of Novel RNA-Editing Sites by Changes in the Binding Affinity of a Conserved PPR Protein.

RNA editing converts cytidines to uridines in plant organellar transcripts. Editing typically restores codons for conserved amino acids. During evolution, specific C-to-U editing sites can be lost from some plant lineages by genomic C-to-T mutations.

Coupling spectral imaging and laboratory analyses to digitally map sediment parameters and stratigraphic layers in Yeha, Ethiopia.

Quantitative analyses of soil and sediment samples are often used to complement stratigraphic interpretations in archaeological and geoscientific research. The outcome of such analyses often is confined to small parts of the examined profiles as only a limited number of samples can be extracted and processed. Recent laboratory studies show that such selectively measured soil and sediment characteristics can be spatially extrapolated using spectral image data, resulting in reliable maps of a variety of parameters.

Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer's Disease.

γ-Secretase (GS) is a key target for the potential treatment of Alzheimer's disease. While inhibiting GS led to serious side effects, its modulation holds a lot of potential to deliver a safe treatment. Herein, we report the discovery of a potent and selective gamma secretase modulator (GSM) ()- (RO7185876), belonging to a novel chemical class, the triazolo-azepines.

Ribosome-Associated Chloroplast SRP54 Enables Efficient Cotranslational Membrane Insertion of Key Photosynthetic Proteins.

Key proteins of the photosynthetic complexes are encoded in the chloroplast genome and cotranslationally inserted into the thylakoid membrane. However, the molecular details of this process are largely unknown. Here, we demonstrate by ribosome profiling that the conserved chloroplast signal recognition particle subunit (cpSRP54) is required for efficient cotranslational targeting of several central photosynthetic proteins, such as the PSII PsbA (D1) subunit, in Arabidopsis ().

Targeting Huntingtin Expression in Patients with Huntington's Disease.

Background: Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in , resulting in a mutant huntingtin protein. IONIS-HTT (hereafter, HTT) is an antisense oligonucleotide designed to inhibit messenger RNA and thereby reduce concentrations of mutant huntingtin.

Methods: We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease.

The oral splicing modifier RG7800 increases full length survival of motor neuron 2 mRNA and survival of motor neuron protein: Results from trials in healthy adults and patients with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a rare genetic and progressively debilitating neuromuscular disease. It is the leading genetic cause of death among infants. In SMA, low levels of survival of motor neuron (SMN) protein lead to motor neuron death and muscle atrophy as the SMN protein is critical to motor neuron survival.

Cancer cells induce interleukin-22 production from memory CD4 T cells via interleukin-1 to promote tumor growth.

IL-22 has been identified as a cancer-promoting cytokine that is secreted by infiltrating immune cells in several cancer models. We hypothesized that IL-22 regulation would occur at the interface between cancer cells and immune cells. Breast and lung cancer cells of murine and human origin induced IL-22 production from memory CD4 T cells.

Sembragiline in Moderate Alzheimer's Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD).

Background: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD).

Objective: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD.

Methods: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks.

Longitudinal characterization of biomarkers for spinal muscular atrophy.

Objective: Recent advances in understanding Spinal Muscular Atrophy (SMA) etiopathogenesis prompted development of potent intervention strategies and raised need for sensitive outcome measures capable of assessing disease progression and response to treatment. Several biomarkers have been proposed; nevertheless, no general consensus has been reached on the most feasible ones. We observed a wide range of measures over 1 year to assess their ability to monitor the disease status and progression.

Specific Correction of Alternative Survival Motor Neuron 2 Splicing by Small Molecules: Discovery of a Potential Novel Medicine To Treat Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality, and there is currently no approved therapy available. SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. These mutations or deletions result in low levels of functional SMN protein.

Operator training simulation for integrating cultivation and homogenisation in protein production.

Operating training simulators (OTS) are virtual simulation tools used for training of process operators in industry in performing procedures and running processes. Based on structured mathematical models of the unit operations of a bioprocess an OTS can train a process operator by visualising changing conditions during the process, allow testing operator actions, testing controller settings, experience unexpected technical problems and getting practice in using prescribed standard procedures for a plant. This work shows the design of an OTS where two sequential steps of a recombinant protein production process, a fed-batch cultivation and a high-pressure homogenisation, are integrated.

Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality.

Operator training in recombinant protein production using a structured simulator model.

Model-based operator training simulators (OTS) could be powerful tools for virtual training of operational procedures and skills of production personnel in recombinant protein processes. The applied model should describe critical events in the bioprocess so accurately that the operators' ability to observe and alertly act upon these events is trained with a high degree of efficiency. In this work is shown how this is accomplished in a structured multi-compartment model for the production of a recombinant protein in an Escherichia coli fed-batch process where in particular the induction procedure, the stress effects and overflow metabolism were highlighted.

5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson's disease.

Excitotoxicity-mediated cell death is involved in Parkinson's disease (PD). 5-HT1A receptor agonists can protect from such mechanisms. The current study demonstrates that the 5-HT1A agonists BAY 639044 and repinotan have neuroprotective effects in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.

A synthetic derivative of the natural product rocaglaol is a potent inhibitor of cytokine-mediated signaling and shows neuroprotective activity in vitro and in animal models of Parkinson's disease and traumatic brain injury.

Many acute and chronic neurodegenerative diseases are characterized by a localized inflammatory response and constitutive activation of the transcription factors nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) as well as their upstream activating signaling cascades. Ample evidence indicates the implication of these processes in the pathogenesis of several diseases of the central nervous system. In this study, we show that a synthetic derivative of the natural product rocaglaol (compound A) displays potent anti-inflammatory properties in human endothelial and murine glial cells in vitro.

Chronic cognitive effects of bilateral subdural haematomas in the rat.

Humans suffering from subdural haematomas often show long-term cognitive dysfunctions. For identifying putative, recovery-enhancing therapeutics, animal models need to be developed in which recovery of function can be measured. For investigating whether and which type of recovery, i.

Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats.

The pathophysiology of traumatic axonal injury (TAI) is only partially understood. In this study, we investigated the inflammatory response as well as the extent of neurological deficit in a rat model of traumatic brain injury (TBI). Forty-two adult rats were subjected to moderate impact-acceleration brain injury and their brains were analyzed immunohistochemically for ICAM-1 expression and neutrophil infiltration from 1 hr up to 14 days after trauma.

Effects of subdural haematoma on sensorimotor functioning and spatial learning in rats.

Twenty per cent of all strokes are haemorrhagic in character and are associated with severe disturbances in sensorimotor behaviour and cognition. Although spontaneous recovery of pre-stroke functioning occurs in some cases, the process is demanding, slow, and often incomplete. A first step in the preclinical testing of new putative, neuroprotective and recovery-supporting therapeutics is to validate animal models of brain injury.

The effects of subdural haematoma on spatial learning in the rat.

Although memory deficits are one of the most persistent consequences of human subdural haematoma, cognitive functioning has hardly been investigated in the rat subdural haematoma model. In the present study, the effects on spatial learning of right- and left-sided unilateral subdural haematoma and of bilateral subdural haematoma induced above the sensorimotor cortical areas were evaluated. Spatial learning was assessed by standard acquisition in the Morris water escape task (five sessions).

Brainstem afferents to the lateral mesencephalic tegmental region of the cat.

The lateral mesencephalic tegmental region (LTR) is a part of the midbrain reticular formation characterized by the presence of neurons exhibiting head movement-related discharge modulation. In addition, the LTR contains directionally selective visual units. Possible sources for these vestibular and visual signals were studied by retrograde axonal transport of horseradish peroxidase and three different fluorescent tracers (rhodamine, fast blue, and fluorogold) injected into various parts of the LTR.

Visual and vestibular signals in the lateral mesencephalic tegmental region of the cat.

Single unit recordings from two alert cats were used in an attempt to further elucidate the function of the lateral mesencephalic tegmental region (LTR), a part of the mesencephalon forming a link between the superior colliculus and the lower brain stem. A total of 155 units recorded from the LTR were tested with visual, vestibular and acoustic stimuli. Of these, 54 cells (36%) were characterized as either visually (n = 33) or vestibularly (n = 21) responsive and an additional 13 cells were driven by complex acoustic stimuli.

[Opinion of mothers on continuous peridural obstetrical anesthesia].

The general opinion on epidural anesthesia in obstetrics may be adversely affected by recent public controversies about the mother's situation during childbirth in hospital, which nowadays is often considered to be a highly technological, impersonal, or "unnatural" procedure. This assumption led us to conduct an inquiry on maternal assessment of obstetric epidural anesthesia and its relation to the clinical and social history. The study included 113 parturients, who received epidural anesthesia (on-demand epidural injections of bupivacaine 0.