The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.

Oscillation of cAMP and Ca(2+) in cardiac myocytes: a systems biology approach.

Cyclic adenosine monophosphate (cAMP) and Ca(2+) levels may oscillate in harmony within excitable cells; a mathematical oscillation loop model, the Cooper model, of these oscillations was developed two decades ago. However, in that model all adenylyl cyclase (AC) isoforms were assumed to be inhibited by Ca(2+), and it is now known that the heart expresses multiple AC isoforms, among which the type 5/6 isoforms are Ca(2+)-inhibitable whereas the other five (AC2, 3, 4, 7, and 9) are not. We used a computational systems biology approach with CellDesigner simulation software to develop a comprehensive graphical map and oscillation loop model for cAMP and Ca(2+).

Effect of temperature shift on levels of acidic charge variants in IgG monoclonal antibodies in Chinese hamster ovary cell culture.

During the production of therapeutic monoclonal antibodies (mAbs), not only enhancement of mAb productivity but also control of quality attributes is critical. Charge variants, which are among the most important quality attributes, can substantially affect the in vitro and in vivo properties of mAbs. During process development for the production of mAbs in a Chinese hamster ovary cell line, we have observed that an improvement in mAb titer is accompanied by an increase in the content of acidic charge variants.

BDNF enhances spontaneous and activity-dependent neurotransmitter release at excitatory terminals but not at inhibitory terminals in hippocampal neurons.

Brain-derived neurotrophic factor (BDNF) is widely reported to enhance synaptic vesicle (SV) exocytosis and neurotransmitter release. But it is still unclear whether BDNF enhances SV recycling at excitatory terminals only, or at both excitatory and inhibitory terminals. In the present study, in a direct comparison using cultured rat hippocampal neurons, we demonstrate that BDNF enhances both spontaneous and activity-dependent neurotransmitter release from excitatory terminals, but not from inhibitory terminals.

Detection and control of combustion instability based on the concept of dynamical system theory.

We propose an online method of detecting combustion instability based on the concept of dynamical system theory, including the characterization of the dynamic behavior of combustion instability. As an important case study relevant to combustion instability encountered in fundamental and practical combustion systems, we deal with the combustion dynamics close to lean blowout (LBO) in a premixed gas-turbine model combustor. The relatively regular pressure fluctuations generated by thermoacoustic oscillations transit to low-dimensional intermittent chaos owing to the intermittent appearance of burst with decreasing equivalence ratio.

Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a disease caused by motor neuron degeneration. Recently, a novel SIGMAR1 gene variant (p.E102Q) was discovered in some familial ALS patients.

Age-dependent redistribution and hypersialylation of the central myelin paranodal loop membrane protein Opalin in the mouse brain.

Opalin/Tmem10 is a myelin-associated sialylglycoprotein that is specific to only the mammalian central nervous system. However, little is known about the properties or function of this protein. Here, we analyzed the expression and glycosylation patterns of Opalin in the postnatal mouse brain.

Difference in left ventricular mass index between hypertensive patients with and without renal artery stenosis by propensity score analysis.

This study aimed to define the difference in cardiac hypertrophy between hypertensive patients with and without renal artery stenosis (RAS). When cardiac ultrasonographic examination was performed in 971 consecutive hypertensive outpatients, renal peak systolic velocity (PSV) was examined. Compared with patients without RAS, those with RAS (PSV ≥180 cm/s, 4.

Axonal localization of Ca2+-dependent activator protein for secretion 2 is critical for subcellular locality of brain-derived neurotrophic factor and neurotrophin-3 release affecting proper development of postnatal mouse cerebellum.

Ca2+-dependent activator protein for secretion 2 (CAPS2) is a protein that is essential for enhanced release of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) from cerebellar granule cells. We previously identified dex3, a rare alternative splice variant of CAPS2, which is overrepresented in patients with autism and is missing an exon 3 critical for axonal localization. We recently reported that a mouse model CAPS2Δex3/Δex3 expressing dex3 showed autistic-like behavioral phenotypes including impaired social interaction and cognition and increased anxiety in an unfamiliar environment.

Mouse models of mutations and variations in autism spectrum disorder-associated genes: mice expressing Caps2/Cadps2 copy number and alternative splicing variants.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by disturbances in interpersonal relationships and behavior. Although the prevalence of autism is high, effective treatments have not yet been identified. Recently, genome-wide association studies have identified many mutations or variations associated with ASD risk on many chromosome loci and genes.

Convergent synaptic inputs from the caudal fastigial nucleus and the superior colliculus onto pontine and pontomedullary reticulospinal neurons.

The caudal fastigial nucleus (FN) is known to be related to the control of eye movements and projects mainly to the contralateral reticular nuclei where excitatory and inhibitory burst neurons for saccades exist [the caudal portion of the nucleus reticularis pontis caudalis (NRPc), and the rostral portion of the nucleus reticularis gigantocellularis (NRG) respectively]. However, the exact reticular neurons targeted by caudal fastigioreticular cells remain unknown. We tried to determine the target reticular neurons of the caudal FN and superior colliculus (SC) by recording intracellular potentials from neurons in the NRPc and NRG of anesthetized cats.

CAPS1 deficiency perturbs dense-core vesicle trafficking and Golgi structure and reduces presynaptic release probability in the mouse brain.

Ca(2+)-dependent activator protein for secretion 1 (CAPS1) plays a regulatory role in the dense-core vesicle (DCV) exocytosis pathway, but its functions at the cellular and synaptic levels in the brain are essentially unknown because of neonatal death soon after birth in Caps1 knock-out mice. To clarify the functions of the protein in the brain, we generated two conditional knock-out (cKO) mouse lines: 1) one lacking Caps1 in the forebrain; and 2) the other lacking Caps1 in the cerebellum. Both cKO mouse lines were born normally and grew to adulthood, although they showed subcellular and synaptic abnormalities.

Application of a quality by design approach to the cell culture process of monoclonal antibody production, resulting in the establishment of a design space.

This case study describes the application of Quality by Design elements to the process of culturing Chinese hamster ovary cells in the production of a monoclonal antibody. All steps in the cell culture process and all process parameters in each step were identified by using a cause-and-effect diagram. Prospective risk assessment using failure mode and effects analysis identified the following four potential critical process parameters in the production culture step: initial viable cell density, culture duration, pH, and temperature.

Multifunctional porous titanium oxide coating with apatite forming ability and photocatalytic activity on a titanium substrate formed by plasma electrolytic oxidation.

Plasma electrolytic oxidation (PEO) was used to make a multifunctional porous titanium oxide (TiO2) coating on a titanium substrate. The key finding of this study is that a highly crystalline TiO2 coating can be made by performing the PEO in an ammonium acetate (CH3COONH4) solution; the PEO coating was formed by alternating between rapid heating by spark discharges and quenching in the solution. The high crystallinity of the TiO2 led to the surface having multiple functions, including apatite forming ability and photocatalytic activity.

Green tea extract containing a highly absorbent catechin prevents diet-induced lipid metabolism disorder.

We investigated the effects of extracts of Benifuuki (a tea cultivar that contains methylated catechins such as epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me)) in mice fed a high-fat/high-sucrose (HF/HS) diet. This tea cultivar was then compared with an extract of Yabukita (a popular tea cultivar that lacks methylated catechins). For 6 weeks, C57BL/6J mice were fed either HF/HS diet with or without tea extracts from tea cultivars, which contained almost identical ingredients except for methylated catechins (i.

Impact of hospital volume on postoperative complications and in-hospital mortality after musculoskeletal tumor surgery: analysis of a national administrative database.

Background: We are aware of only one report describing the relationship between operative volume and outcomes in musculoskeletal tumor surgery, although numerous studies have described such relationships in other surgical procedures. The aim of the present study was to use a nationally representative inpatient database to evaluate the impact of hospital volume on the rates of postoperative complications and in-hospital mortality after musculoskeletal tumor surgery.

Methods: We used the Japanese Diagnostic Procedure Combination administrative database to retrospectively identify 4803 patients who had undergone musculoskeletal tumor surgery during 2007 to 2010.

Facile synthesis of free-standing polymer brush films based on a colorless polydopamine thin layer.

A free-standing polymer brush film with tailored thicknesses based on a colorless polydopamine (PDA) thin layer is prepared and characterized. The surface-initiated atom transfer radical polymerization (ATRP) of 2-hydroxyethyl methacrylate (HEMA) is performed on a PDA layer with thickness of ca. 6 nm, which generated an optically transparent and colorless free-standing PHEMA brush film (1.

A Novel Splicing Variant of Peroxisome Proliferator-Activated Receptor-γ (Pparγ1sv) Cooperatively Regulates Adipocyte Differentiation with Pparγ2.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate expression of a number of genes associated with the cellular differentiation and development. Here, we show the abundant and ubiquitous expression of a newly identified splicing variant of mouse Pparγ (Pparγ1sv) that encodes PPARγ1 protein, and its importance in adipogenesis. The novel splicing variant has a unique 5'-UTR sequence, relative to those of Pparγ1 and Pparγ2 mRNAs, indicating the presence of a novel transcriptional initiation site and promoter for Pparγ expression.

Evaluation of changes in left ventricular myocardial function observed in canine myocardial dysfunction model using a two-dimensional tissue tracking technique.

This study was conducted to assess the ability of two-dimensional tissue tracking (2DTT) to evaluate changes in left ventricular (LV) myocardial function associated with sustained high electrical pacing. Pacemakers were implanted at the right ventricular (RV) apex of five female Beagles, and sustained high electrical pacing of 250 beats per minute (bpm) was performed for three consecutive weeks. Conventional echocardiography and 2DTT were performed at baseline, and at every week for three weeks with pacing.

Input-output organization of inhibitory neurons in the interstitial nucleus of Cajal projecting to the contralateral trochlear and oculomotor nucleus.

Neurons in the interstitial nucleus of Cajal (INC) that are known to be involved in eye and head movements are excitatory. We investigated the input-output organization of inhibitory INC neurons involved in controlling vertical saccades. Intracellular recordings were made in INC neurons activated antidromically by stimulation of the contralateral trochlear or oculomotor nucleus, and their synaptic input properties from the superior colliculi (SCs) and the contralateral INC were analyzed in anesthetized cats.

Animal models of autism spectrum disorder (ASD): a synaptic-level approach to autistic-like behavior in mice.

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders and is thought to be closely associated with genetic factors. It is noteworthy that many ASD-associated genes reported by genome-wide association studies encode proteins related to synaptic formation, transmission, and plasticity. Therefore, it is essential to elucidate the relationship between deficiencies in these genes and the relevant ASD-related phenotypes using synaptic and behavioral phenotypic analysis of mice that are genetically modified for genes related to ASD (e.

Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice.

Dehydroepiandrosterone (DHEA) is the most abundant neurosteroid synthesized de novo in the central nervous system. We previously reported that stimulation of the sigma-1 receptor by DHEA improves cognitive function by activating calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C and extracellular signal-regulated kinase in the hippocampus in olfactory bulbectomized (OBX) mice. Here, we asked whether DHEA enhances neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors observed in OBX mice.

Critical anomalies in thermal diffusivity of liquid-crystalline terephthal-bis-(4-n-butylaniline).

A temperature wave method has been applied to observe the thermal diffusivity through the isotropic (Iso)-nematic (N)-smectic Sm-A-Sm-C-Sm-B-crystals VI-VII-VIII phase transitions of terephthal-bis-(4-n-butylaniline) (TBBA). Critical anomalies have been found in the N-Sm-A and Sm-C-Sm-B phase transitions as diplike shaped, consistent with the predictions based on the dissipative couplings between the order parameter and the conserved free-energy density. Singular points with a gap have been observed at the Sm-B-crystal VI, crystals VI-VII, and crystals VII-VIII phase transitions, which show polymorphic behaviors on heating and cooling.

Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice.

Ca(2)(+)-dependent activator protein for secretion 2 (CAPS2 or CADPS2) potently promotes the release of brain-derived neurotrophic factor (BDNF). A rare splicing form of CAPS2 with deletion of exon3 (dex3) was identified to be overrepresented in some patients with autism. Here, we generated Caps2-dex3 mice and verified a severe impairment in axonal Caps2-dex3 localization, contributing to a reduction in BDNF release from axons.

Autistic-like behavioral phenotypes in a mouse model with copy number variation of the CAPS2/CADPS2 gene.

Ca²⁺-dependent activator protein for secretion 2 (CAPS2 or CADPS2) facilitates secretion and trafficking of dense-core vesicles. Recent genome-wide association studies of autism have identified several microdeletions due to copy number variation (CNV) in one of the chromosome 7q31.32 alleles on which the locus for CAPS2 is located in autistic patients.