ADAMTS-1: A metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function

金沢大学医薬保健研究域医学系A disintegrin and metalloproteinase (ADAM) represents a protein family possessing both metalloproteinase and disintegrin domains. ADAMTS-1, an ADAM family member cloned from cachexigenic colon adenocarcinoma, is unusual in that it contains thrombospondin type I motifs and anchors to the extracellular matrix. To elucidate the biological role of ADAMTS-1, we developed ADAMTS-1-null mice by gene targeting. Targeted disruption of the mouse ADAMTS-1 gene resulted in growth retardation with adipose tissue malformation. Impaired female fertilization accompanied by histological changes in the uterus and ovaries also resulted. Furthermore, ADAMTS-1(-/-) mice demonstrated enlarged renal calices with fibrotic changes from the ureteropelvic junction through the ureter, and abnormal adrenal medullary architecture without capillary formation. ADAMTS-1 thus appears necessary for normal growth, fertility, and organ morphology and function. Moreover, the resemblance of the renal phenotype to human ureteropelvic junction obstruction may provide a clue to the pathogenesis of this common congenital disease

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Serotonergic dysfunction mediates decrease in motivation for instrumental action in hypothyroidism model monkeys

8th IBRO World Congress of Neuroscienc

Behavioral characteristics of low motivation and its relation to serotonin in a primate model of depression

The motivation to engage in behavior arises from both incentive factors (e.g., size or timing of reward) and drive (e.g., thirst or hunger). Motivation is also affected by mood, which is related to mental or biological states as well. For example, depression is associated with low motivation in general. What is altered in motivational function in the brain in depression? Here we studied motivational alteration in depression with a monkey model of hypothyroidism, which is associated with symptoms, such as fatigue or depression. Three monkeys were injected with antithyroid agent, methimazole (10-100 mg/day), which inhibits production of thyroid hormone. After about a month of application, the thyroxin level became less than half of normal (5 -> 2.5 mu g/dl). We examined the behavioral effect of hypothyroidism by using a reward-size task (Minamimoto et al., 2009). In this task, the monkey earned a reward if it correctly released a bar after a signal changes to green. A visual cue presented at the beginning of each trial indicated the size of the reward (1, 2, 4 or 8 drops) after the correct bar release. In the hypothyroid state, the monkey\u27s error rate went up dramatically without increasing reaction time. To analyze the effect quantitatively, we fitted the data with an inverse function of reward size with 2 free parameters, reward sensitive and reward unrelated terms. We found significant decrease of reward sensitivity (0.6 +/- 0.2 of normal) and increase of reward-unrelated "general errors" of 5.3 +/- 2.8%. Moreover, by application of SSRI (citalopram, 1-8 mg/day), the general error dropped without recovery of reward-size sensitivity. These results suggest that the hypothyroid-induced low motivational state can be characterized by reward desensitization and increase of general error, and that the latter is associated with a low serotonin level.第33回日本神経科学大会（Neuro2010

Changes in dopaminergic function associated with low motivation in a primate model of hypothyroidism: a PET study

The motivation to engage in action can be influenced not only by the value of outcome but also by moods of the subject. We previously reported low motivational state in a monkey model of hypothyroidism, which was characterized by lower instrumental task performance (Minamimoto et al., SFN 2010). Since dopamine has a major role in reward and motivation, we hypothesized that hypothyroidism induces dysfunctions of the dopaminergic system, which in turn lead to low motivation. To address this issue, we examined dopamine receptor density in hypothyroidism model monkeys using positron emission tomography (PET). PET scan data were obtained with [11C]FLB457 (high affinity for extrastriatal D2 receptors) for both pre-hypothyroid control and hypothyroid state. Hypothyroid state was defined as when the monkey\u27s thyroxin level reached less than 2 &#181;g/dl continuously after administration of antithyroid agent (methimazole, 100 mg/day) for 2 months. The analysis of parametric images of control and hypothyroidism revealed increased binding potential of [11C]FLB457 in the ventromedial prefrontal cortex (VMPFC). This result suggests that the upregulation of D2 receptors occurred by the decrease of dopamine release in VMPFC in hypothyroidism, resulting in low motivation for task performance.Neuroscience 2011, SfN\u27s 41th annual meetin

Preparation of acute living hippocampal slice from common marmoset (Callithrix jacchus) for synaptic function analysis

We described the preparation of acute living slices from the hippocampus of the neonatal common marmoset (Callithrix jacchus). Slices from a temporal lobe section were prepared quickly using a rotary slicer. By this method, we successfully recorded field potentials, namely, pre-synaptic fiber volley and field excitatory post-synaptic potentials, from the hippocampal CA1 region with conventional electrophysiological techniques, and analyzed the indicators of synaptic function such as input-output curve. This study thus presents an efficient preparation method for acute living hippocampal slice from which synaptic function of the hippocampus in non-human primate can be analyzed

Decreased motivational value in an instrumental task after a single injection of haloperidol with quantitative assessment of dopamine D2-like receptor occupancy

The motivation to engage in action is regulated by valuation of predicted outcome comprised from external factor (i.e., incentive) and internal factor (i.e., drive). Function-mediated dopamine D2-like receptor (D2R) is widely known to be involved in processing motivation, incentive, and drive. However, it is unclear how the transmission via D2R is related to the computation of motivational value from these factors. To address this issue, we quantitatively assessed the relationship between motivational value of instrumental action and dopamine D2-like receptor availability after systemic injection of D2R antagonist. We performed positron emission tomography (PET) measurements for D2R binding with [11C]raclopride in 2 monkeys. With a systemic injection of a low dose of D2R antagonist, haloperidol (0.01mg/kg, i.m.), occupancy of D2R in the striatum was 74~81%. This occupancy lasted to at least post-injection day 3 (~40% occupancy), and [11C]raclopride binding recovered to the pre-treatment level at day 7. We tested 2 monkeys with reward-size task (Minamimoto et al., 2009), in which they were required to release a bar to receive predicted water rewards (1, 2, 4 or 8 drops). The error rate of the task (i.e., proportion of trials with low motivation) increased during days 0 to 3 after the haloperidol injection. We quantified the motivational value by using error rate (E), since it is inversely related to the predicted reward size (R): E = 1/aR, where a is a free parameter. The best-fit parameter a was discounted from the pre-treatment level by 50% at day 0 and by 30~40% at day 3, returning to the pre-treatment level at day 7, suggesting that the impact of outcome on motivational value attenuated in parallel with D2R occupancy. In contrast, the injection of haloperidol did not affect sucrose preference or water amount intake in the home cage, indicating that incentive valence and drive were unimpaired. These results suggest that attenuation of dopamine transmission via D2 receptors reduces computation of motivational value from external and internal information.Neuroscience 2012, SfN\u27s 42th annual meetin