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1.
Neuroscience ; 445: 130-143, 2020 10 01.
Article in English | MEDLINE | ID: mdl-31472213

ABSTRACT

Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene cause CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental syndrome where patients exhibit early-onset seizures, intellectual disability, stereotypies, limited or absent speech, autism-like symptoms and sensory impairments. Mounting evidences indicate that disrupted sensory perception and processing represent core signs also in mouse models of CDD; however we have very limited knowledge on their underlying causes. In this study, we investigated how CDKL5 deficiency affects synaptic organization and experience-dependent plasticity in the thalamo-cortical (TC) pathway carrying whisker-related tactile information to the barrel cortex (BC). By using synapse-specific antibodies and confocal microscopy, we found that Cdkl5-KO mice display a lower density of TC synapses in the BC that was paralleled by a reduction of cortico-cortical (CC) connections compared to wild-type mice. These synaptic defects were accompanied by reduced BC activation, as shown by a robust decrease of c-fos immunostaining, and atypical behavioral responses to whisker-mediated tactile stimulation. Notably, a 2-day paradigm of enriched whisker stimulation rescued both number and configuration of excitatory synapses in Cdkl5-KO mice, restored cortical activity and normalized behavioral responses to wild-type mice levels. Our findings disclose a novel and unsuspected role of CDKL5 in controlling the organization and experience-induced modifications of excitatory connections in the BC and indicate how mutations of CDKL5 produce failures in higher-order processing of somatosensory stimuli. This article is part of a Special Issue entitled: Animal Models of Neurodevelopmental Disorders.


Subject(s)
Epileptic Syndromes , Protein Serine-Threonine Kinases/deficiency , Spasms, Infantile , Animals , Humans , Infant , Mice , Protein Serine-Threonine Kinases/genetics , Synapses , Vibrissae
2.
Science ; 364(6444): 981-984, 2019 Jun 07.
Article in English | MEDLINE | ID: mdl-31171695

ABSTRACT

Galaxy clusters are the most massive gravitationally bound structures in the Universe. They grow by accreting smaller structures in a merging process that produces shocks and turbulence in the intracluster gas. We observed a ridge of radio emission connecting the merging galaxy clusters Abell 0399 and Abell 0401 with the Low-Frequency Array (LOFAR) telescope network at 140 megahertz. This emission requires a population of relativistic electrons and a magnetic field located in a filament between the two galaxy clusters. We performed simulations to show that a volume-filling distribution of weak shocks may reaccelerate a preexisting population of relativistic particles, producing emission at radio wavelengths that illuminates the magnetic ridge.

3.
Nature ; 568(7752): 360-363, 2019 04.
Article in English | MEDLINE | ID: mdl-30996312

ABSTRACT

Lightning is a dangerous yet poorly understood natural phenomenon. Lightning forms a network of plasma channels propagating away from the initiation point with both positively and negatively charged ends-called positive and negative leaders1. Negative leaders propagate in discrete steps, emitting copious radio pulses in the 30-300-megahertz frequency band2-8 that can be remotely sensed and imaged with high spatial and temporal resolution9-11. Positive leaders propagate more continuously and thus emit very little high-frequency radiation12. Radio emission from positive leaders has nevertheless been mapped13-15, and exhibits a pattern that is different from that of negative leaders11-13,16,17. Furthermore, it has been inferred that positive leaders can become transiently disconnected from negative leaders9,12,16,18-20, which may lead to current pulses that both reconnect positive leaders to negative leaders11,16,17,20-22 and cause multiple cloud-to-ground lightning events1. The disconnection process is thought to be due to negative differential resistance18, but this does not explain why the disconnections form primarily on positive leaders22, or why the current in cloud-to-ground lightning never goes to zero23. Indeed, it is still not understood how positive leaders emit radio-frequency radiation or why they behave differently from negative leaders. Here we report three-dimensional radio interferometric observations of lightning over the Netherlands with unprecedented spatiotemporal resolution. We find small plasma structures-which we call 'needles'-that are the dominant source of radio emission from the positive leaders. These structures appear to drain charge from the leader, and are probably the reason why positive leaders disconnect from negative ones, and why cloud-to-ground lightning connects to the ground multiple times.

4.
Neuroscience ; 192: 524-36, 2011 Sep 29.
Article in English | MEDLINE | ID: mdl-21635938

ABSTRACT

Stress and genetic predisposition are two of the major risk factors for a variety of psychiatric illnesses. Inbred mouse strains are considered useful tools in dissecting the genetic basis of complex disorders. Indeed, mice of the C57BL/6 and BALB/c strains, differing markedly in anxiety behaviours, are among the most widely used in psychopharmacological research. However, there is a paucity of studies investigating the impact of social stress in these two strains. Moreover, whether these two mouse strains exhibit different sensitivities to chronic social defeat stress remains poorly studied. Thus in this study we compared the impact of repeated (10 days) social defeat stress on a variety of behavioural and endocrine parameters including social interaction, locomotor activity, plasma corticosterone, body weight and stress-related physiological parameters in both mouse strains. Given that the duration of stress exposure may differentially affect such responses we also compared stressors of short (Social Defeat-Short; SD-S) and of long (Social Defeat-Long; SD-L) duration. Our results show that although mice from both strains were defeated in both social defeat paradigms, only BALB/c mice displayed social interaction impairments following SD-S, whereas both strains were behaviourally sensitive to SD-L. Moreover, both strains also differed in some of the physiological alterations induced by social defeat stress. Specifically, SD-S did not induce any change in corticosterone levels in either of the two strains, whereas SD-L was able to induce significant changes in C57BL/6 mice only. SD-S induced differential effects on bodyweight gain in both strains, increasing it in C57BL/6 and decreasing it in BALB/c mice, whereas SD-L had no effect. On the other hand, exposure to SD-S resulted in cardiac hypertrophy in C57BL/6 mice and SD-L induced spleen hypertrophy and thymus atrophy in BALB/c mice in addition to decreasing faecal output. Overall, the innately anxious BALB/c mice were more sensitive to social stress than C57BL/6, with differential behavioural and physiological alterations emerging as a function of stress severity. These data suggest different coping strategies to social interaction stress between the two mouse strains. The genetic basis of this stress-resilience/susceptibility warrants further investigation.


Subject(s)
Anxiety/genetics , Anxiety/psychology , Social Behavior , Stress, Psychological/genetics , Stress, Psychological/psychology , Animals , Genetic Predisposition to Disease , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
5.
J Int Neuropsychol Soc ; 16(1): 130-7, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19849881

ABSTRACT

Recent studies have reported specific executive and attentional deficits in preterm children. However, the majority of this research has used multidetermined tasks to assess these abilities, and the interpretation of the results lacks an explicit theoretical backdrop to better understand the origin of the difficulties observed. In the present study, we used the Child Attention Network Task (Child ANT; Rueda et al. 2004) to assess the efficiency of the alerting, orienting and executive control networks. We compared the performance of 25 preterm children (gestational age < or = 32 weeks) to 25 full-term children, all between 5(1/2) and 6(1/2) years of age. Results showed that, as compared to full-term children, preterm children were slower on all conditions of the Child ANT and had a specific deficit in executive control abilities. We also observed a significantly higher correlation between the orienting and executive control networks in the preterm group, suggesting less differentiation of these two networks in this population.


Subject(s)
Attention Deficit Disorder with Hyperactivity/etiology , Attention Deficit Disorder with Hyperactivity/pathology , Attention/physiology , Executive Function/physiology , Neuropsychological Tests , Premature Birth/physiopathology , Analysis of Variance , Child , Child, Preschool , Female , Humans , Male , Numerical Analysis, Computer-Assisted , Reaction Time/physiology , Statistics as Topic
6.
Pediatr Res ; 32(1): 118-24, 1992 Jul.
Article in English | MEDLINE | ID: mdl-1635837

ABSTRACT

Taurine is an organic osmolyte in brain cells. We studied whether cerebral taurine transport is enhanced as part of the cell volume regulatory adaptation to hypernatremia. Hypernatremic dehydration was induced for 48 h. Synaptosomes, metabolically active nerve terminal vesicles, were isolated by homogenization of brain and purification on a discontinuous Ficoll gradient. Taurine transport was evaluated in vitro using a rapid filtration assay. After 48 h of hypernatremia, there was a 22.4% increment in Na(+)-specific taurine transport from 2.99 +/- 0.16 to 3.66 +/- 0.13 mumol/mg protein/30 min (p less than 0.001). Dehydration for 48 h without hypertonic saline loading had no effect on taurine uptake. Glycine transport was unaltered by hypernatremia. The adaptation in taurine uptake resulted from an enhanced Vmax of the high affinity-low capacity transport system [265 +/- 17, control versus 337 +/- 19 nmol/min/mg protein, experimental (p less than 0.03)] without a change in the Km (approximately 60 microM). Under both control and hypernatremic conditions, Na+ and Cl- were required for maximal total Na(+)-mediated taurine uptake. Oubain (1 mM) decreased taurine uptake by 25%, whereas addition of beta-alanine or hypotaurine (500 microM) to the external media reduced taurine transport by 45-65% in both control and experimental conditions (p less than 0.01). Synaptosomal taurine uptake in hypernatremic rats was inhibited by 15-20% (p less than 0.01) after addition of 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (0.1 mM) or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (0.1 mM) or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (0.1 mM) to the external medium.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Brain/metabolism , Dehydration/metabolism , Hypernatremia/metabolism , Taurine/metabolism , Animals , Biological Transport, Active , Dehydration/complications , Hypernatremia/complications , Kinetics , Male , Rats , Rats, Inbred Strains , Synaptosomes/metabolism , Water-Electrolyte Balance
7.
Am J Physiol ; 262(1 Pt 2): F117-23, 1992 Jan.
Article in English | MEDLINE | ID: mdl-1733287

ABSTRACT

Repeated administration of low doses of puromycin aminonucleoside (PAMN) to rats induces a proteinuric renal disease that resembles focal segmental glomerulosclerosis (FSGS). Reactive oxygen molecules may be involved in the progressive course of this nephropathy. Therefore we evaluated whether taurine, an endogenous antioxidant, could limit the extent of renal injury. Sprague-Dawley rats received low-dose injections of PAMN, 2 mg/100 g body wt, over a 12-wk period. Two groups were studied: 1) controls given tap water (n = 23), and 2) an experimental group that drank 1% taurine-supplemented water (n = 22). Taurine-treated nephrotic rats had a reduction in albuminuria, as assessed by the urinary albumin-to-creatinine ratio (26 +/- 4 vs. 44 +/- 4, P less than 0.0001). After 12 wk, creatinine clearance was 0.33 +/- 0.03 (experimental) vs. 0.17 +/- 0.03 ml.min-1.100 g body wt-1 (control) (P less than 0.001), and inulin clearance (n = 6 pairs) was 0.26 +/- 0.04 (experimental) vs. 0.13 +/- 0.02 ml.min-1.100 g body wt-1 (control) (P less than 0.025). Administration of taurine reduced the percentage of segmentally sclerosed glomeruli (9.8 +/- 1.7 vs. 16.2 +/- 1.8%, P less than 0.02) and the tubulointerstitial injury score (1.36 +/- 0.19 vs. 2.61 +/- 0.25, P less than 0.0025) in experimental vs. control rats. Taurine treatment normalized the elevated renal cortical malondialdehyde level in rats with PAMN nephropathy (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Kidney Diseases/physiopathology , Puromycin Aminonucleoside , Taurine/pharmacology , Animals , Chronic Disease , Creatinine/blood , Kidney/drug effects , Kidney/pathology , Kidney/physiopathology , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Male , Proteinuria/chemically induced , Rats , Rats, Inbred Strains
8.
Pediatr Nephrol ; 4(5): 501-4, 1990 Sep.
Article in English | MEDLINE | ID: mdl-2242316

ABSTRACT

Glomerular diseases are characterized by increased urinary protein excretion. Treatment of this abnormality frequently involves administration of corticosteroids and angiotensin-converting enzyme inhibitors. There has been much recent interest in the potential impact of these drugs on progressive renal dysfunction, since they have opposing effects on intraglomerular hemodynamics. Therefore, we investigated the effect of methylprednisolone or captopril treatment on animals with chronic puromycin aminonucleoside nephropathy. In rats given a single injection of puromycin aminonucleoside, 15 mg/100 g body weight, both methylprednisolone and captopril significantly reduced proteinuria at 6 months [83 +/- 14 untreated (n = 7), 34 +/- 6 with methylprednisolone (n = 8), and 6 +/- 1 mg/24 h with captopril (n = 5), P less than 0.001]. Segmental glomerulosclerosis occurred with equal frequency in the untreated (7.8 +/- 2.3%) and methylprednisolone-treated rats (5.0 +/- 1.11%), but was significantly reduced by the administration of captopril (1.0 +/- 0.5%, P less than 0.001). We conclude that in chronic puromycin aminonucleoside nephropathy, treatment with corticosteroids reduces proteinuria without increasing the incidence of segmental glomerulosclerosis. Therapy with an angiotensin-converting enzyme inhibitor substantially decreases proteinuria and lessens the severity of glomerular scarring.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Captopril/therapeutic use , Kidney Failure, Chronic/drug therapy , Methylprednisolone/therapeutic use , Nephrotic Syndrome/drug therapy , Proteinuria/drug therapy , Animals , Disease Models, Animal , Glomerular Filtration Rate/drug effects , Glomerulosclerosis, Focal Segmental/prevention & control , Kidney Failure, Chronic/chemically induced , Kidney Failure, Chronic/physiopathology , Male , Nephrotic Syndrome/chemically induced , Nephrotic Syndrome/physiopathology , Proteinuria/etiology , Puromycin Aminonucleoside , Rats , Rats, Inbred Strains
9.
Pediatr Res ; 27(1): 85-8, 1990 Jan.
Article in English | MEDLINE | ID: mdl-2296475

ABSTRACT

Taurine is a cerebral osmoprotective molecule during chronic hypernatremic dehydration. In these experiments, we investigated the role of taurine in osmoregulation during acute hyponatremia. Taurine deficiency was induced in experimental cats (n = 6) by feeding a taurine-free diet for 8-10 wk, whereas control counterparts (n = 6) consumed a regular diet. Hyponatremia was provoked in all cats over 54 h by daily injections of 5% dextrose in water (7.5% body wt) and vasopressin (20 U/d). The serum Na+ concentration was abruptly lowered to 110 +/- 3 and 117 +/- 2 mmol/L, in experimental and control animals, respectively. The cerebral total and intracellular water compartment sizes were reduced from 486 +/- 11 to 441 +/- 11 ml/100 g dry wt and from 357 +/- 7 to 309 +/- 12 mL/100 g dry wt, respectively, in control versus experimental cats, p less than 0.05. There was a significant linear relationship between cerebral taurine content and the intracellular water compartment size in all animals, p less than 0.02. Taurine displayed a similar osmoprotective capacity in muscle tissue in these studies. We conclude that taurine is an osmoregulatory molecule in cerebral and extracerebral tissues during severe hyponatremia. Reductions in tissue taurine content may complement decreases in cytosolic electrolyte levels during adaptation to more prolonged hyponatremia.


Subject(s)
Brain Edema/metabolism , Hyponatremia/metabolism , Taurine/metabolism , Animals , Brain Edema/physiopathology , Cats , Hyponatremia/physiopathology , Osmolar Concentration
10.
Life Sci ; 46(16): 1139-44, 1990.
Article in English | MEDLINE | ID: mdl-2188050

ABSTRACT

Since hypertension may compromise the ability to withstand hypernatremic dehydration, we investigated the impact of two experimental models of hypertension and pharmacologic normalization of blood pressure on the tolerance to chronic hypernatremic dehydration. In DOCA-salt hypertensive animals and the spontaneously-hypertensive rat (SHR), there was increased mortality and cerebral cell shrinkage during hypernatremic dehydration, compared to control Sprague-Dawley or Wistar-Kyoto rats. These findings were paralleled by significant differences in the brain intracellular water compartment size (ml/100 g dry weight), i.e. 233 +/- 6, Sprague-Dawley vs 189 +/- 8, DOCA-salt, P less than 0.01; 246 +/- 3, Wistar-Kyoto vs 194 +/- 6, SHR, P less than 0.01. Normalization of the blood pressure in the SHR with captopril restored 48% of the cerebral cell volume regulatory capacity observed in normotensive Wistar-Kyoto rats. We conclude that sustained hypertension increases the risk of hypernatremic dehydration in select circumstances. Correction of the elevated blood pressure promotes partial recovery of normal cerebral cell volume regulation.


Subject(s)
Brain/physiopathology , Dehydration/physiopathology , Hypernatremia/physiopathology , Hypertension/physiopathology , Animals , Body Water/analysis , Brain Chemistry , Captopril/therapeutic use , Hypertension/drug therapy , Male , Muscles/analysis , Osmolar Concentration , Potassium/analysis , Rats , Rats, Inbred SHR , Rats, Inbred Strains , Rats, Inbred WKY , Sodium/analysis
11.
Am J Hypertens ; 2(12 Pt 1): 909-12, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2610995

ABSTRACT

Taurine, a sulfur aminoacid, has been studied for a role in blood pressure regulation since it functions as a generalized inhibitory neurotransmitter and is found in high concentrations in the myocardium. We reinvestigated the magnitude of the hypotensive effect of chronic taurine administration to the spontaneously hypertensive rat (SHR) and the role of catecholamines in such an action. The SHR received either a 1% taurine solution or tap water to drink for 16 weeks. Taurine treatment caused a significant persistent reduction in blood pressure by 4 weeks that was maximal at 16 weeks (146 +/- 6 [exp.] v 182 +/- 5 [control] mm Hg, P less than .01). While this taurine-induced decline in blood pressure in the SHR was not accompanied by alterations in plasma epinephrine levels, there was a steady 235% increment in the norepinephrine concentration from 231 +/- 31 pg/mL initially to 542 +/- 126 pg/mL at completion of the study, P less than .02. The reduction in blood pressure was associated with decreased proteinuria in the taurine-treated SHR (9.6 +/- 4 [exp.] v 21.5 +/- 7 [control] mg/24 h, P less than .02) and less cardiac and renal hypertrophy. We conclude that taurine administration results in a 20 to 25% reduction in blood pressure in the SHR. The mechanism of this hypotensive action requires further study but is independent of changes in plasma catecholamine levels. The vasodepressor effect of taurine leads to less hypertensive injury to the kidney and heart in the SHR.


Subject(s)
Blood Pressure/drug effects , Catecholamines/blood , Rats, Inbred SHR/physiology , Rats, Inbred Strains/physiology , Taurine/pharmacology , Animals , Biomechanical Phenomena , Heart/anatomy & histology , Kidney/anatomy & histology , Norepinephrine/blood , Organ Size , Rats , Rats, Inbred SHR/anatomy & histology , Rats, Inbred SHR/blood
12.
Am J Dis Child ; 142(11): 1194-8, 1988 Nov.
Article in English | MEDLINE | ID: mdl-3177325

ABSTRACT

We have previously shown that in the cat, taurine is an osmoprotective molecule that lessens mortality, neurological morbidity, and brain-cell dehydration during chronic hypernatremic dehydration. We examined the ability of two taurine analogues to afford cerebral osmoprotection in rats. Pretreatment with guanidinoethane sulfonate, a competitive antagonist for beta-amino acid transport, as a 1% drinking solution for ten days led to a significant reduction in brain-cell dehydration. Thus, total brain-cell water was higher in experimental vs control animals (544.3 +/- 36.8 vs 478.2 +/- 12.7 mL/100 g of fat-free dry solids [FFDS]) and the difference was almost exclusively derived from the intracellular water compartment (452.7 +/- 27.3 vs 371.4 +/- 7.7 mL/100 g of FFDS). Pretreatment with taltrimide, a lipophilic taurine derivative (intraperitoneal injection of 200 mg/kg for four days), led to similar results. Total brain-tissue water was significantly higher in experimental vs control rats (507.6 +/- 18.8 vs 363.2 +/- 9.5 mL/100 g of FFDS), with the difference primarily derived from the intracellular water space (372.8 +/- 18.1 vs 221.3 +/- 13.1 mL/100 g of FFDS). These results suggest that the cerebral response to chronic hypertonic stress includes accelerated transmembrane flux of osmoprotective solutes in addition to mobilization from sequestered intracellular storage sites in an attempt to increase the cytosolic pool of osmotically active molecules.


Subject(s)
Brain/metabolism , Dehydration/metabolism , Hypernatremia/metabolism , Taurine/analogs & derivatives , Taurine/pharmacology , Water-Electrolyte Balance/drug effects , Animals , Body Water/metabolism , Chronic Disease , Dehydration/complications , Hypernatremia/complications , Muscles/metabolism , Phthalimides/pharmacology , Rats , Rats, Inbred Strains , Taurine/metabolism
13.
Ann Hum Genet ; 50(3): 217-21, 1986 07.
Article in English | MEDLINE | ID: mdl-2833154

ABSTRACT

The segregation of the human gene for beta-glycerol phosphatase (GPB) was examined in human-Syrian hamster and human-Chinese hamster somatic cell hybrids. Electrophoretic analysis of the GPB in hybrids suggested that the enzyme is a dimer. Human GPB cosegregated with chromosome 8 in the twenty-five hybrids examined.


Subject(s)
Chromosome Mapping , Chromosomes, Human, Pair 8 , Genes , Phosphoric Monoester Hydrolases/genetics , Animals , Cell Line , Cricetinae , Electrophoresis, Starch Gel , Humans , Hybrid Cells , Isoenzymes/genetics
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