Achievement of Target Gain Larger than Unity in an Inertial Fusion Experiment.

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Lawson Criterion for Ignition Exceeded in an Inertial Fusion Experiment.

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

A simple explanation for declining temperature sensitivity with warming.

Recently, multiple studies have reported declining phenological sensitivities (∆ days per ℃) with higher temperatures. Such observations have been used to suggest climate change is reshaping biological processes, with major implications for forecasts of future change. Here, we show that these results may simply be the outcome of using linear models to estimate nonlinear temperature responses, specifically for events that occur after a cumulative thermal threshold is met-a common model for many biological events. Corrections for the nonlinearity of temperature responses consistently remove the apparent decline. Our results show that rising temperatures combined with linear estimates based on calendar time produce the observations of declining sensitivity-without any shift in the underlying biology. Current methods may thus undermine efforts to identify when and how warming will reshape biological processes.

New Measures for Research on Men Who Have Sex with Men and for At-Risk Heterosexuals: Tools to Study Links Between Structural Interventions or Large-Scale Social Change and HIV Risk Behaviors, Service Use, and Infection.

Large-scale structural interventions and "Big Events" like revolutions, wars and major disasters can affect HIV transmission by changing the sizes of at-risk populations, making high-risk behaviors more or less likely, or changing contexts in which risk occurs. This paper describes new measures to investigate hypothesized pathways that could connect macro-social changes to subsequent HIV transmission. We developed a "menu" of novel scales and indexes on topics including norms about sex and drug injecting under different conditions, experiencing denial of dignity, agreement with cultural themes about what actions are needed for survival or resistance, solidarity and other issues. We interviewed 298 at-risk heterosexuals and 256 men who have sex with men in New York City about these measures and possible validators for them. Most measures showed evidence of criterion validity (absolute magnitude of Pearson's r ≥ 0.20) and reliability (Cronbach's alpha ≥ 0.70). These measures can be (cautiously) used to understand how macro-changes affect HIV and other risk. Many can also be used to understand risk contexts and dynamics in more normal situations. Additional efforts to improve and to replicate the validation of these measures should be conducted.

Genetic basis of octanoic acid resistance in Drosophila sechellia: functional analysis of a fine-mapped region.

Drosophila sechellia is a species of fruit fly endemic to the Seychelles islands. Unlike its generalist sister species, D. sechellia has evolved to be a specialist on the host plant Morinda citrifolia. This specialization is interesting because the plant's fruit contains secondary defence compounds, primarily octanoic acid (OA), that are lethal to most other Drosophilids. Although ecological and behavioural adaptations to this toxic fruit are known, the genetic basis for evolutionary changes in OA resistance is not. Prior work showed that a genomic region on chromosome 3R containing 18 genes has the greatest contribution to differences in OA resistance between D. sechellia and D. simulans. To determine which gene(s) in this region might be involved in the evolutionary change in OA resistance, we knocked down expression of each gene in this region in D. melanogaster with RNA interference (RNAi) (i) ubiquitously throughout development, (ii) during only the adult stage and (iii) within specific tissues. We identified three neighbouring genes in the Osiris family, Osiris 6 (Osi6), Osi7 and Osi8, that led to decreased OA resistance when ubiquitously knocked down. Tissue-specific RNAi, however, showed that decreasing expression of Osi6 and Osi7 specifically in the fat body and/or salivary glands increased OA resistance. Gene expression analyses of Osi6 and Osi7 revealed that while standing levels of expression are higher in D. sechellia, Osi6 expression is significantly downregulated in salivary glands in response to OA exposure, suggesting that evolved tissue-specific environmental plasticity of Osi6 expression may be responsible for OA resistance in D. sechellia.

Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells.

Embryonic stem (ES) cells are clonal cell lines derived from the inner cell mass of the developing blastocyst that can proliferate extensively in vitro and are capable of adopting all the cell fates in a developing embryo. Clinical interest in the use of ES cells has been stimulated by studies showing that isolated human cells with ES properties from the inner cell mass or developing germ cells can provide a source of somatic precursors. Previous studies have defined in vitro conditions for promoting the development of specific somatic fates, specifically, hematopoietic, mesodermal, and neurectodermal. In this study, we present a method for obtaining dopaminergic (DA) and serotonergic neurons in high yield from mouse ES cells in vitro. Furthermore, we demonstrate that the ES cells can be obtained in unlimited numbers and that these neuron types are generated efficiently. We generated CNS progenitor populations from ES cells, expanded these cells and promoted their differentiation into dopaminergic and serotonergic neurons in the presence of mitogen and specific signaling molecules. The differentiation and maturation of neuronal cells was completed after mitogen withdrawal from the growth medium. This experimental system provides a powerful tool for analyzing the molecular mechanisms controlling the functions of these neurons in vitro and in vivo, and potentially for understanding and treating neurodegenerative and psychiatric diseases.

A pulsed-air model of blue whale B call vocalizations.

Blue whale sound production has been thought to occur by Helmholtz resonance via air flowing from the lungs into the upper respiratory spaces. This implies that the frequency of blue whale vocalizations might be directly proportional to the size of their sound-producing organs. Here we present a sound production mechanism where the fundamental and overtone frequencies of blue whale B calls can be well modeled using a series of short-duration (<1 s) wavelets. We propose that the likely source of these wavelets are pneumatic pulses caused by opening and closing of respiratory valves during air recirculation between the lungs and laryngeal sac. This vocal production model is similar to those proposed for humpback whales, where valve open/closure and vocal fold oscillation is passively driven by airflow between the lungs and upper respiratory spaces, and implies call frequencies could be actively changed by the animal to center fundamental tones at different frequency bands during the call series.

Children at risk for schizophrenia: the Jerusalem Infant Development Study. II. Neurobehavioral deficits at school age.

The development of school-age children born to parents with serious mental disorders was assessed on a variety of perceptual-cognitive and motoric tasks. These same children have been followed up from birth as part of the Jerusalem Infant Development Study. Children with schizophrenic parents, when compared with children with healthy parents or parents having other psychiatric disorders, were more likely to show neurobehavioral dysfunctioning in perceptual-cognitive and motoric areas. Forty-four percent of the offspring of schizophrenics (11 of 25 subjects) showed such dysfunctioning. Male subjects were overrepresented in this poorly functioning group. A stable subgroup (40%) of the offspring of schizophrenics (six of 15 subjects) showed dysfunctioning during infancy and school age. None of the offspring of nonschizophrenic parents showed dysfunctioning during both age periods. While most of the poorly functioning children with schizophrenic parents showed perceptual-cognitive and motoric signs, only perceptual-cognitive signs were strongly linked to parental diagnosis and infant dysfunctioning. Motoric signs, but not cognitive signs, were related to pregnancy and birth complications. These findings provide further support to the schizotaxia hypothesis that some neurointegrative deficits may reflect vulnerability to schizophrenia and that these deficits are clearly apparent at school age, long before the onset of illness. However, these signs are not exclusive to schizophrenic illness, although they occur with a greater prevalence in this group. Definitive statements about the validity of early neurobehavioral signs as indicators of genetic vulnerability await further longitudinal follow-up into the age of risk for actual schizophrenic breakdown or when a diagnosis of schizotypal personality disorder may be made.

Infants at risk for schizophrenia. The Jerusalem Infant Development Study.

The development of infants born to parents with serious mental disorders was followed up from birth through the first year of life. An individual-differences approach to statistical analysis. Multidimensional Scalogram Analysis (MSA), was shown to be an effective statistical procedure for examining heterogeneous psychiatric populations. The MSA revealed the existence of a subgroup of infants born to schizophrenics who repeatedly performed poorly in motor and sensorimotor areas of functioning during their first year of life. These infants were especially vulnerable to external insults, and many had low to low-normal birth weights. These findings, taken together with similar findings from other investigations, add support to the hypothesis that these infants may have a genetically determined neurointegrative deficit.

Familial risk of dementia associated with a biologic subtype of Alzheimer's disease.

Increased platelet membrane fluidity is a stable familial trait that identifies a prominent subgroup of patients with Alzheimer's disease. Patients in this subgroup have distinct clinical features, including an early age at symptomatic onset and a rapidly progressive course. The morbid risk of Alzheimer's-type dementia was studied in 421 first-degree relatives of 43 patients who met current consensus criteria for probable Alzheimer's disease and 47 healthy controls. Relatives of patients showed an approximate 50% (90- to 95-year) lifetime risk of dementia, regardless of the platelet membrane phenotype of the respective proband, which was over four times the control value. However, relatives of patients with increased platelet membrane fluidity who developed dementia exhibited symptoms significantly earlier than relatives of patients with normal platelet membrane fluidity. Alternative genetic models that describe the relationship of platelet membrane fluidity and Alzheimer's disease are discussed.

Infants at risk for schizophrenia: sequelae of a genetic neurointegrative defect. A review and replication analysis of pandysmaturation in the Jerusalem Infant Development Study.

A 1975 report stated that a schizophrenic genotype may be manifested in infants by a neurointegrative defect called pandysmaturation. Recent evidence supports this: (1) 12 studies found delayed development in schizophrenics' infants and in preschizophrenics; (2) "blind" psychometric evaluations favored an adult schizotypal disorder in four to six of seven high-risk subjects with pandysmaturation in the New York study; and (3) finally, in a partial replication of this method using the Jerusalem data, blind diagnoses of "probable" and "possible" pandysmaturation were significantly related to a parental diagnosis of schizophrenia and to cognitive and motor neurointegrative deficits at 10 years. Obstetrical complications were unrelated to diagnosis, pandysmaturation, or outcome in the overall sample. However, we found a small subgroup of schizophrenic offspring in whom the most severe motor deficits at follow-up were related to obstetrical complications, pandysmaturation, and low birth weight.

Neurobehavioral deficits at adolescence in children at risk for schizophrenia: The Jerusalem Infant Development Study.

BACKGROUND: The Jerusalem Infant Development Study is a prospective investigation comparing offspring of schizophrenic parents with offspring of parents who have no mental disorder or have nonschizophrenic mental disorders. During infancy and school age, a subgroup of offspring of schizophrenic parents showed global neurobehavioral deficits that were hypothesized to be indicators of vulnerability to schizophrenia. The purposes of the present investigation were to determine if neurobehavioral deficits were present in the offspring of schizophrenics at adolescence, to examine their stability over time, and to explore their relation to concurrent mental adjustment. METHODS: Sixty-five Israeli adolescents were assessed on a battery of neurologic and neuropsychological assessments. They were also administered psychiatric interviews from which best-estimate DSM-III-R diagnoses and scores of global adjustment were derived. RESULTS: Adolescents with poor neurobehavioral functioning were identified from composites of motor and cognitive-attentional variables. A disproportionate number of offspring of schizophrenic parents (42%; 10/24), and especially male offspring of schizophrenic parents (73%; 8/11), showed poor neurobehavioral functioning relative to offspring of nonschizophrenic parents (22%; 9/41). Adolescent offspring of schizophrenics with poor neurobehavioral functioning had been poorly functioning at earlier ages and had poor psychiatric adjustment at adolescence. All 4 offspring of schizophrenics receiving schizophrenia spectrum diagnoses by adolescence showed a pattern of poor neurobehavioral functioning across developmental periods. CONCLUSIONS: Results are consistent with the hypothesis that individuals at genetic risk for schizophrenia may display lifelong neurobehavioral signs that are indicators of vulnerability to schizophrenia and that are associated with psychiatric adjustment generally and schizophrenic spectrum disorder specifically.

A role for norepinephrine in stress-induced cognitive deficits: alpha-1-adrenoceptor mediation in the prefrontal cortex.

BACKGROUND: Stress exacerbates many neuropsychiatric disorders associated with prefrontal cortical (PFC) dysfunction. Stress also impairs the working memory functions of the PFC. Although stress research has focused on dopaminergic mechanisms, stress also increases norepinephrine (NE) release in PFC, and intra-PFC infusions of NE alpha-1-adrenoceptor agonists impair working memory. The current study examined whether NE alpha-1-adrenoceptor actions in PFC contribute to stress-induced deficits in working memory performance. METHODS: Rats were treated with a pharmacological stressor, FG7142 (30 mg/kg) or vehicle 30 min before testing on a test of spatial working memory, delayed alternation. The alpha-1-adrenoceptor antagonist, urapidil (0.1 microgram/0.5 microL), or saline vehicle, was infused into the PFC 15 min before delayed alternation testing. RESULTS: As observed previously, FG7142 significantly impaired the accuracy of delayed alternation performance, and induced a perseverative pattern of responding consistent with PFC dysfunction. FG7142 also slowed motor response times. Infusion of urapidil into the PFC completely reversed the FG7142-induced impairment in delayed alternation performance, but did not alter the slowed motor responding. CONCLUSIONS: These findings indicate that alpha-1-adrenoceptor stimulation in the PFC contributes to stress-induced impairments in PFC cognitive functions. These neurochemical actions may contribute to symptoms of working memory impairment, poor attention regulation, or disinhibited behaviors in neuropsychiatric disorders sensitive to stress exposure.

Characterization of Streptomyces promoter sequences using the Escherichia coli galactokinase gene.

A gene fusion system that uses the Escherichia coli galK gene has been developed to characterize Streptomyces transcriptional regulatory sequences. The system consists of galK-deficient Streptomyces lividans mutants and plasmids containing the E. coli galK gene with its natural ribosome-binding site and sites upstream of galK for insertion of transcription signals. Expression of the E. coli galK gene in S. lividans can be quantitated by either an enzymatic or immunoblot assay or detected by genetic complementation of an S. lividans galK- mutant. The utility of the plasmid to select, detect and assess promoter function was examined using the S. lividans XP55 and S. fradiae aph gene promoters. The potential use of the galK fusion system to isolate and characterize Streptomyces transcription signals is discussed.

Risk of dementia in relatives of patients with Alzheimer's disease.

Using a family history questionnaire, we investigated the occurrence of dementia among relatives of patients with a clinical diagnosis of Alzheimer's disease (AD) and among the relatives of age-matched control subjects. Cumulative lifetime risk of developing AD-type dementia was greater among relatives of AD probands and was consistent with an autosomal dominant genetic mode of transmission. Although the lifetime risk of AD-type dementia was similar among relatives of early-onset and late-onset AD probands, relatives of early-onset probands tended to have an earlier onset of dementia than did relatives of late-onset AD probands. This result raises the possibility that age at onset of dementia in AD may be genetically determined.

DRD4 related to infant attention and information processing: a developmental link to ADHD?

The dopamine D4 receptor (DRD4) exon III polymorphism has generated interest because of its association with attention deficit hyperactivity disorder (ADHD), with an increased frequency of the seven-repeat allele being reported in children with ADHD. Deficits in sustained attention and information processing characterize ADHD, and individual differences in these functions are apparent from infancy. We found that in a structured play situation and on an information-processing task, 1-year-old infants with the 7-DRD4 allele showed less sustained attention and novelty preference than do infants without the 7-DRD4 allele. There was also a significant interaction between DRD4 and the serotonin transporter promoter (5-HTTLPR) gene on a measure of sustained attention. Our results provide evidence for a possible developmental link between DRD4 and ADHD via early sustained attention and information processing. It also points to the importance of considering the influence of more than one gene in studies of behavior.

Social adjustment of adolescents at risk for schizophrenia: the Jerusalem Infant Development Study.

OBJECTIVE: To better understand whether poor social adjustment, a core characteristic of schizophrenic illness, may also be an indicator of vulnerability in young people who are at genetic risk for schizophrenia, but who do not have schizophrenia. METHOD: Between 1992 and 1996, 27 Israeli adolescents with a schizophrenic parent, 29 adolescents with no mentally ill parent, and 30 adolescents with a parent having a nonschizophrenic mental disorder were assessed on multiple domains of social adjustment measured using the Social Adjustment Inventory for Children and Adolescents and the Youth Self-Report. RESULTS: Young people with a schizophrenic parent showed poor peer engagement, particularly heterosexual engagement, and social problems characterized by immaturity and unpopularity with peers. These social adjustment difficulties in youths at risk for schizophrenia could not be attributed solely to the presence of early-onset mental disorders, although problems were greater in those with disorders in the schizophrenia spectrum. Young people whose parents had other disorders showed different patterns of social maladjustment characterized by difficult, conflictual relationships with peers and family. CONCLUSION: Adolescents at risk for schizophrenia have social deficits that extend beyond early-onset psychopathology and that may reflect vulnerability to schizophrenic disorder.

Review of the NIMH Israeli Kibbutz-City Study and the Jerusalem Infant Development Study.

The National Institute of Mental Health (NIMH) Israeli Kibbutz-City Study has followed the development of offspring of schizophrenic parents from middle childhood through early adulthood. During childhood, a subgroup of offspring of schizophrenic patients showed clear neurobehavioral deficits often accompanied by poor social competence. Early followup data suggest that this subgroup of high-risk children is at greatest risk for adult schizophrenia spectrum illness. The Jerusalem Infant Development Study has followed a similar population of children at risk for schizophrenia from before birth through middle childhood. A subgroup of dysfunctioning in the high-risk children showed sensorimotor dysfunctioning in the first year of life, which was followed by perceptual, motor, and attentional dysfunctioning in childhood--identical to that found in the NIMH cohort. Results from both studies support the hypothesis that schizophrenic illness involves constitutional factors whose expression can be observed as early as infancy. Results also illustrate the importance of using data-analytic approaches that (1) look for subgroups within high-risk groups rather than only group differences between high- and low-risk groups, and (2) examine profiles of behavior rather than only single variables.

Muscarinic receptors involved in hippocampal plasticity.

The cholinergic septohippocampal system has been associated with learning and memory, as evidenced by the severe loss of these functions in lesioned animals as well as in senile demented patients. In an attempt to comprehend the physiological basis of the cholinergic innervation for hippocampal functions, numerous studies employed the in-vitro hippocampal slice preparation and analyzed the consequences of exposing the cells to cholinergic ligands. Many effects of activating a cholinergic receptor in the hippocampus were thus described, including blockade of several types of potassium conductances, yet few of these effects are intuitively related to the involvement of the cholinergic system in hippocampal plasticity. An alternative approach involves focusing on the possible effect of low concentration of cholinergic ligands on reactivity of the hippocampus to afferent stimulation. We found two new actions of acetylcholine (ACh); The first one is a fast onset, short lived increase in cellular responses to activation of the N-methyl-D-aspartate (NMDA) receptor, and the second one is a slow onset, long lasting increase in reactivity to afferent stimulation, resembling that produced by a tetanic stimulation, which we called muscarinic long term potentiation (LTPm). The latter effect is mediated by a postsynaptic M2 receptor, and it shares several properties with the more familiar tetanic LTP. In addition, LTPm involves a rise of intracellular calcium concentration and an activation of both a tyrosine kinase and a serine/threonine kinase. Intuitively, LTPm is better related to hippocampal plasticity than the other reported effects of ACh in the hippocampus. Indeed, aged rats, which are cognitively impaired, lack LTPm while they do express other muscarinic actions. It is proposed that LTPm is an important link between the cholinergic action and function in the hippocampus.