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.

Endothelins, peptides with potent vasoactive properties, are produced by human macrophages.

Endothelins are peptides, originally isolated from endothelial cells, with potent vasoactive and mitogenic properties. In this study, we demonstrate that human macrophages synthesize and secrete endothelins. Cultured human macrophages were found by immunocytochemistry to stain positively for endothelin 1 and endothelin 3. Their capability to produce and release these peptides was confirmed by a combination of reverse-phase high-performance liquid chromatography and radioimmunoassays, specific for endothelin 1 and 3, respectively. Immunoreactive peptides were identified both in cellular extracts and in macrophage-conditioned medium. The secretion of endothelin 1, but not of endothelin 3, from macrophages could be stimulated 6-10-fold by lipopolysaccharide or phorbol myristate acetate (PMA). Northern blot analysis of total macrophage RNA using an endothelin 1 cDNA probe revealed induction of endothelin mRNA in PMA-treated macrophages. Furthermore, immunoreactive endothelin 1 and 3 were found in U937 cells, a human promonocytic line, and in freshly isolated human monocytes. In contrast, no immunoreactive endothelin was detected in cell extracts from human neutrophils and lymphocytes. The expression of endothelins in tissue macrophages was demonstrated in paraffin sections of human lung using immunohistochemistry. In conclusion, the finding that human macrophages produce endothelins suggests an important role for these peptides in the microenvironment of tissue macrophages. Macrophage-derived endothelins may have an essential function in blood vessel physiology, and aberrant production may contribute to vessel pathology.

A novel method for calculating beta band burst durations in Parkinson's disease using a physiological baseline.

BACKGROUND: Pathologically prolonged bursts of neural activity in the 8-30 Hz frequency range in Parkinson's disease have been measured using high power event detector thresholds. NEW METHOD: This study introduces a novel method for determining beta bursts using a power baseline based on spectral activity that overlapped a simulated 1/f spectrum. We used resting state local field potentials from people with Parkinson's disease and a simulated 1/f signal to measure beta burst durations, to demonstrate how tuning parameters (i.e., bandwidth and center frequency) affect burst durations, to compare burst duration distributions with high power threshold methods, and to study the effect of increasing neurostimulation intensities on burst duration. RESULTS: The baseline method captured a broad distribution of resting state beta band burst durations. Mean beta band burst durations were significantly shorter on compared to off neurostimulation (p = 0.0046), and their distribution shifted towards that of the 1/f spectrum during increasing intensities of stimulation. COMPARISON WITH EXISTING METHODS: High power event detection methods, measure duration of higher power bursts and omit portions of the neural signal. The baseline method captured the broadest distribution of burst durations and was more sensitive than high power detection methods in demonstrating the effect of neurostimulation on beta burst duration. CONCLUSIONS: The baseline method captured a broad range of fluctuations in beta band neural activity and demonstrated that subthalamic neurostimulation shortened burst durations in a dose (intensity) dependent manner, suggesting that beta burst duration is a useful control variable for closed loop algorithms.

A DNA sequence conferring high postmeiotic segregation frequency to heterozygous deletions in Saccharomyces cerevisiae is related to sequences associated with eucaryotic recombination hotspots.

The meiotic behavior of two graded series of deletion mutations in the ADE8 gene in Saccharomyces cerevisiae was analyzed to investigate the molecular basis of meiotic recombination. Postmeiotic segregation (PMS) was observed for a subset of the deletion heterozygosities, including deletions of 38 to 93 base pairs. There was no clear relationship between deletion length and PMS frequency. A common sequence characterized the novel joint region in the alleles which displayed PMS. This sequence is related to repeated sequences recently identified in association with recombination hotspots in the human and mouse genomes. We propose that these particular deletion heterozygosities escape heteroduplex DNA repair because of fortuitous homology to a binding site for a protein.

Deficiency in Epstein-Barr virus receptors on B-lymphocytes of preleukemia patients.

Lymphocytes from eight preleukemia patients were exposed to Epstein-Barr virus (EBV) in vitro in an attempt to establish lymphoblastoid cell lines. No signs of viral infection were detected, and no cell lines were obtained. Studies using fluorescein-labeled EBV and flow cytometry revealed an unusual and consistent deficiency in EBV receptors in all patients examined. In control studies, about 15% of the unseparated lymphocytes from healthy donors bound fluorescein-labeled EBV. In spite of the lack of EBV receptors, B-lymphocytes amounted to 10 to 20% of the preleukemia lymphocyte populations, a proportion similar to that in healthy donors. When lymphocytes from preleukemic patients were first implanted with functional EBV receptors and then exposed to EBV, synthesis of EBV-determined nuclear, early, and viral capsid antigens was induced. Subsequently, several cell lines originating from preleukemic patients' lymphocytes were established. These lines are of a B-lymphocyte origin and carry EBV genome. They will provide experimental material for the molecular analysis of lymphocytic defects in preleukemia and their possible role in the transition to acute leukemia.

An estimate of the effectiveness of an in-vehicle automatic collision notification system in reducing road crash fatalities in South Australia.

OBJECTIVES: The aim of this study was to estimate the potential effectiveness of an in-vehicle automatic collision notification (ACN) system in reducing all road crash fatalities in South Australia (SA). METHODS: For the years 2008 to 2009, traffic accident reporting system (TARS) data, emergency medical services (EMS) road crash dispatch data, and coroner's reports were matched and examined. This was done to initially determine the extent to which there were differences between the reported time of a fatal road crash in the mass crash data and the time EMS were notified and dispatched. In the subset of fatal crashes where there was a delay, injuries detailed by a forensic pathologist in individual coroner's reports were examined to determine the likelihood of survival had there not been a delay in emergency medical assistance. RESULTS: In 25% (N = 53) of fatalities in SA in the period 2008 to 2009, there was a delay in the notification of the crash event, and hence dispatch of EMS, that exceeded 10 min. In the 2-year crash period, 5 people were likely to have survived through more prompt crash notification enabling quicker emergency medical assistance. Additionally, 3 people potentially would have survived if surgical intervention (or emergency medical assistance to sustain life until surgery) occurred more promptly. CONCLUSIONS: The minimum effectiveness rate of an ACN system in SA with full deployment is likely to be in the range of 2.4 to 3.8% of all road crash fatalities involving all vehicle types and all vulnerable road users (pedestrians, cyclists, and motorcyclists) from 2008 to 2009. Considering only passenger vehicle occupants, the benefit is likely to be 2.6 to 4.6%. These fatality reductions could only have been achieved through earlier notification of each crash and their location to enable a quicker medical response. This might be achievable through a fully deployed in-vehicle ACN system.

The diagnosis of postprandial hypoglycemia.

Our observation that hypoglycemia, often self-diagnosed by our patients, was seldom confirmed led the authors to establish norms for the glucose tolerance test. We first obtained values for 650 patients who were entirely free from symptoms before and during testing. The median nadir in this group was 64 mg/dl. Ten percent of the patients had plasma glucose nadirs of 47 mg/dl or below and 2.5% had values of 39 mg/dl or less. Utilizing these values in combination with clinical criteria, we confirmed hypoglycemia after glucose load in 16 (median nadir 39.5 mg/dl) of 118 patients presenting with this diagnosis, and only 5 of the 16 were hypoglycemic after their usual meals. The other 102 patients, whose many complaints were unrelated to measured plasma glucose levels, had nadirs similar to those of the control group. Placebo tests performed on 14 nonhypoglycemic patients provoked symptoms (recorded by the patients themselves) and they considered indicative of hypoglycemia. Some accepted other diagnoses after we demonstrated that their symptoms occurred when they were normoglycemic. Since nadirs of hypoglycemics and control subjects overlap, we conclude that accurate diagnosis of hypoglycemia requires that symptoms develop concurrently with low blood sugar and that they are absent at other times. Low plasma glucose must be considered only one of the criteria in diagnosing functional hypoglycemia along with a relationship between food intake, timing of symptoms, correlation of symptoms and low glucose levels, and reproducibility of test results.

Prevention of recurrent sudden cardiac arrest: role of provocative electropharmacologic testing.

This study evaluates the usefulness of serial provocative electropharmacologic testing for predicting the efficacy of prophylactic antiarrhythmic treatment regimens in patients resuscitated from sudden cardiac arrest in the absence of acute myocardial infarction. Testing was carried out in 34 consecutive patients (28 men and 6 women) who required cardiopulmonary resuscitation and direct current countershock for treatment of primary ventricular fibrillation (28 patients), ventricular tachycardia (5 patients) or excessively rapid heart rate during atrial fibrillation with preexcitation (1 patient). In 8 (24%) of the 34 patients, drug testing either was not feasible because of absence of inducible arrhythmia or was incomplete because of patient withdrawal from study; and 3 of these 8 patients had recurrent sudden cardiac arrest within 10 to 19 months. In an additional five patients, treatment regimens failed to prevent initiation of sustained ventricular tachyarrhythmias in the catheterization laboratory, and two of these five patients had cardiac arrest recurrences within 2 weeks to 25 months of follow-up. In the remaining 21 (62%) of the 34 patients, including 3 patients with preexcitation syndrome, a drug regimen or surgical treatment, or both, was found that prevented inducible life-threatening tachyarrhythmias in the laboratory. Subsequently, only 1 (5%) of these 21 patients died suddenly within a 7 to 38 month (mean +/- standard deviation, 18 +/- 8.3) follow-up period. Thus, provocative electropharmacologic testing appears to be useful in predicting response to therapy in survivors of sudden cardiac arrest.

Complementation of Amoebal-Plasmodial Transition Mutants in PHYSARUM POLYCEPHALUM.

Amoebae of the Myxomycete Physarum polycephalum differentiate to yield plasmodia in two ways: in crossing, haploid amoebae of appropriate genotypes fuse to form diploid plasmodia; in selfing, plasmodia form without amoebal fusion or increase in ploidy. Amoebae carrying the mating-type allele matAh (formerly mt(h)) self efficiently, but occasionally give rise to mutants that self at very low frequencies. Such "amoebal-plasmodial transition" mutants were mixed in pairs to test their ability to complement one another in the formation of plasmodia by crossing. The pattern of crossing permitted 33 mutants to be assigned to four complementation groups (aptA(-), npfA(-), npfB(-) and npfC(-)). Similar tests had previously proved only partially successful, as crossing had occurred only rarely in mixtures of compatible strains. The efficiency of complementation was greatly increased in the current work by mixing strains that carried different alleles of a newly-discovered mating-compatibility locus, matB; this locus had no effect on the specificity of complementation. A possible interpretation of the complementation behavior of the mutants is suggested.

Two Multiallelic Mating Compatibility Loci Separately Regulate Zygote Formation and Zygote Differentiation in the Myxomycete PHYSARUM POLYCEPHALUM.

The mating of Physarum polycephalum amoebae, the ultimate consequence of which is a "plasmodium," was recently shown to be governed by two compatibility loci, matA (or mt) and matB (Dee 1978; Youngmanet al. 1979). We present evidence that matA and matB separately regulate two discrete stages of mating: in the first stage, amoebae (which are normally haploid) fuse in pairs, with a specificity determined by matB genotype, to form diploid zygotes; subsequent differentiation of the zygotes into plasmodia is regulated by matA and is unaffected by matB. Mixtures of amoebae carrying unlike matA and matB alleles formed diploids to the extent of 10 to 15% of the cells present, and the diploids differentiated into plasmodia. When only the matB alleles differed, diploid cells still formed to a comparable (5 to 10%) extent, but rather than differentiating, these diploids remained amoebae. When strains carried the same alleles of matB, formation of diploid cells was greatly reduced: in like-matB, like-matA mixtures, none of 320 cells examined was diploid; in like-matB, unlike mat-A mixtures, differentiating diploids could be detected, but at only 10(-3) to 10(-2) the frequency of unlike-matB, unlike-matA mixtures. The nondifferentiating diploid amoebae recovered from unlike-matB, like-matA mixtures were genetically stable through extensive growth, even though they grew more slowly than haploids (10-hr vs. 8-hr doubling period), and could be crossed with both haploids and diploids. The results of such higher ploidy and mixed ploidy crosses indicate that karyogamy does not invariably accompany zygote formation and differentiation.

Influenza basic polymerase 2 peptides are recognized by influenza nucleoprotein-specific cytotoxic T lymphocytes.

Cytotoxic T lymphocytes (CTL) play an important role in limiting viral infections and in eradicating virus from host tissues. Recent progress in understanding the processing and presentation of viral antigens to CTL indicates that the CTL antigen receptor recognizes peptides derived from viral proteins that are bound to an antigen binding groove present in class I major histocompatibility complex (MHC) molecules. In understanding CTL anti-viral responses and in creating vaccines designed to elicit CTL responses, it is critical to identify the portions of viral proteins that bind class I molecules and are recognized by T cell receptors. Previous findings have indicated that a significant portion of the CTL response of H-2d mice to influenza virus is specific for one of the viral polymerases (PB2). To identify the region of PB2 naturally processed and presented by influenza virus-infected mouse cells to CTL, 31 PB2 peptides of 9-16 residues in length were chosen and chemically synthesized. Two peptides, PB2, residues 146-159 and 187-195, were found to sensitize histocompatible target cells for recognition by influenza virus-specific CTL. When CTL were generated to individual viral proteins using influenza-vaccinia recombinant viruses, we found, to our surprise, that PB2-specific CTL failed to recognize cells sensitized with PB2 peptides 146-159 and 187-195. Further analysis showed that these PB2 peptides were, in fact, recognized by nucleoprotein (NP)-specific CTL generated by NP-vac virus priming and influenza A virus stimulation, or NP peptide stimulation in vitro of NP-vac or influenza A-primed CTL. These results demonstrate that while screening peptide libraries one cannot assume that positive peptides necessarily identify the viral protein to which the CTL response is directed.

H-2K molecules have two different C-termini, one of which is K-region specific.

Amino acid sequences encoded by exon 8 of the H-2K and H-2D/L genes appear to be locus specific. The majority of H-2Kb molecules contain 10 amino acids that are derived from exon 8. In contrast, the H-2Db, -Dd and -Ld molecules contain only one amino acid which is encoded by exon 8, even though the genetic information exists to encode 10 amino acids analogous to those encoded by the majority of H-2Kb transcripts. We have produced a rabbit anti-peptide serum reactive with the exon 8 encoded sequence of H-2Kb (alpha K-C) that specifically immunoprecipitates a molecule of 45 K mol. wt from spleen cell lysates of b, d, p, q and k haplotype mice. Further analysis by Western blots indicated that virtually all mouse strains express a 45 K protein reactive with alpha K-C. In sequential immunoprecipitations of spleen cell lysates from b, q, p and d haplotype mice using alpha K-C followed by H-2K or H-2D private specificity alloantisera, the anti-peptide serum removed nearly all of the molecules reactive with the anti-H-2K alloantisera (except in the k haplotype) and none of the molecules reactive with the anti-H-2D serum. In addition, no D-region molecules possessing a long C-terminal sequence were detected with an antiserum directed against a representative D-region long C-terminal peptide. We conclude that even though the genetic information for an extended exon 8 exists in K, D and L locus genes, apparently only K-region molecules are expressed with such a C-terminus. Furthermore, in most haplotypes the great majority of H-2K molecules are produced using long exon 8; however, H-2Kk is produced mostly from short exon 8. The absence or presence of key adenosine residues is predicted to be responsible for the variability in class I exon 8 splicing.

Evaluation of monolayer, liquid, gelfoam sponge and artificial capillary culture systems for the study of hematopoiesis.

This study evaluated the usefulness of a matrix culture system, the artificial capillary culture system, for the growth of hematopoietic cells, the maintenance of CFUS and the collection of GM-CSF. The system was compared to monolayer, gelfoam sponge and Dexter liquid cultures. Monolayer cultures of adherent lymphohematopoietic stromal cells were prepared from bone fragments, whole bone marrow (Dexter system), spleen, fetal liver and thymus preparations. Morphologically, all the adherent cell populations were similar and tended to accumulate macrophages. Despite these morphological similarities, the ability of bone marrow adherent cell monolayers to maintain CFUS early in the culture period was significantly greater than adherent cells from other sources. Low but significant levels of GM-CSF were detected by bioassay in the supernatants of all but bone marrow adherent cell cultures. However, adherent cells selected from whole marrow cultures by differential trypsinization contained bioassayable levels of CSF suggesting that Dexter cultures contain a supernatant inhibitor/inactivator of GM-CSF. The greatest capability of the artificial capillary culture system was to increase about 500-fold over monolayers the GM-CSF collected from bone fragment derived stromal cells. Unfortunately, CFUS maintenance was poor, the system was more expensive than monolayer cultures and in our hands, suffered many mechanical failures usually resulting in loss of sterility. Histological evaluation suggested there was inadequate matrix for optimal attachment and growth of lymphohematopoietic stromal cells. Even so this system has a much greater potential for development than gelfoam sponges. Overall, Dexter cultures appear to be the most useful system currently available for the study of hematopoiesis and hematopoietic regulatory interactions.

Use of age-period-cohort models to estimate effects of vehicle age, year of crash and year of vehicle manufacture on driver injury and fatality rates in single vehicle crashes in New South Wales, 2003-2010.

A novel application of age-period-cohort methods are used to explain changes in vehicle based crash rates in New South Wales, Australia over the period 2003-2010. Models are developed using vehicle age, crash period and vehicle cohort to explain changes in the rate of single vehicle driver fatalities and injuries in vehicles less than 13 years of age. Large declines in risk are associated with vehicle cohorts built after about 1996. The decline in risk appears to have accelerated to 12 percent per vehicle cohort year for cohorts since 2004. Within each cohort, the risk of crashing appears to be a minimum at two years of age and increases as the vehicle ages beyond this. Period effects (i.e., other road safety measures) between 2003 and 2010 appear to have contributed to declines of up to about two percent per annum to the driver-fatality single vehicle crash rate, and possibly only negligible improvements to the driver-injury single vehicle crash rate. Vehicle improvements appear to have been responsible for a decline in per-vehicle crash risk of at least three percent per calendar year for both severity levels over the same period. Given the decline in risk associated with more recent vehicle cohorts and the dynamics of fleet turnover, continued declines in per-vehicle crash risk over coming years are almost certain.

The HIV cytopathic effect: potential target for therapy?

HIV kills activated infected CD4+ T cells after a burst of replication and the release of large numbers of virions. From a review of the literature on HIV regulatory genes and from preliminary mathematical models of HIV dynamics at four levels (host population epidemiology, the immune system, gene regulation within infected cells, and selection of mutants) we have arrived at the theory that in the etiology of HIV the HIV cytopathic effect may actively be caused by a viral regulatory gene product. The most likely candidate is the rev regulatory protein. Rev and the analogous rex protein from HTLV-I (human T cell leukemia virus) both have two active sites with similar function: one site locates the protein in the nucleus/nucleolus, and the other site interacts with viral mRNAs, facilitating their export from the nucleus to the cytoplasm. Rev seems to have a third functional site near the 3' end. We conjecture that this site may be responsible for the cytopathic effect. We think that rev acts on cellular genes that normally induce senescence and cell death during development, or T-cell maturation, or on terminal differentiation. We propose that mathematical and computer models of the immune system could be used to explore whether suppression of the cytopathic action of the rev protein could be of therapeutic benefit in restoring the ability of the immune system to clear HIV or at least to extend latency. We also suggest how immune deficiency disease might be created as laboratory artifact in animal populations.

Mathematical models of HIV infection. I. Threshold conditions for transmission and host survival.

This is the second in a series of papers modeling human immunodeficiency virus (HIV) infections at four levels: transmission, interaction with the immune system, gene regulation, and selection of mutants. In the previous paper (1) we described and presented a theory of the HIV cytopathic effect based upon the models (and a review of the literature). In this article we give mathematical equations of threshold conditions that connect infectivity, length of host survival, and frequency of acts conducive to transmission. The formula is derived not only for homogeneous populations but also for populations of an arbitrary number of subgroups with varying frequencies of risk behavior, varying rates of infection and latency periods, and varying frequencies of interaction with other groups.

Tricuspid valve Candida endocarditis. Successful treatment with valve-sparing debridement and antifungal chemotherapy in a multiorgan transplant recipient.

Tricuspid valve Candida albicans endocarditis developed in a multiple-organ transplant recipient six months after successful treatment of Candida peritonitis. She has had no recurrence or valvular incompetence two years after valve-sparing debridement of the vegetation and prolonged therapy with amphotericin B. This is the second report of long-term success following valve-sparing debridement for tricuspid valve Candida endocarditis. In selected patients without annular involvement or gross valve destruction, excision of the fungal vegetation may allow for long-term cure and a competent valve.

Cardiac arrest in young, ostensibly healthy patients: clinical, hemodynamic, and electrophysiologic findings.

This study examines the clinical, hemodynamic, and electrophysiologic findings in a unique group of 11 young (aged 15 months to 29 years) survivors of a cardiac arrest. All patients were previously in good health, and cardiac arrest was the initial manifestation of cardiac disease in all. Overt clinical and hemodynamic abnormalities were not as common as previously reported, and in some instances apparent cardiac abnormalities failed to provide a link to cardiac arrest. No patient had congenital heart disease or hypertrophic cardiomyopathy. However, during multicatheter electrophysiologic study, sustained tachyarrhythmia was reproducibly initiated in 8 of 11 patients (73%). Young, ostensibly healthy patients who survive cardiac arrest form a diverse group. Diligent programmed intracardiac electrical stimulation may demonstrate life-threatening tachycardias in these patients. Treatment to prevent recurrence of cardiac arrest is difficult in this group of patients. However, the ability to initiate tachycardia in the electrophysiologic laboratory may be useful in the management of these patients.