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.

Bulk-solvent and overall scaling revisited: faster calculations, improved results. Corrigendum.

Equations in Sections 2.3 and 2.4 of the article by Afonine et al. [Acta Cryst. (2013). D69, 625-634] are corrected.

The role of aging in cancer.

Many cancers show an increase in incidence with age, and age is the biggest single risk factor for many cancers. However, the molecular basis of this relationship is poorly understood. Through a collection of review articles, our thematic issue discusses the link between aging and cancer in aspects including somatic mutations, proteostasis, mitochondria, metabolism, senescence, epigenetic regulation, immune regulation, DNA damage, and telomere function.

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.

Quantifying Brain Iron in Hereditary Hemochromatosis Using R2* and Susceptibility Mapping.

BACKGROUND AND PURPOSE: Brain iron dyshomeostasis is increasingly recognized as an important contributor to neurodegeneration. Hereditary hemochromatosis is the most commonly inherited disorder of systemic iron overload. Although there is an increasing interest in excessive brain iron deposition, there is a paucity of evidence showing changes in brain iron exceeding that in healthy controls. Quantitative susceptibility mapping and R2* mapping are established MR imaging techniques that we used to noninvasively quantify brain iron in subjects with hereditary hemochromatosis. MATERIALS AND METHODS: Fifty-two patients with hereditary hemochromatosis and 47 age- and sex-matched healthy controls were imaged using a multiecho gradient-echo sequence at 3T. Quantitative susceptibility mapping and R2* data were generated, and regions within the deep gray matter were manually segmented. Mean susceptibility and R2* relaxation rates were calculated for each region, and iron content was compared between the groups. RESULTS: We noted elevated iron levels in patients with hereditary hemochromatosis compared with healthy controls using both R2* and QSM methods in the caudate nucleus, putamen, pulvinar thalamus, red nucleus, and dentate nucleus. Additionally, the substantia nigra showed increased susceptibility while the thalamus showed an increased R2* relaxation rate compared with healthy controls, respectively. CONCLUSIONS: Both quantitative susceptibility mapping and R2* showed abnormal levels of brain iron in subjects with hereditary hemochromatosis compared with controls. Quantitative susceptibility mapping and R2* can be acquired in a single MR imaging sequence and are complementary in quantifying deep gray matter iron.

Contamination of chicken carcasses and the abattoir environment with Listeria monocytogenes in Taiwan.

1. The following study provides the first data on the detection and types of Listeria monocytogenes isolated from broiler chickens during processing and from six Taiwanese abattoir environments.2. Listeria monocytogenes was not detected in any cloacal (n = 120) or environmental (n = 256) samples collected before and during processing, indicating that faecal material and the environment of abattoirs were not important sources of L. monocytogenes for poultry carcases. However, 28 of 246 (11.4%; 95% CI: 7.7-16.0) rinse samples collected from carcases post-evisceration from three abattoirs were positive for L. monocytogenes.3. The only serotypes detected were 1/2a (82.1%; 95% CI: 63.1-93.9) and 1/2b (14.3%; 95% CI: 4.0-32.7), with 3.6% (95% CI: 0.1-18.3) non-typable isolates.4. Characterisation by Pulsed Field Gel Electrophoresis (PFGE) identified five PFGE types, confirming cross-contamination with L. monocytogenes during evisceration, chilling and post-chilling.5. These findings highlight the potential for cross-contamination to occur through direct contact between carcases, especially whilst in chilling tanks.

SP rTaTME: initial clinical experience with single-port robotic transanal total mesorectal excision (SP rTaTME).

BACKGROUND: The technical difficulty and steep learning curve of transanal total mesorectal excision (taTME) has limited widespread adoption. The single-port (SP) daVinci robot is designed to facilitate single-incision and natural-orifice transluminal endoscopic surgery (NOTES). This paper describes the first clinical experience of single-port robotic taTME (SP rTaTME). METHODS: This was a prospective study on consecutive patients with rectal cancer who underwent SP rTaTME proctosigmoidectomy with handsewn coloanal anastomosis in December 2018 and January 2019. The primary outcome was technical feasibility of the procedure. The secondary outcomes include blood loss, intraoperative complications, length of hospital stay, quality of the TME specimen, short- and long-term morbidity and mortality, as well as short-term oncologic follow -up. RESULTS: There were two patients, a 48-year-old male and a 38-year-old female. Both operations were completed successfully without complications or conversion. Estimated blood loss was 200 mL and 130 mL. In both cases the TME was completed transanally using the SP robot. In the first patient, the abdominal portion was completed through an abdominal single-incision; in the second patient the operation was entirely performed transanally as a pure NOTES procedure. In both cases, the final pathology report showed a complete TME with negative margins. Patients were discharged on postoperative day 3 and 4,respectively. There was no long-term morbidity or mortality. CONCLUSIONS: SP rTaTME is feasible and can be safely performed. It provides excellent optics and dexterity to work in a limited space. Future studies are required to further define the safety profile and the ultimate utility of the SP robot for taTME.

Correção de fratura Salter-Harris tipo I em porquinho-da-índia (Cavia porcellus) - relato de caso / [Correction of Salter-Harris type 1 fracture in guinea pig (Cavia porcellus) - case report]

Um filhote de porquinho-da-índia (Cavia porcellus) foi recebido para atendimento após histórico de ataque por cão. Na avaliação física, observou-se edema, dor e crepitação em membro pélvico direito, sugestivo de fratura. Na avaliação radiográfica, confirmou-se fratura Salter-Harris tipo I em epífise distal da tíbia. A resolução cirúrgica escolhida foi a associação de pino transarticular e coaptação externa com tala de Altman. O paciente teve acompanhamento radiográfico semanal e obteve alta médica no 35o dia de pós-cirúrgico, quando se observou consolidação com completo remodelamento ósseo.(AU)

A guinea pig (Cavia porcellus) cub presented edema, pain, and crepitus in the right pelvic limb after being attacked by a dog. Radiographic examination revealed Salter-Harris type 1 fracture on the distal region of the tibia. The surgery technique to correct the fracture involved an association of transarticular pinning and external coaptation with Altman splint. After surgery, radiographs of the patient were performed weekly and on the 35th post-surgery day, the bone was completely remodeled and healed, and the animal was dismissed.(AU)

Emergence of intrinsic superconductivity below 1.178 K in the topologically non-trivial semimetal state of CaSn3.

Topological materials which are also superconducting are of great current interest, since they may exhibit a non-trivial topologically-mediated superconducting phase. Although there have been many reports of pressure-tuned or chemical-doping-induced superconductivity in a variety of topological materials, there have been few examples of intrinsic, ambient pressure superconductivity in a topological system having a stoichiometric composition. Here, we report that the pure intermetallic CaSn3 not only exhibits topological fermion properties, but also has a superconducting phase at ~1.178 K under ambient pressure. The topological fermion properties, including the nearly zero quasi-particle mass and the non-trivial Berry phase accumulated in cyclotron motions, were revealed from the de Haas-van Alphen (dHvA) quantum oscillation studies of this material. Although CaSn3 was previously reported to be superconducting with T c = 4.2 K, our studies show that the T c = 4.2 K superconductivity is extrinsic and caused by Sn on the degraded surface, whereas its intrinsic bulk superconducting transition occurs at 1.178 K. These findings make CaSn3 a promising candidate for exploring new exotic states arising from the interplay between non-trivial band topology and superconductivity, e.g. topological superconductivity (TSC).

Biomedical publications in the selected CARICOM countries

Objective: To compare biomedical research productivity among selected CARICOM countries. Design and Methodology: Biomedical publications of the selected CARICOM countries (Bahamas, Barbados, Dominica, Guyana, Grenada, Haiti, Jamaica, Suriname, and Trinidad & Tobago) were retrieved using 'PubMed' and 'ScImago Journal & country Rank' (SJR) databases. The publications for each country were then normalized by factors such as total population, gross domestic product (GDP) and Internet usage rate. Results: Total number of papers published by all 9 countries was 7,281 and 8,378 in PubMed (1990- 2015) and SJR databases (1996-2017) respectively. Jamaica produced highest number of biomedical publications [PubMed: 3,928 (54%) and SJR: 2,850 (34%)]. However, when adjusted, Grenada had the highest research publications per million populations, per billion GDP and per 1,000 Internet users in both databases. For trend analysis, PubMed showed that Jamaica produced highest number of additional publications each year ­ on an average 4.8 followed by Trinidad & Tobago (4.4). According to SJR, Jamaica had also highest number of citations (42,311) and H-index (76) followed by Trinidad & Tobago (29,152 and 71). Barbados had the highest number of citations per document (24.9) followed by Haiti (18.4). Conclusion: There was a marked imbalance noted among the CARICOM countries in terms of biomedical research and publications. A CARICOM-wide research may be embarked to explore disparities in biomedical research productivity and thus formulate informed health policies to alleviate diseases and eradicate poverty.

AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11.

Deregulated AKT kinase activity due to PTEN deficiency in cancer cells contributes to oncogenesis by incompletely understood mechanisms. Here, we show that PTEN deletion in HCT116 and DLD1 colon carcinoma cells leads to suppression of CHK1 and CHK2 activation in response to irradiation, impaired G2 checkpoint proficiency and radiosensitization. These defects are associated with reduced expression of MRE11, RAD50 and NBS1, components of the apical MRE11/RAD50/NBS1 (MRN) DNA damage response complex. Consistent with reduced MRN complex function, PTEN-deficient cells fail to resect DNA double-strand breaks efficiently after irradiation and show greatly diminished proficiency for DNA repair via the error-free homologous recombination (HR) repair pathway. MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. In primary human fibroblasts, activated AKT suppresses MRN complex expression to escalate RAS-induced DNA damage and thereby reinforce oncogene-induced senescence. Taken together, our data demonstrate that deregulation of the PI3K-AKT/ mTORC1/ p70S6K pathways, an event frequently observed in cancer, exert profound effects on genome stability via MRE11 with potential implications for tumour initiation and therapy.

Open-Label Allopregnanolone Treatment of Men with Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and ataxia and neuropsychological evaluations. Brain activity consisted of event-related potential N400 word repetition effect during a semantic memory processing task. Structural MRI outcomes comprised volumes of the hippocampus, amygdala, and fluid-attenuated inversion recovery hyperintensities, and microstructural integrity of the corpus callosum. The results of the study showed that allopregnanolone infusions were well tolerated in all subjects. Before treatment, the patients disclosed impairment in executive function, verbal fluency and learning, and progressive deterioration of all MRI measurements. After treatment, the patients demonstrated improvement in executive functioning, episodic memory and learning, and increased N400 repetition effect amplitude. Although MRI changes were not significant as a group, both improved and deteriorated MRI measurements occurred in individual patients in contrast to uniform deterioration before the treatment. Significant correlations between baseline MRI measurements and changes in neuropsychological test scores indicated the effects of allopregnanolone on improving executive function, learning, and memory for patients with relatively preserved hippocampus and corpus callosum, while reducing psychological symptoms for patients with small hippocampi and amygdalae. The findings show the promise of allopregnanolone in improving cognitive functioning in patients with FXTAS and in partially alleviating some aspects of neurodegeneration. Further studies are needed to verify the efficacy of allopregnanolone for treating FXTAS.

ChIP-Sequencing to Map the Epigenome of Senescent Cells Using Benzonase Endonuclease.

Cellular senescence is a state of stable cell cycle arrest triggered by diverse stresses. Establishment of senescence occurs in conjunction with a multitude of chromatin changes, which are just beginning to be studied. These chromatin changes are hypothesized to be causative for senescence. Currently, a preferred method to study such changes is chromatin immunoprecipitation followed by sequencing (ChIP-Seq). This is usually done by cross-linking the cells with formaldehyde and then generating chromatin fragments between 150 and 300bp by sonication. The DNA replication-independent histone chaperone HIRA plays an important role in control of chromatin in nonproliferating senescent cells. While investigating the role of HIRA in senescence, we found conventional ChIP protocols to be problematic, routinely yielding too low amounts of DNA for sequencing. To overcome these problems we adapted and optimized an alternative ChIP method that does not rely on cross-linking and sonication for chromatin fragmentation, and is able to easily isolate chromatin from senescent cells ready for immunoprecipitation. This method uses Benzonase endonuclease for solubilization of uncross-linked chromatin by digestion of DNA and RNA, in the absence of proteolytic activity. Using this protocol, we were easily able to immunoprecipitate HIRA with sufficient DNA for Illumina sequencing.

Epidemiology and diagnostic testing for hemochromatosis and iron overload.

Hemochromatosis is the most common genetic disease in northern European populations. Body iron stores progressively increase in most patients, which can lead to cirrhosis of the liver, hepatocellular carcinoma, heart failure, arthritis, and pigmentation. Simple blood tests such as the serum ferritin and transferrin saturation are useful to suggest the diagnosis which can be confirmed in most cases with a simple genetic test for the C282Y mutation of the HFE gene. However, these blood tests are often misinterpreted and there are rare patients with iron overload without HFE mutations. A diagnostic approach is presented based on a large referral practice and a population-based study (HEIRS) which screened for iron overload in 101,168 participants.

A computational analysis of flanker interference in depression.

BACKGROUND: Depression is characterized by poor executive function, but - counterintuitively - in some studies, it has been associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study. METHOD: One hundred unmedicated, depressed adults and 40 healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials). RESULTS: Consistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = -0.28, p = 0.007). CONCLUSIONS: Executive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression.

Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.

Fasciola hepatica tegumental antigens indirectly induce an M2 macrophage-like phenotype in vivo.

The M2 subset of macrophages has a critical role to play in host tissue repair, tissue fibrosis and modulation of adaptive immunity during helminth infection. Infection with the helminth, Fasciola hepatica, is associated with M2 macrophages in its mammalian host, and this response is mimicked by its excretory-secretory products (FhES). The tegumental coat of F. hepatica (FhTeg) is another major source of immune-modulatory molecules; we have previously shown that FhTeg can modulate the activity of both dendritic cells and mast cells inhibiting their ability to prime a Th1 immune response. Here, we report that FhTeg does not induce Th2 immune responses but can induce M2-like phenotype in vivo that modulates cytokine production from CD4(+) cells in response to anti-CD3 stimulation. FhTeg induces a RELMα expressing macrophage population in vitro, while in vivo, the expression of Arg1 and Ym-1/2 but not RELMα in FhTeg-stimulated macrophages was STAT6 dependent. To support this finding, FhTeg induces RELMα expression in vivo prior to the induction of IL-13. FhTeg can induce IL-13-producing peritoneal macrophages following intraperitoneal injection This study highlights the important role of FhTeg as an immune-modulatory source during F. hepatica infection and sheds further light on helminth-macrophage interactions.

Hebbian learning from higher-order correlations requires crosstalk minimization.

Activity-dependent synaptic plasticity should be extremely connection specific, though experiments have shown it is not, and biophysics suggests it cannot be. Extreme specificity (near-zero "crosstalk") might be essential for unsupervised learning from higher-order correlations, especially when a neuron has many inputs. It is well known that a normalized nonlinear Hebbian rule can learn "unmixing" weights from inputs generated by linearly combining independently fluctuating nonGaussian sources using an orthogonal mixing matrix. We previously reported that even if the matrix is only approximately orthogonal, a nonlinear-specific Hebbian rule can usually learn almost correct unmixing weights (Cox and Adams in Front Comput Neurosci 3: doi: 10.3389/neuro.10.011.2009 2009). We also reported simulations that showed that as crosstalk increases from zero, the learned weight vector first moves slightly away from the crosstalk-free direction and then, at a sharp threshold level of inspecificity, jumps to a completely incorrect direction. Here, we report further numerical experiments that show that above this threshold, residual learning is driven instead almost entirely by second-order input correlations, as occurs using purely Gaussian sources or a linear rule, and any amount of crosstalk. Thus, in this "ICA" model learning from higher-order correlations, required for unmixing, requires high specificity. We compare our results with a recent mathematical analysis of the effect of crosstalk for exactly orthogonal mixing, which revealed that a second, even lower, threshold, exists below which successful learning is impossible unless weights happen to start close to the correct direction. Our simulations show that this also holds when the mixing is not exactly orthogonal. These results suggest that if the brain uses simple Hebbian learning, it must operate with extraordinarily accurate synaptic plasticity to ensure powerful high-dimensional learning. Synaptic crowding would preclude this when inputs are numerous, and we propose that the neocortex might be distinguished by special circuitry that promotes extreme specificity for high-dimensional nonlinear learning.

Phase II trial of vorinostat in advanced melanoma.

INTRODUCTION: Vorinostat is a small molecule inhibitor of class I and II histone deacetylases with preclinical activity in melanoma. METHODS: We evaluated 32 patients with advanced primary cutaneous or ocular melanoma in a multi-institutional setting (PMH Phase II Consortium) with continuous daily oral vorinostat 400 mg. The primary endpoint was response rate by RECIST, with time to progression as a secondary endpoint. The study was designed to distinguish a response rate of 20 % from a RR of 5 % and to distinguish a 2 month median progression-free survival (PFS), from one of 3.1 months. The study proceeded to stage 2 following 2 of 16 responses.. We also assessed VEGF, FGF levels, P52 polymorphisms and chromatin-associated proteins as potential biomarkers. RESULTS: Therapy was associated with significant side effects, including fatigue, nausea, lymphopenia, and hyperglycemia. Eleven patients experienced at least one grade 3 or higher adverse event. There were two confirmed PRs in patients with cutaneous melanoma. Sixteen patients had stable disease and 14 patients had progressive disease for best response. In addition, two patients with cutaneous melanoma scored as stable disease had early unconfirmed partial responses with subsequent progression. Patients with stable disease or partial response (n = 18) had a median progression free survival of 5 months. (range 2-12 months). CONCLUSIONS: Vorinostat demonstrated some early responses and a high proportion of patients with stable disease, but did not meet its primary endpoint of response. Different schedules of this agent with BRAF mutation status and markers of histone acetylation could be explored in melanoma.

Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing.

A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/ß signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.