The response of Earth’s climate system to orbital forcing has been highly state dependent over the past 66 million years.
The states of past climate
Deep-sea benthic foraminifera preserve an ...essential record of Earth's past climate in their oxygen- and carbon-isotope compositions. However, this record lacks sufficient temporal resolution and/or age control in some places to determine which climate forcing and feedback mechanisms were most important. Westerhold
et al.
present a highly resolved and well-dated record of benthic carbon and oxygen isotopes for the past 66 million years. Their reconstruction and analysis show that Earth's climate can be grouped into discrete states separated by transitions related to changing greenhouse gas levels and the growth of polar ice sheets. Each climate state is paced by orbital cycles but responds to variations in radiative forcing in a state-dependent manner.
Science
, this issue p.
1383
Much of our understanding of Earth’s past climate comes from the measurement of oxygen and carbon isotope variations in deep-sea benthic foraminifera. Yet, long intervals in existing records lack the temporal resolution and age control needed to thoroughly categorize climate states of the Cenozoic era and to study their dynamics. Here, we present a new, highly resolved, astronomically dated, continuous composite of benthic foraminifer isotope records developed in our laboratories. Four climate states—Hothouse, Warmhouse, Coolhouse, Icehouse—are identified on the basis of their distinctive response to astronomical forcing depending on greenhouse gas concentrations and polar ice sheet volume. Statistical analysis of the nonlinear behavior encoded in our record reveals the key role that polar ice volume plays in the predictability of Cenozoic climate dynamics.
The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of an adult. However, the key drivers of this process remain poorly defined. We are ...currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), limiting their potential as a model system to discover regenerative therapeutics. Here, we provide a summary of our studies, where we developed a 96-well device for functional screening in human pluripotent stem cell-derived cardiac organoids (hCOs). Through interrogation of >10,000 organoids, we systematically optimize parameters, including extracellular matrix (ECM), metabolic substrate, and growth factor conditions, that enhance cardiac tissue viability, function, and maturation. Under optimized maturation conditions, functional and molecular characterization revealed that a switch to fatty acid metabolism was a central driver of cardiac maturation. Under these conditions, hPSC-CMs were refractory to mitogenic stimuli, and we found that key proliferation pathways including β-catenin and Yes-associated protein 1 (YAP1) were repressed. This proliferative barrier imposed by fatty acid metabolism in hCOs could be rescued by simultaneous activation of both β-catenin and YAP1 using genetic approaches or a small molecule activating both pathways. These studies highlight that human organoids coupled with higher-throughput screening platforms have the potential to rapidly expand our knowledge of human biology and potentially unlock therapeutic strategies.
To report the relative frequencies of childhood and early onset glaucoma subtypes and their genetic findings in a large single cohort.
Retrospective clinical and molecular study.
All individuals with ...childhood glaucoma (diagnosed 0 to <18 years) and early onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry.
We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma.
The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age.
A total of 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG), and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma. Juvenile open-angle glaucoma constituted 73.2% of the early onset glaucoma cohort (271/370, 513 eyes). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). Biallelic variants in CYP1B1 (n = 29, 23.2%) and heterozygous variants in MYOC (n = 24, 19.2%) and FOXC1 (n = 21, 16.8%) were most commonly reported among probands with a molecular diagnosis. Biallelic CYP1B1 variants were reported in twice as many female individuals as male individuals with PCG (66.7% vs. 33.3%, P = 0.02).
We report on the largest cohort of individuals with childhood and early onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counseling. International collaborative efforts are required to identify further genes because the majority of individuals still lack a clear molecular diagnosis.
The 2-component leukotoxin LukAB is critical for Staphylococcus aureus targeting and killing of human neutrophils ex vivo and is produced in the setting of human infection. We report 3 LukAB-specific ...human monoclonal antibodies (mAbs) with distinct mechanisms of toxin neutralization and in vivo efficacy. Three hybridomas secreting mAbs with anti-LukAB activity (designated SA-13, -15, and -17) were generated from B cells obtained from a 12-year-old boy with S. aureus osteomyelitis. Each of the 3 mAbs neutralized LukAB-mediated neutrophil toxicity, exhibited differing levels of potency, recognized different antigenic sites on the toxin, and displayed at least 2 distinct mechanisms for cytotoxic inhibition. SA-15 bound exclusively to the dimeric form of the toxin, suggesting that human B cells recognize epitopes on the dimerized form of LukAB during natural infection. Both SA-13 and SA-17 bound the LukA monomer and the LukAB dimer. Although all 3 mAbs potently neutralized cytotoxicity, only SA-15 and SA-17 significantly inhibited toxin association with the cell surface. Treatment with a 1:1 mixture of mAbs SA-15 and SA-17 resulted in significantly lower bacterial colony counts in heart, liver, and kidneys in a murine model of S. aureus sepsis. These data describe the isolation of diverse and efficacious antitoxin mAbs.
Summary Background Information and behaviour can spread through interpersonal ties. By targeting influential individuals, health interventions that harness the distributive properties of social ...networks could be made more effective and efficient than those that do not. Our aim was to assess which targeting methods produce the greatest cascades or spillover effects and hence maximise population-level behaviour change. Methods In this cluster randomised trial, participants were recruited from villages of the Department of Lempira, Honduras. We blocked villages on the basis of network size, socioeconomic status, and baseline rates of water purification, for delivery of two public health interventions: chlorine for water purification and multivitamins for micronutrient deficiencies. We then randomised villages, separately for each intervention, to one of three targeting methods, introducing the interventions to 5% samples composed of either: randomly selected villagers (n=9 villages for each intervention); villagers with the most social ties (n=9); or nominated friends of random villagers (n=9; the last strategy exploiting the so-called friendship paradox of social networks). Participants and data collectors were not aware of the targeting methods. Primary endpoints were the proportions of available products redeemed by the entire population under each targeting method. This trial is registered with ClinicalTrials.gov , number NCT01672580. Findings Between Aug 4, and Aug 14, 2012, 32 villages in rural Honduras (25–541 participants each; total study population of 5773) received public health interventions. For each intervention, nine villages (each with 1–20 initial target individuals) were randomised, using a blocked design, to each of the three targeting methods. In nomination-targeted villages, 951 (74·3%) of 1280 available multivitamin tickets were redeemed compared with 940 (66·2%) of 1420 in randomly targeted villages and 744 (61·0%) of 1220 in indegree-targeted villages. All pairwise differences in redemption rates were significant (p<0·01) after correction for multiple comparisons. Targeting nominated friends increased adoption of the nutritional intervention by 12·2% compared with random targeting (95% CI 6·9–17·9). Targeting the most highly connected individuals, by contrast, produced no greater adoption of either intervention, compared with random targeting. Interpretation Introduction of a health intervention to the nominated friends of random individuals can enhance that intervention's diffusion by exploiting intrinsic properties of human social networks. This method has the additional advantage of scalability because it can be implemented without mapping the network. Deployment of certain types of health interventions via network targeting, without increasing the number of individuals targeted or the resources used, could enhance the adoption and efficiency of those interventions, thereby improving population health. Funding National Institutes of Health, The Bill & Melinda Gates Foundation, Star Family Foundation, and the Canadian Institutes of Health Research.
We have previously developed a high-throughput bioengineered human cardiac organoid (hCO) platform, which provides functional contractile tissue with biological properties similar to native heart ...tissue, including mature, cell-cycle-arrested cardiomyocytes. In this study, we perform functional screening of 105 small molecules with pro-regenerative potential. Our findings reveal surprising discordance between our hCO system and traditional 2D assays. In addition, functional analyses uncovered detrimental effects of many hit compounds. Two pro-proliferative small molecules without detrimental impacts on cardiac function were identified. High-throughput proteomics in hCO revealed synergistic activation of the mevalonate pathway and a cell-cycle network by the pro-proliferative compounds. Cell-cycle reentry in hCO and in vivo required the mevalonate pathway as inhibition of the mevalonate pathway with a statin attenuated pro-proliferative effects. This study highlights the utility of human cardiac organoids for pro-regenerative drug development, including identification of underlying biological mechanisms and minimization of adverse side effects.
Display omitted
•Drug screening in human PSC-cardiac organoids for pro-proliferative compounds•Functional screening to identify compounds with side effects on contractility•Single-organoid proteomics to uncover biological mechanisms of compounds•Systems approaches to identify core CM proliferation signatures
Hudson, Porrello, et al. perform drug screening in human mini-hearts to identify compounds that promote human heart muscle cell proliferation. Drug screening also eliminated potential side effects on heart rhythm and function. Induction of heart muscle cell proliferation required activation of the cholesterol biosynthesis pathway.
Purpose: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available
salvage therapy. This study was conducted to determine if the ...combination of a novel antiangiogenic therapy, bevacizumab,
and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma.
Experimental Design: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence
of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab
and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was
determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m 2 , whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m 2 . Toxicity and response were assessed.
Results: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted
in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival
was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade
III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was
72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli,
and one patient had an arterial ischemic stroke.
Conclusions: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.
After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and ...injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular ...endothelial growth factor, in combination with irinotecan.
This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging.
The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli).
Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.
PDF
