Experiments Of Nature Research Articles

Telomere Length Shortening in Alzheimer's Disease: Procedures for a Causal Investigation Using Single Nucleotide Polymorphisms in a Mendelian Randomization Study.

Measuring the length of telomeres, repetitive nucleotide sequences capping the chromosomes which shortens by each cell division, has become a popular way of attaining a marker of biological aging processes. Several observational studies have investigated the associations between telomere length and Alzheimer's disease (AD) with the overall conclusion being shorter telomeres provide an increased risk for AD development. Here we present an alternative approach for addressing the topic where additional evidence on causality can be drawn. To do so, we include information on single nucleotide polymorphisms (SNPs) using nature's own experiment with random segregation of alleles at conception. The protocol describes the full process of the so-called Mendelian Randomization by selecting appropriate SNPs for the analysis, discussing different data sources that can be used and inform about methods, assumptions and suitable software packages including Stata code.

Chitin Increases Mycobacterium ulcerans Growth in Acidic Environments.

Species with a chitinous exoskeleton are overrepresented among the aquatic organisms carrying Mycobacterium ulcerans (MU) in nature and laboratory experiments have demonstrated the enhancing effects of chitin on the growth of MU. Field surveys identified pH as one of the key parameters delineating the distribution of MU in tropical regions. The present study investigated the relationship between chitin and pH in MU growth. By focusing on pH variations in the field, our results revealed that chitin enhanced MU growth in acidic environments. The present study provides new information on the ecological conditions favoring the development of this mycobacterium in nature.

Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.

When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and postmarketing activities. We present here a safety signal identification approach applied to a new set of drug entities, inhibitors of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9). Using phenome-wide association study (PheWAS) methods, we analyzed available genotype and clinical data from 29,722 patients, leveraging the known effects of changes in PCSK9 to identify novel phenotypes in which this protein and its inhibitors may have impact. PheWAS revealed a significantly reduced risk of hypercholesterolemia (odds ratio [OR] 0.68, p=7.6×10-4) in association with a known loss-of-function variant in PCSK9, R46L. Similarly, laboratory data indicated significantly reduced beta mean low-density lipoprotein cholesterol (-14.47mg/dL, p=2.58×10-23) in individuals carrying the R46L variant. The R46L variant was also associated with an increased risk of spina bifida (OR 5.90, p=2.7×10-4), suggesting that further investigation of potential connections between inhibition of PCSK9 and neural tube defects may be warranted. This novel methodology provides an opportunity to put in place new mechanisms to assess the safety and long-term tolerability of PCSK9 inhibitors specifically, and other new agents in general, as they move into human testing and expanded clinical use.

A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo.

The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which is caused by mutations in tau. In vitro, FTDP-17 mutant versions of tau can reduce microtubule binding and increase the aggregation of tau, but the mechanism by which these mutations promote disease in vivo is not clear. Here we take a combined biochemical and in vivo modeling approach to define functional properties of tau driving neurotoxicity in vivo We express wild-type human tau and five FTDP-17 mutant forms of tau in Drosophila using a site-directed insertion strategy to ensure equivalent levels of expression. We then analyze multiple markers of neurodegeneration and neurotoxicity in transgenic animals, including analysis of both males and females. We find that FTDP-17 mutations act to enhance phosphorylation of tau and thus promote neurotoxicity in an in vivo setting. Further, we demonstrate that phosphorylation-dependent excess stabilization of the actin cytoskeleton is a key phosphorylation-dependent mediator of the toxicity of wild-type tau and of all the FTDP-17 mutants tested. Finally, we show that important downstream pathways, including autophagy and the unfolded protein response, are coregulated with neurotoxicity and actin cytoskeletal stabilization in brains of flies expressing wild-type human and various FTDP-17 tau mutants, supporting a conserved mechanism of neurotoxicity of wild-type tau and FTDP-17 mutant tau in disease pathogenesis.SIGNIFICANCE STATEMENT The microtubule protein tau aggregates and forms insoluble inclusion bodies known as neurofibrillary tangles in the brain tissue of patients with a variety of neurodegenerative disorders, including Alzheimer's disease. The tau protein is thus widely felt to play a key role in promoting neurodegeneration. However, precisely how tau becomes toxic is unclear. Here we capitalize on an "experiment of nature" in which rare missense mutations in tau cause familial neurodegeneration and neurofibrillary tangle formation. By comparing the biochemical activities of different tau mutations with their in vivo toxicity in a well controlled Drosophila model system, we find that all mutations tested increase phosphorylation of tau and trigger a cascade of neurotoxicity critically impinging on the integrity of the actin cytoskeleton.

Understanding fetal factors that contribute to preterm birth: Sjögren-Larsson syndrome as a model.

Preterm birth is the world's leading cause of neonatal death. Unfortunately, the pathophysiology of preterm birth remains poorly understood. Sjögren-Larsson syndrome is a rare, neurometabolic disorder caused by a fatty aldehyde dehydrogenase deficiency. A majority of patients with Sjögren-Larsson syndrome is born preterm. Data of all known Dutch patients with Sjögren-Larsson syndrome and all cases reported in literature were analyzed to learn from preterm birth in context of this rare disease. Exact gestational age was known in 33 Dutch patients; 24 (73%) of them were born preterm, with a median gestational age of 36 weeks. The literature search confirmed our findings: 13 (59%) of 22 cases was born preterm. Preterm birth is a hallmark of Sjögren-Larsson syndrome, presumably caused by the abnormal lipid metabolism of the fetus. At least five additional rare genetic disorders (namely Ehlers-Danlos syndrome, ichthyosis prematurity syndrome, congenital analbuminemia, osteogenesis imperfecta type II and restrictive dermopathy) were found in literature that lead to preterm birth of the affected fetus. These disorders are in fact "experiments of nature" and as such they shed new lights on the mechanisms causing preterm birth.

Measuring high-altitude adaptation.

High altitudes (>8,000 ft or 2,500 m) provide an experiment of nature for measuring adaptation and the physiological processes involved. Studies conducted over the past ~25 years in Andeans, Tibetans, and, less often, Ethiopians show varied but distinct O2 transport traits from those of acclimatized newcomers, providing indirect evidence for genetic adaptation to high altitude. Short-term (acclimatization, developmental) and long-term (genetic) responses to high altitude exhibit a temporal gradient such that, although all influence O2 content, the latter also improve O2 delivery and metabolism. Much has been learned concerning the underlying physiological processes, but additional studies are needed on the regulation of blood flow and O2 utilization. Direct evidence of genetic adaptation comes from single-nucleotide polymorphism (SNP)-based genome scans and whole genome sequencing studies that have identified gene regions acted upon by natural selection. Efforts have begun to understand the connections between the two with Andean studies on the genetic factors raising uterine blood flow, fetal growth, and susceptibility to Chronic Mountain Sickness and Tibetan studies on genes serving to lower hemoglobin and pulmonary arterial pressure. Critical for future studies will be the selection of phenotypes with demonstrable effects on reproductive success, the calculation of actual fitness costs, and greater inclusion of women among the subjects being studied. The well-characterized nature of the O2 transport system, the presence of multiple long-resident populations, and relevance for understanding hypoxic disorders in all persons underscore the importance of understanding how evolutionary adaptation to high altitude has occurred.NEW & NOTEWORTHY Variation in O2 transport characteristics among Andean, Tibetan, and, when available, Ethiopian high-altitude residents supports the existence of genetic adaptations that improve the distribution of blood flow to vital organs and the efficiency of O2 utilization. Genome scans and whole genome sequencing studies implicate a broad range of gene regions. Future studies are needed using phenotypes of clear relevance for reproductive success for determining the mechanisms by which naturally selected genes are acting.

Genome-wide profiling of congenital insulin-like growth factor-1 deficient patients: translational implications in cancer prevention and metabolism

Laron syndrome (LS) is a rare genetic disorder identified in the 1950s by Professor Zvi Laron. LS results from mutation of the growth hormone receptor (GH-R) gene, leading to congenital insulin-like growth factor-1 (IGF1) deficiency and dwarfism. Recent epidemiological studies have shown that LS patients do not develop cancer, emphasizing the crucial role of the IGF1 axis in cancer biology. Genome-wide profiling of LS patients conducted in our laboratory led to the identification of genes and signaling pathways that are over- or under-represented in LS compared to healthy controls of the same age range and ethnic group. Differentially expressed genes may be responsible for the association between lifetime low IGF1 values and protection from cancer. This experiment of nature may provide invaluable information that might translate into novel therapeutic approaches in modern oncology.

A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa.

One in three people has been infected with Mycobacterium tuberculosis (MTB), and the risk for MTB infection in HIV-infected individuals is even higher. We hypothesized that HIV-positive individuals living in tuberculosis-endemic regions who do not get infected by Mycobacterium tuberculosis are genetically resistant. Using an “experiment of nature” design that proved successful in our previous work, we performed a genome-wide association study of tuberculin skin test positivity using 469 HIV-positive patients from prospective study cohorts of tuberculosis from Tanzania and Uganda to identify genetic loci associated with MTB infection in the context of HIV-infection. Among these individuals, 244 tested were tuberculin skin test (TST) positive either at enrollment or during the >8 year follow up, while 225 were not. We identified a genome-wide significant association between a dominant model of rs877356 and binary TST status in the combined cohort (Odds ratio = 0.2671, p = 1.22x10-8). Association was replicated with similar significance when examining TST induration as a continuous trait. The variant lies in the 5q31.1 region, 57kb downstream from IL9. Two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an IL9 missense variant, rs2069885, had the most significant association (p = 1.59x10-12). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and TH2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected, HIV-positive participants with extensive exposure increases the power to detect associations in complex infectious disease.

Article Commentary: The Natural Course of Psoriasis: Data from a Rare ‘Experiment of Nature’ in Maoist China

Article Commentary: The Natural Course of Psoriasis: Data from a Rare ‘Experiment of Nature’ in Maoist China

The experimental debris flows in the Chemolgan river basin

Debris flows are one of the most dangerous and common hydrological phenomena in mountainous regions. They are extremely various in their type and character, but they are always mountain flows consisting of a mixture of water and loose-fragmental debris. The problem of calculation and forecasting the mudflows still remains intractable. There are several reasons for that: Firstly, the representatives of the whole spectrum of the Earth Sciences (Hydrology, Geology, Geomorphology, Geography, Mechanics, Rheology) deal with this problem from their point of view. Secondly, systematic monitoring of passing debris flows are currently held only in several countries only (USA, Canada, Austria, Switzerland, Japan, China), because they require significant funding. Thirdly, the calculation methods, having been accepted for the present time, give certain errors. In this article, the results of the artificially triggered debris flow experiments conducted in 1972–1976 in the Chemolgan river basin, organized by the Kazakh Research Hydrometeorological Institute are described. These were the first full-scale experiments with the detailed recording of the numerous debris flows characteristics ever conducted. The movie is attached as supplementary material to the Editorial of the Special Issue. The information about the used measurement equipment, the obtained characteristics of debris flows, the debris flow classification accepted as a result of the experiments is given. Conducting such experiments in nature allowed us to assess various aspects of the formation of these natural phenomena and made it possible to build the mathematical models of the debris flow processes.

Nature's Parkin experiment: Nix-a novel protective mechanism in Parkinson's disease.

Nature's Parkin experiment: Nix-a novel protective mechanism in Parkinson's disease.

The “ tension transformation zone” model of amorphous alloys

An amorphous alloy is a glassy solid that is formed through the supercooling of a melt. As the melt cools via the glass transition, its atoms freeze into a long-range disordered structure. Amorphous alloys represent a relatively young class of materials, having been first reported in 1960 when Duwez and co-workers produced Au-Si alloys by developing the rapid-quenching technology. The advent of amorphous alloys, especially the bulk samples with their characteristic size in excess of 1 mm, has aroused much interests in the basic science of glass transition, glass structure, and their intriguing properties. For crystalline metals, their structure can be well described by the period lattices and lattice defects including dislocations, twins, stacking faults, grain doundaries, etc. However, these traditional structural defects are not defined in amorphous alloys. Therefore, this type of atomic-disordered alloys manifest a series of excellent mechanical properties, including extraordinary strength, high hardness, large elastic limit and relatively high fracture toughness, making them attractive candidates for many potential applications as structural materials. At temperatures far below the glass transition temperature, the failure of amorphous alloys is generally induced by 10 nm thick shear banding with the single-dominated or multiple mode. It is well known that the shear banding is an instability mode of plastic flow from homogeneous to localized feature. Although the precise mechanism for amorphous plasticity is not well discovered, it is widely accepted that the shear-banding-mediated plasticity originates from a cascade of inelastic shear rearrangements of local atomic groups, called shear transformation zones (STZs). The STZs are thermally activated events with the transient nature, driven by shear stress and giving rise spatially to Eshelby fields. However, many recent works have shown that the failure of amorphous alloys is not always dominated by the shear banding; instead, a brittle failure will take place with a tension mode. The latter is usually accompanied with a new type of fracture surface morphology: fine dimples and/or nanoscale periodic corrugations. In order to understand such a dissipation process of fracture energy, we proposed the “tension transformation zone (TTZ)” model of amorphous alloys in 2008. The TTZ describes the brittle nucleation-controlled cavitation of local atomic groups that can be activated by shear-induced dilatation or direct hydrostatic tension. Here, we review how the TTZ model was developed, including its inherent nature, activation conditions, atomistic simulations and relevant experiments. The difference and relationship between the proposed TTZ and the classical cavitation are extensively discussed. Therefore, the energy dissipation in fracture of amorphous alloys is determined by two competing elementary processes, via. STZs and TTZs ahead of the crack tip. Based on this STZ vs. TTZ picture, the ductile-to-brittle transition of amorphous alloys can be understood as the change in the nature of transformation zones from shear-dominated STZs to dilatation-dominated TTZs. This review ends with the key aspects that deserve further study regarding the TTZ model. These aspects, at least, include (1) the experimental capture of TTZs, (2) the dynamics properties, (3) the spatio-temporal evolution, and (4) the theoretical construction from TTZs to brittle failure in amorphous alloys.

Lysosomal Storage Disorders and Malignancy.

Lysosomal storage disorders (LSDs) are infrequent to rare conditions caused by mutations that lead to a disruption in the usual sequential degradation of macromolecules or their transit within the cell. Gaucher disease (GD), a lipidosis, is among the most common LSD, with an estimated incidence of 1 in 40,000 among the Caucasian, non-Jewish population. Studies have indicated an increased frequency of polyclonal and monoclonal gammopathy among patients with GD. It has been shown that two major sphingolipids that accumulate in GD, namely, β-glucosylceramide 22:0 (βGL1-22) and glucosylsphingosine (LGL1), can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Investigations undertaken in an affected mouse model revealed βGL1-22- and LGL1-specific NKT cells were present and constitutively promoted the expression of a T-follicular helper (TFH) phenotype; injection of these lipids led to downstream induction of germinal center B cells, hypergammaglobulinemia, and the production of antilipid antibodies. Subsequent studies have found clonal immunoglobulin in 33% of sporadic human monoclonal gammopathies is also specific for the lysolipids LGL1 and lysophosphatidylcholine (LPC). Furthermore, substrate reduction ameliorated GD-associated gammopathy in mice. It had been hypothesized that chronic antigenic stimulation by the abnormal lipid storage and associated immune dysregulation may be the underlying mechanism for the increased incidence of monoclonal and polyclonal gammopathies, as well as an increased incidence of multiple myeloma in patients with GD. Current observations support this proposition and illustrate the value of investigations into rare diseases, which as ‘experiments of nature’ may provide insights into conditions found in the general population that continue to remain incompletely understood.

HSP90 Shapes the Consequences of Human Genetic Variation

HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between reduced phenotypic severity and a dominant (HSP90≥ HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90's buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an "experiment of nature" in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases.

ÍNDICE DE HORIZONTALIDADE E REMOÇÃO DE TECIDOS DO CAPIM-MARANDÚ

Resumo É possível que a maior disponibilidade de nutrientes no solo promova modificação mais acentuada da forma de crescimento da planta forrageira sob alta frequência de desfolhação. Para testar essa hipótese, caracterizaram-se as modificações na forma de crescimento da Brachiaria brizantha cv. Marandu syn. Urochloa brizantha cv. Marandu (capim-marandu) submetida aos intervalos de corte e à adubação, bem como avaliou-se o efeito dessas modificações sobre as forragens removida e remanescente do corte. O trabalho foi realizado em dois períodos experimentais. Em cada período, experimentos independentes, porém com natureza semelhante, foram realizados. No Experimento 1, de outubro de 2013 até fevereiro de 2014, o capim-marandu foi adubado com 70 kg.ha-1 de N e 50 kg.ha-1 de P2O5 e foram avaliados intervalos de corte (sete, 14, 28, 56 e 112 dias), em delineamento em blocos casualizados, com quatro repetições. No Experimento 2, de novembro de 2014 até março de 2015, além dos mesmos intervalos de corte avaliados no Experimento 1, também foram estudadas duas condições de adubação, sendo uma baixa (50 kg.ha-1 de P2O5 e de 75 kg.ha-1 de N) e outra alta (100 kg.ha-1 de P2O5 e 300 kg.ha-1 de N). No Experimento 2, utilizou-se o esquema fatorial, com dois níveis de adubação e cinco níveis de intervalos de corte, e o delineamento em blocos casualizados, com quatro repetições. No Experimento 1, os maiores índices de horizontalidade (IH) ocorreram (p<0,05) nas plantas sob intervalos de corte de sete, 14 e 28 dias, em relação às plantas cortadas a cada 56 e 112 dias. No Experimento 2, apenas a planta cortada a cada sete dias apresentou (p<0,05) aumento do IH (de 1,3 para 1,5) com a melhoria da alta condição de adubação. A massa de forragem remanescente aumentou (p<0,05) com o intervalo de corte, de 412 para 483 g.m-2 e de 412 para 571 g.m-2 nos Experimentos 1 e 2, respectivamente. No Experimento 2, ocorreu aumento (p<0,05) da massa de forragem remanescente (de 447 para 505 g.m-2) e da percentagem de colmo vivo (de 23 para 33%) com a adubação em todos os intervalos de corte. Em ambos os experimentos, os maiores intervalos de corte incrementaram (p<0,05) a massa de forragem removida (de 95 para 840 g.m-2 e de 44,8 para 843 g.m-2 nos experimentos 1 e 2, respectivamente) e o índice de área foliar (IAF) removido (de 1,0 para 4,3 e de 0,4 para 3,9 nos experimentos 1 e 2, respectivamente). No Experimento 2, a melhoria da condição de adubação resultou em aumento (p<0,05) da massa de forragem removida (de 261,3 para 391,8 g.m-2) e do IAF removido (de 1,6 para 2,1). No Experimento 2, quando a condição de adubação foi alta, houve (p<0,05) menor percentagem de folha viva removida nos dosséis sob cortes intermediários (28 e 56 dias). Quando a desfolhação é muito frequente, a maior disponibilidade de nutrientes no solo contribui para que o capim-marandu modifique sua forma de crescimento de ereta para prostrada, em comparação à condição de menor disponibilidade de nutrientes no solo. O aumento do intervalo de corte e a adubação incrementam a remoção da forragem do capim-marandu.

On the absolute meaning of motion

The present manuscript aims to clarify why motion causes matter to age slower in a comparable sense, and how this relates to relativistic effects caused by motion. A fresh analysis of motion, build on first axiom, delivers proof with its result, from which significant new understanding and computational power is gained.A review of experimental results demonstrates, that unaccelerated motion causes matter to age slower in a comparable, observer independent sense. Whilst focusing on this absolute effect, the present manuscript clarifies its context to relativistic effects, detailing their relationship and incorporating both into one consistent picture. The presented theoretical results make new predictions and are testable through suggested experiment of a novel nature. The manuscript finally arrives at an experimental tool and methodology, which as far as motion in ungravitated space is concerned or gravity appreciated, enables us to find the absolute observer independent picture of reality, which is reflected in the comparable display of atomic clocks.The discussion of the theoretical results, derives a physical causal understanding of gravity, a mathematical formulation of which, will be presented.

Political Connections, Audit Opinions, and Auditor Choice: Evidence from the Ouster of Government Officers

SUMMARYIn this study, we examine changes in audit opinions and auditor choice decisions in politically connected firms before and after the exogenous termination of their political connections. We use 84 anti-corruption cases involving high-level Chinese bureaucrats between 2004 and 2014 to construct a nature experiment, and identify a set of listed firms whose executives bribe or have connections through family affiliation with these corrupt bureaucrats. We find that within the event years of the ouster of corrupt bureaucrats, connected state-owned enterprises (SOEs) receive more favorable audit opinions than their non-connected counterparts, whereas connected non-SOEs obtain less favorable opinions. Moreover, after the termination of political connections, connected SOEs are more likely, while connected non-SOEs are less likely, to hire local small auditors. Additional analyses show that termination of political ties has more pronounced effects after the recent anti-corruption campaign. Furthermore, the levels of earnings management and audit fees in SOEs decrease when political connections are terminated, but they increase in non-SOEs. In summary, our study suggests that the termination of corporate political connections has a significant influence on auditors' assessments of audit risk and firms' auditor choice patterns, and this influence is subject to corporate ownership structures.

Invited Commentary

Does the likeness in means and ranges of hemoglobin (Hgb) from birds to mammals suggest that this physiological equilibrium has emerged more than once by natural selection? Is it by chance that the “ideal hematocrit” across the animal kingdom, when plotted against viscosity, usually follows a similar concave curve, peaking around a value of 40? Are events that evolved to maximize survival and reproductive fitness hundreds of millions of years ago relevant to perioperative management of patients? And should the anemia of a child with a moderately sized ventricular septal defect be corrected to avoid surgery? Cholette and colleagues [1Cholette J.M. Swartz M.F. Rubenstein J. et al.Outcomes using a conservative versus liberal red blood cell transfusion strategy in infants requiring cardiac operation.Ann Thorac Surg. 2017; 103: 206-215Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar] do not address these questions. I congratulate them, however, for their perseverance (this is a follow-up study) and for completing likely a difficult study. Further, they clearly show that one can avoid red blood cell (RBC) transfusion in most children after biventricular repair and in a reasonable fraction of those palliated with cavopulmonary or systemic-to-pulmonary artery shunting. They randomized 134 patients after biventricular and 57 patients after palliative surgery (including 12 s/p Norwood), to either a “restrictive” (Hgb of 7.0) or “liberal” (Hgb of 9.0 g/dL) threshold for transfusion. They report similar lactate, avO2 differences, and clinical results between the two groups and, therefore, infer that clinical judgment should guide transfusion decisions. But whose judgment? Once a critical care colleague said that just because you can stand in a canoe in the middle of the lake, it does not mean you should. Therefore, without specific guidelines, one is left with the judgment of one clinician versus another. Most would agree that RBC transfusions are not without risk; for example, many have shown the associated increased risk of infection. The typical reason (tachycardia, low blood pressure, low urine output, low mixed venous saturations) for treating anemia are practical starting points, but some patients have much less reserve than others do, and clinical circumstances may mask or decrease the potential for applicability of such features. The baby with pulmonary atresia/intact ventricular septum and RV dependent coronary circulation and coronary atresia may not tolerate heart rates in the 150s or 160s, let alone the 170s or 180s. Lactate, as used by the authors, is a late marker of tissue hypoxia, only to rise with anaerobic glycolysis. Other notable findings from the study include the difference in transfusion rates between the two groups: one transfusion. Authors provide no information on number of laboratory tests, which is perhaps the primary driving force for blood loss after surgery (all patients started with same baseline Hgb). It is tempting to speculate that the restrictive approach perhaps influenced the perioperative management. If true, adopting a restrictive strategy would be a laudable goal in lessening the number of such tests. It is also notable that 4 of the 6 babies for whom the restrictive strategy was violated were newborns who had undergone one form or another of arch reconstruction. Over 80 years ago, Robin Fahraeus remarked on the fall of hematocrit in blood flowing through smaller-caliber tubes. Future observations confirmed the differential segregation of RBCs and plasma in divisions of microvasculature, whether by default or because of vasoactive agents. These observations and other experiments of nature (e.g., the Antarctic Icefish compensates for no Hgb by having a much larger heart, high stroke volume, and dense capillary network) highlight that while an arbitrary Hgb value is not a signal for transfusion, great caution should be exercised when deciding whether a patient should or should not receive a transfusion. The decision not to transfuse could be just as dangerous as the one to transfuse. Outcomes Using a Conservative Versus Liberal Red Blood Cell Transfusion Strategy in Infants Requiring Cardiac OperationThe Annals of Thoracic SurgeryVol. 103Issue 1PreviewThe optimal hemoglobin for infants after cardiac operation is unknown. Red blood cells (RBCs) are commonly transfused to maintain high hemoglobin concentrations in the absence of a clinical indication. We hypothesized that infants can be managed with a postoperative conservative RBC transfusion strategy, resulting in lower daily hemoglobin concentrations, without evidence of impaired oxygen delivery (ie, lactate, arteriovenous oxygen difference [avO2diff]), or adverse clinical outcomes. Full-Text PDF

Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge's disease.

In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge's disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.

Tambora 1815 as a test case for high impact volcanic eruptions: Earth system effects.

The eruption of Tambora (Indonesia) in April 1815 had substantial effects on global climate and led to the ‘Year Without a Summer’ of 1816 in Europe and North America. Although a tragic event—tens of thousands of people lost their lives—the eruption also was an ‘experiment of nature’ from which science has learned until today. The aim of this study is to summarize our current understanding of the Tambora eruption and its effects on climate as expressed in early instrumental observations, climate proxies and geological evidence, climate reconstructions, and model simulations. Progress has been made with respect to our understanding of the eruption process and estimated amount of SO2 injected into the atmosphere, although large uncertainties still exist with respect to altitude and hemispheric distribution of Tambora aerosols. With respect to climate effects, the global and Northern Hemispheric cooling are well constrained by proxies whereas there is no strong signal in Southern Hemisphere proxies. Newly recovered early instrumental information for Western Europe and parts of North America, regions with particularly strong climate effects, allow Tambora's effect on the weather systems to be addressed. Climate models respond to prescribed Tambora‐like forcing with a strengthening of the wintertime stratospheric polar vortex, global cooling and a slowdown of the water cycle, weakening of the summer monsoon circulations, a strengthening of the Atlantic Meridional Overturning Circulation, and a decrease of atmospheric CO2. Combining observations, climate proxies, and model simulations for the case of Tambora, a better understanding of climate processes has emerged. WIREs Clim Change 2016, 7:569–589. doi: 10.1002/wcc.407This article is categorized under: 1Paleoclimates and Current Trends > Paleoclimate