Experiments Of Nature Research Articles

In vivo selection of hepatocytes

The liver is a highly regenerative organ capable of significant proliferation and remodeling during homeostasis and injury responses. Experiments of nature in rare genetic diseases have illustrated that healthy hepatocytes may have a selective advantage, outcompete diseased cells and result in extensive liver repopulation. This observation has given rise to the concept of therapeutic liver repopulation by providing an engineered selective advantage to a subpopulation of beneficial hepatocytes. In vivo selection can greatly enhance the efficiency of both gene and cell transplantation therapies for hepatic diseases. In vivo hepatocyte selection has also enabled the expansion of human hepatocytes in animals, creating novel models of human liver disease and biology. Finally, recent work has shown that somatic mutations produce clonal expansion of injury resistant hepatocytes in most chronic liver diseases. In this review, we will address the role of hepatocyte selection in disease pathophysiology and therapeutic strategies.

Interferon Gamma in Sickness Predisposing to Mycobacterial Infectious Diseases

In recent decades, the prevalence of inborn errors of immunity has increased, necessitating the development of more effective treatment and care options for these highly morbid conditions. Due to these “experiments of nature,” the complicated nature of the immune system is being revealed. Based on the functional and molecular tests, targeted therapies are now being developed which offer a more effective approach and reduce damage. This study aimed to investigate a key cytokine of the cellular immune response, interferon‐gamma (IFN-γ), which is linked to Mendelian susceptibility to Mycobacterial disease, and its potential as a therapeutic option for IFN-γ deficiency.

Absence of Neutropenia in Patients With Early Exon Nonsense Mutations in ELANE : Clinical Evidence to Support Gene Therapy Approaches for Severe Congenital Neutropenia.

Severe congenital neutropenia is an inherited bone marrow failure disorder characterized by profoundly low neutrophil counts and promyelocytic maturation arrest in bone marrow. Severe congenital neutropenia is most often caused by heterozygous ELANE mutations. In vitro and mouse xenograft studies using CRISPR/Cas9 have shown that introduction of frameshift/nonsense mutations in mutant ELANE may restore neutrophil counts, providing a model for gene therapy. Here, we present 2 children with inherited nonsense mutations in ELANE analogous to those proposed for gene therapy. Their normal peripheral blood neutrophil counts provide support for this approach through human "experiments of nature."

Defective FGFR1 Signaling Disrupts Glucose Regulation: Evidence From Humans With FGFR1 Mutations.

Activation of fibroblast growth factor receptor 1 (FGFR1) signaling improves the metabolic health of animals and humans, while inactivation leads to diabetes in mice. Direct human genetic evidence for the role of FGFR1 signaling in human metabolic health has not been fully established. We hypothesized that individuals with naturally occurring FGFR1 variants ("experiments of nature") will display glucose dysregulation. Participants with rare FGFR1 variants and noncarrier controls. Using a recall-by-genotype approach, we examined the β-cell function and insulin sensitivity of 9 individuals with rare FGFR1 deleterious variants compared to 27 noncarrier controls, during a frequently sampled intravenous glucose tolerance test at the Reproductive Endocrine Unit and the Harvard Center for Reproductive Medicine, Massachusetts General Hospital. FGFR1-mutation carriers displayed higher β-cell function in the face of lower insulin sensitivity compared to controls. These findings suggest that impaired FGFR1 signaling may contribute to an early insulin resistance phase of diabetes pathogenesis and support the candidacy of the FGFR1 signaling pathway as a therapeutic target for improving the human metabolic health.

Is competitive ability the key adaptation to benign environments? Revisiting experiments on closely related species of tidal plants.

A central goal in biology is to understand which traits underlie adaptation to different environments. Yet, few studies have examined the relative contribution of competitive ability towards adaptive divergence among species occupying distinct environments. Here, we test the relative importance of competitive ability as an adaptation to relatively benign versus challenging environments, using previously published studies of closely related species pairs of primarily tidal plants subjected to reciprocal removal with transplant experiments in nature. Subordinate species typically occupy more challenging environments and showed consistent evidence for adaptation to challenging conditions, with no significant competitive effect on non-local, dominant species. In contrast, dominant species typically occupy relatively benign environments and performed significantly better than non-local, subordinate species that faced competition from the dominant species. Surprisingly, when the two species were not allowed to compete, the subordinate species performed as well as the dominant species in the benign environments where the subordinate species do not occur. These results suggest that competitive ability is the most important adaptation distinguishing the species that occupy relatively benign environments. The limited scope and number of suitable experimental studies encourage future work to test if these results are generalizable across taxa and environments.

Multiphase simulations of nonlinear fluids with SPH

A modified apparent viscosity approach has been implemented for a weakly compressible SPH scheme for two-phase flows where a nonlinear phase must yield under erosive dynamics but also maintain a pseudosolid behaviour under the right conditions. The final purpose is to provide a means to model both dam-break dynamics and erosive interactions between different phases simultaneously while also keeping smooth pressure fields in spite of discontinuities introduced by viscosity variations of a nonlinear phase along with significant differences in mean density. Key contributions include purposeful avoidance of nonphysical elastic behaviour and the integration of a specific particle shifting technique that allows for proper replication of erosion and scouring. In this work, the method is validated by applying it to model a silted-up dam that collapses over a static water bed, effectively including all main elements of interest. Although the formulation is inherently three dimensional, validation is done by direct comparison with data from physical experiments of a dominant two-dimensional nature, assuming variable yield stress of medium-grain quartz sand according to the Drucker–Prager equation. Overall results show most of the expected interface dynamics, such as erosion and transportation of the nonlinear phase, sustained piling of the non-yielded volume of silt, and good correspondence of both granular and water surface position with experimental data. Finally, a series of modelling assumptions and implications for future developments are explicitly stated because of their direct impact on stability and versatility for multiphase, nonlinear flows in general.

Experiments in nature: the young microspheric (diploid) life cycle stage of benthic softbottom foraminiferans is adapted for planktonic dispersal

Experiments in nature: the young microspheric (diploid) life cycle stage of benthic softbottom foraminiferans is adapted for planktonic dispersal

The competitive exclusion-tolerance rule explains habitat partitioning among co-occurring species of burying beetles.

Habitat partitioning among co-occurring, ecologically similar species is widespread in nature and thought to be an important mechanism for coexistence. The factors that cause habitat partitioning, however, are unknown for most species. We experimentally tested among three alternative hypotheses to explain habitat partitioning among two species of co-occurring burying beetle (Nicrophorus) that occupy forest (Nicrophorus orbicollis) and wetland (Nicrophorus hebes) habitats. Captive experiments revealed that the larger N. orbicollis (forest) was consistently dominant to N. hebes (wetland) in competitive interactions for carcasses that they require for reproduction. Transplant enclosure experiments in nature revealed that N. hebes had poor reproductive success whenever the dominant N. orbicollis was present. In the absence of N. orbicollis, N. hebes performed as well, or better, in forest versus its typical wetland habitat. In contrast, N. orbicollis performed poorly in wetlands regardless of the presence of N. hebes. These results support the competitive exclusion-tolerance rule where the competitively dominant N. orbicollis excludes the subordinate N. hebes from otherwise suitable or preferable forest habitat, while the subordinate N. hebes is uniquely able to tolerate the challenges of breeding in wetlands. Transplant experiments further showed that carcass burial depth-an important trait thought to enhance the competitive ability of the dominant N. orbicollis-is costly in wetland habitats. In the presence of N. hebes, N. orbicollis buried carcasses deeper; deeper burial is thought to provide a competitive advantage in forests but further compromised the reproductive success of N. orbicollis in wetlands. Overall, results provide evidence that the competitive exclusion-tolerance rule underlies habitat partitioning among ecologically similar species and that the traits important for competitive dominance in relatively benign environments are costly in more challenging environments, consistent with a trade-off.

A perception-induced /t/-to-/k/ sound change: evidence from a cross-linguistic study.

John Ohala claimed that the source of sound change may lie in misperceptions which can be replicated in the laboratory. We tested this claim for a historical change of /t/ to /k/ in the coda in the Southern Min dialect of Chaoshan. We conducted a forced-choice segment identification task with CVC syllables in which the final C varied across the segments [p t k ʔ] in addition to a number of further variables, including the V, which ranged across [i u a]. The results from three groups of participants whose native languages have the coda systems /p t k ʔ/ (Zhangquan), /p k ʔ/ (Chaoshan) and /p t k/ (Dutch) indicate that [t] is the least stably perceived segment overall. It is particularly disfavoured when it follows [a], where there is a bias towards [k]. We argue that this finding supports a perceptual account of the historically documented scenario whereby a change from /at/ to /ak/ preceded and triggered a more general merger of /t/ with /k/ in the coda of Chaoshan. While we grant that perceptual sound changes are not the only or even the most common type of sound change, the fact that the perception results are essentially the same across the three language groups lends credibility to Ohala's perceptually motivated sound changes.

Organic geochemistry of in situ thermal-based analyses on Mars: the importance and influence of minerals

A high-priority goal for past, present and future missions to Mars is the search for evidence of past or present life. Some of the most information-rich signals are those represented by organic biomarkers. Thermal extraction has historically been the most popular in situ analysis technique employed on Mars owing to its elegance and ability to liberate both smallounds and large macromolecular networks. The geological record of Mars contains a variety of minerals, some of which can interact with organic matter when subjected to thermal extraction. We discuss the organic records that may be associated with these mineral hosts and the problems encountered when mineral–organic mixtures are analysed by thermal-based methods. We also suggest potential mitigations for future experiments of a similar nature and note that these mitigating steps can be applied not only in situ on Mars, but also after samples are returned to Earth as part of the Mars Sample Return mission, where more resources and time for sample preparation are available. Thematic collection: This article is part of the Astrobiology: Perspectives from the Geology of Earth and the Solar System collection available at: https://www.lyellcollection.org/topic/collections/astrobiology

Hydric effects on thermal tolerances influence climate vulnerability in a high-latitude beetle.

Species' thermal tolerances are used to estimate climate vulnerability, but few studies consider the role of the hydric environment in shaping thermal tolerances. As environments become hotter and drier, organisms often respond by limiting water loss to lower the risk of desiccation; however, reducing water loss may produce trade-offs that lower thermal tolerances if respiration becomes inhibited. Here, we measured the sensitivity of water loss rate and critical thermal maximum (CTmax ) to precipitation in nature and laboratory experiments that exposed click beetles (Coleoptera: Elateridae) to acute- and long-term humidity treatments. We also took advantage of their unique clicking behavior to characterize subcritical thermal tolerances. We found higher water loss rates in the dry acclimation treatment compared to the humid, and water loss rates were 3.2-fold higher for individuals that had experienced a recent precipitation event compared to individuals that had not. Acute humidity treatments did not affect CTmax , but precipitation indirectly affected CTmax through its effect on water loss rates. Contrary to our prediction, we found that CTmax was negatively associated with water loss rate, such that individuals with high water loss rate exhibited a lower CTmax . We then incorporated the observed variation of CTmax into a mechanistic niche model that coupled leaf and click beetle temperatures to predict climate vulnerability. The simulations indicated that indices of climate vulnerability can be sensitive to the effects of water loss physiology on thermal tolerances; moreover, exposure to temperatures above subcritical thermal thresholds is expected to increase by as much as 3.3-fold under future warming scenarios. The correlation between water loss rate and CTmax identifies the need to study thermal tolerances from a "whole-organism" perspective that considers relationships between physiological traits, and the population-level variation in CTmax driven by water loss rate complicates using this metric as a straightforward proxy of climate vulnerability.

Exercise and Experiments of Nature.

In this article, we highlight the contributions of passive experiments that address important exercise-related questions in integrative physiology and medicine. Passive experiments differ from active experiments in that passive experiments involve limited or no active intervention to generate observations and test hypotheses. Experiments of nature and natural experiments are two types of passive experiments. Experiments of nature include research participants with rare genetic or acquired conditions that facilitate exploration of specific physiological mechanisms. In this way, experiments of nature are parallel to classical "knockout" animal models among human research participants. Natural experiments are gleaned from data sets that allow population-based questions to be addressed. An advantage of both types of passive experiments is that more extreme and/or prolonged exposures to physiological and behavioral stimuli are possible in humans. In this article, we discuss a number of key passive experiments that have generated foundational medical knowledge or mechanistic physiological insights related to exercise. Both natural experiments and experiments of nature will be essential to generate and test hypotheses about the limits of human adaptability to stressors like exercise. © 2023 American Physiological Society. Compr Physiol 13:4879-4907, 2023.

SECURITY VERSUS THE INCLUSIVE VISION OF THE DIGITAL SOCIETY DETERMINANTS OF SELECTED ASPECTS OF CYBER SECURITY

An analysis of the security of the state and its citizens in terms of individual critical infrastructuresystems in a situation of threats from cyberspace is one of the topics taken up by the authors ofthis article. As part of an experiment of a research nature conducted among students of the courseCybernetics Engineering, National Security at the Pomeranian Academy in Slupsk and studentsof the course Internal Security at the Kazimierz Pulaski University of Technology and Humanitiesin Radom, an analysis was carried out of the students opinion of the impact of the phenomenonof cyber-terrorism on the level of national security and actions taken to combat and counteract itwas presented. The article is focused on assessing the incidence of threats to critical infrastructuresystems from cyberspace. The main objective of the study is to identify selected aspects of aninclusive vision of the digital society in terms of forecasting the direction of information flow andstorage management in the opinion of security students of two purposefully selected universities.

Is Kawasaki Disease Caused by a Respiratory Virus?

Kawasaki disease is characterized by high fever, rash, cervical lymphadenopathy, conjunctival injection, oral mucous membrane changes and swelling of the extremities followed by skin sloughing. Despite >50 years of study, no bacterial, viral or other infectious agent has been consistently associated with the illness. The lockdown and social distancing for COVID-19 in March 2020 led to a marked decrease in respiratory virus circulation. This provided an "experiment of nature" to determine whether Kawasaki disease would decline in parallel. Discharge ICD-10 diagnosis codes were obtained from the Vizient Clinical Data Base for Kawasaki disease and respiratory viruses, and analyzed for the age group < 5 years. Weekly respiratory virus positivity data were also obtained from BioFire Diagnostics. Common enveloped respiratory viruses declined precipitously from April 2020 through March 2021 to levels at or below historical seasonal minimum levels. Kawasaki Disease declined about 40% compared with 2018-2019, which is distinctly different from the pattern seen for the enveloped respiratory viruses. Strong seasonality was seen for Kawasaki disease as far back as 2010, and correlated most closely with respiratory syncytial virus, human metapneumovirus and less so with influenza virus suggesting there is a baseline level of Kawasaki disease activity that is heightened during yearly respiratory virus activity but that remains at a certain level even in the near total absence of respiratory viruses. The striking decrease in enveloped respiratory viruses after lockdown and social distancing was not paralleled by a comparable decrease in Kawasaki disease incidence, suggesting a different epidemiology.

Visualization of recirculation zones over a perforated plate: An optical flow technique for characterization of fluid dynamics in structured packing

In the context of increasing the performance of structured packing used in distillation columns, we develop a state-of-the-art flow diagnostic method to investigate the intricate fluid dynamics of a falling film interacting with a perforation. Perforations are one of the several key microstructure elements in industrial structured packing whose role in mass transfer enhancement and liquid redistribution is yet not well understood. We focus the present investigation on the liquid curtain, or "twin film", blanketing the perforation. Twin films are prone to strong capillary waves and recirculation zones, and experiments of fundamental nature are required to assess the fluid dynamics in the curtain formation in the perforations and ultimately uncover mechanisms that intensify interfacial mass transfer. Here, a three-dimensional two-component (3D-2C PTV) optical-flow-based technique using the concept of defocus is implemented on a test bench designed to study the effect of perforations on falling liquid films. This method provides an opportunity to evaluate the hydrodynamics of the liquid curtain through streamline patterns and dynamic modes and to describe key features that could promote mass transfer intensification in structured packing.

Tratamiento anestésico de la neuromiotonía. Descripción de un caso

The importance of neutrophils in fighting infections is clearly evidenced by “Experiments of Nature,” in which various gene mutations cause quantitative and qualitative abnormalities in the neutrophils. In such conditions, patients will suffer from infancy with life-threatening infections that must be treated promptly. In many cases delay in diagnosis and therapy may have serious consequences including death. This article focuses on severe congenital neutropenia, chronic granulomatous disease, leukocyte adhesion defects, and leukocyte motility abnormalities—all conditions that are related to congenital defects of the phagocytes.

Human genetic and immunological determinants of SARS-CoV-2 and Epstein-Barr virus diseases in childhood: Insightful contrasts.

There is growing evidence to suggest that severe disease in children infected with common viruses that are typically benign in other children can result from inborn errors of immunity or their phenocopies. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a cytolytic respiratory RNA virus, can lead to acute hypoxemic COVID-19 pneumonia in children with inborn errors of type I interferon (IFN) immunity or autoantibodies against IFNs. These patients do not appear to be prone to severe disease during infection with Epstein-Barr virus (EBV), a leukocyte-tropic DNA virus that can establish latency. By contrast, various forms of severe EBV disease, ranging from acute hemophagocytosis to chronic or long-term illnesses, such as agammaglobulinemia and lymphoma, can manifest in children with inborn errors disrupting specific molecular bridges involved in the control of EBV-infected B cells by cytotoxic T cells. The patients with these disorders do not seem to be prone to severe COVID-19 pneumonia. These experiments of nature reveal surprising levels of redundancy of two different arms of immunity, with type I IFN being essential for host defense against SARS-CoV-2 in respiratory epithelial cells, and certain surface molecules on cytotoxic T cells essential for host defense against EBV in B lymphocytes.

Implementation of probe rheology simulation technique in atomistically detailed molecular dynamics simulations

The probe rheology simulation technique is a technique for measuring the viscosity of a fluid by measuring the motion of an inserted probe particle. This approach has the benefit of greater potential accuracy at a lower computational cost than other conventional simulation techniques used for the calculation of mechanical properties, such as the Green-Kubo approach and nonequilibrium molecular dynamics simulations, and the potential to allow for sampling local variations of properties. This approach is implemented and demonstrated for atomistically detailed models. The viscosity of four different simple Newtonian liquids is calculated from both the Brownian motion (passive mode) and the forced motion (active mode) of an embedded probe particle. The probe particle is loosely modeled as a nano-sized diamond particle: a rough sphere cut out of an FCC lattice made of carbon atoms. The viscosities obtained from the motion of the probe particle are compared with those obtained from the periodic perturbation method, and good agreement between the two sets of values is observed once the probe-fluid interaction strength (i.e., in the pair-wise Lennard-Jones interaction) is two times higher than their original values, and the artificial hydrodynamic interactions between the probe particle and its periodic images are accounted for. The success of the proposed model opens new opportunities for applying such a technique in the rheological characterization of local mechanical properties in atomistically detailed molecular dynamics simulations, which can be directly compared with or help guide experiments of similar nature.

Calibration of Watershed Conceptual Models Using Local and Global ptimization

Many issues related to water resources require the solution of optimization problems. Optimization problems can be quite difficult such as the calibration of many conceptual watershed models. Conceptual watershed models are formulated using empirical relationships between hydrological variables observed in nature or field experiments .The success of automatic calibration depends mainly on the choice of optimization method. Most early attempts to calibrate watershed models have been based on local-search optimization methods. Local optimization methods are not designed to handle the presence of multiple regions of attraction, multi-local optima, insensitivities and parameter interdependencies, and other problems encountered in the calibration of watersheds models. It is therefore imperative that global optimization procedures that are capable of dealing with these various difficulties be employed. In this study, one local search optimization method and one global search method are used to calibrate the parameters a simple tenparameter rainfall-runoff model. The local search method is the well-known Rosenbrock's direct search method; the global search method is the newly developed Shuffled Complex Evolution (SCE) method . The results revealed that Shuffle Complex Evolution optimization method is more superior to Rosenbrok’s direct search method. The results confirmed the finding of many watershed modellers about the dependency of Rosenbrock’s method on the choice of initial search points. It further adds that Rosenbrock’s method is only effective when the initial search points are taken within 5 % or less from the true optimum parameter set. The results indicate that a proper choice of optimization methods can enhance the possibility of obtaining unique and conceptually realistic parameter estimate.

An experiment of nature links muscle glycogen unavailability with very high fat oxidation rates despite low aerobic fitness.

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.