Neural lineage differentiation of human pluripotent stem cells: Advances in disease modeling

Brain diseases affect 1 in 6 people worldwide. These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease. Recent advancements in tissue-engineered brain disease models have overcome many of the different shortcomings associated with the various animal models, tissue culture models, and epidemiologic patient data that are commonly used to study brain disease. One innovative method by which to model human neurological disease is via the directed differentiation of human pluripotent stem cells (hPSCs) to neural lineages including neurons, astrocytes, and oligodendrocytes. Three-dimensional models such as brain organoids have also been derived from hPSCs, offering more physiological relevance due to their incorporation of various cell types. As such, brain organoids can better model the pathophysiology of neural diseases observed in patients. In this review, we will emphasize recent developments in hPSC-based tissue culture models of neurological disorders and how they are being used to create neural disease models.     

Dynamic Processes in Regulation and Some Implications for Biofeedback and Biobehavioral Interventions

Systems theory has long been used in psychology, biology, and sociology. This paper applies newer methods of control systems modeling for assessing system stability in health and disease. Control systems can be characterized as open or closed systems with feedback loops. Feedback produces oscillatory activity, and the complexity of naturally occurring oscillatory patterns reflects the multiplicity of feedback mechanisms, such that many mechanisms operate simultaneously to control the system. Unstable systems, often associated with poor health, are characterized by absence of oscillation, random noise, or a very simple pattern of oscillation. This modeling approach can be applied to a diverse range of phenomena, including cardiovascular and brain activity, mood and thermal regulation, and social system stability. External system stressors such as disease, psychological stress, injury, or interpersonal conflict may perturb a system, yet simultaneously stimulate oscillatory processes and exercise control mechanisms. Resonance can occur in systems with negative feedback loops, causing high-amplitude oscillations at a single frequency. Resonance effects can be used to strengthen modulatory oscillations, but may obscure other information and control mechanisms, and weaken system stability. Positive as well as negative feedback loops are important for system function and stability. Examples are presented of oscillatory processes in heart rate variability, and regulation of autonomic, thermal, pancreatic and central nervous system processes, as well as in social/organizational systems such as marriages and business organizations. Resonance in negative feedback loops can help stimulate oscillations and exercise control reflexes, but also can deprive the system of important information. Empirical hypotheses derived from this approach are presented, including that moderate stress may enhance health and functioning.     

Detecting Lung Diseases from Exhaled Aerosols: Non-Invasive Lung Diagnosis Using Fractal Analysis and SVM Classification

Background

Each lung structure exhales a unique pattern of aerosols, which can be used to detect and monitor lung diseases non-invasively. The challenges are accurately interpreting the exhaled aerosol fingerprints and quantitatively correlating them to the lung diseases.

Objective and Methods

In this study, we presented a paradigm of an exhaled aerosol test that addresses the above two challenges and is promising to detect the site and severity of lung diseases. This paradigm consists of two steps: image feature extraction using sub-regional fractal analysis and data classification using a support vector machine (SVM). Numerical experiments were conducted to evaluate the feasibility of the breath test in four asthmatic lung models. A high-fidelity image-CFD approach was employed to compute the exhaled aerosol patterns under different disease conditions.

Findings

By employing the 10-fold cross-validation method, we achieved 100% classification accuracy among four asthmatic models using an ideal 108-sample dataset and 99.1% accuracy using a more realistic 324-sample dataset. The fractal-SVM classifier has been shown to be robust, highly sensitive to structural variations, and inherently suitable for investigating aerosol-disease correlations.

Conclusion

For the first time, this study quantitatively linked the exhaled aerosol patterns with their underlying diseases and set the stage for the development of a computer-aided diagnostic system for non-invasive detection of obstructive respiratory diseases.     

Elimination of Onchocerciasis from Mexico

Background

Mexico is one of the six countries formerly endemic for onchocerciasis in Latin America. Transmission has been interrupted in the three endemic foci of that country and mass drug distribution has ceased. Three years after mass drug distribution ended, post-treatment surveillance (PTS) surveys were undertaken which employed entomological indicators to check for transmission recrudescence.

Methodology/Principal findings

In-depth entomologic assessments were performed in 18 communities in the three endemic foci of Mexico. None of the 108,212 Simulium ochraceum s.l. collected from the three foci were found to contain parasite DNA when tested by polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA), resulting in a maximum upper bound of the 95% confidence interval (95%-ULCI) of the infective rate in the vectors of 0.035/2,000 flies examined. This is an order of magnitude below the threshold of a 95%-ULCI of less than one infective fly per 2,000 flies tested, the current entomological criterion for interruption of transmission developed by the international community. The point estimate of seasonal transmission potential (STP) was zero, and the upper bound of the 95% confidence interval for the STP ranged from 1.2 to 1.7 L₃/person/season in the different foci. This value is below all previous estimates for the minimum transmission potential required to maintain the parasite population.

Conclusions/Significance

The results from the in-depth entomological post treatment surveillance surveys strongly suggest that transmission has not resumed in the three foci of Mexico during the three years since the last distribution of ivermectin occurred; it was concluded that transmission remains undetectable without intervention, and Onchocerca volvulus has been eliminated from Mexico.     

Laboratory Investigations of African Pouched Rats (Cricetomys gambianus) as a Potential Reservoir Host Species for Monkeypox Virus

Monkeypox is a zoonotic disease endemic to central and western Africa, where it is a major public health concern. Although Monkeypox virus (MPXV) and monkeypox disease in humans have been well characterized, little is known about its natural history, or its maintenance in animal populations of sylvatic reservoir(s). In 2003, several species of rodents imported from Ghana were involved in a monkeypox outbreak in the United States with individuals of three African rodent genera (Cricetomys, Graphiurus, Funisciurus) shown to be infected with MPXV. Here, we examine the course of MPXV infection in Cricetomys gambianus (pouched Gambian rats) and this rodent species’ competence as a host for the virus. We obtained ten Gambian rats from an introduced colony in Grassy Key, Florida and infected eight of these via scarification with a challenge dose of 4X10⁴ plaque forming units (pfu) from either of the two primary clades of MPXV: Congo Basin (C-MPXV: n = 4) or West African (W-MPXV: n = 4); an additional 2 animals served as PBS controls. Viral shedding and the effect of infection on activity and physiological aspects of the animals were measured. MPXV challenged animals had significantly higher core body temperatures, reduced activity and increased weight loss than PBS controls. Viable virus was found in samples taken from animals in both experimental groups (C-MPXV and W-MPXV) between 3 and 27 days post infection (p.i.) (up to 1X10⁸ pfu/ml), with viral DNA found until day 56 p.i. The results from this work show that Cricetomys gambianus (and by inference, probably the closely related species, Cricetomys emini) can be infected with MPXV and shed viable virus particles; thus suggesting that these animals may be involved in the maintenance of MPXV in wildlife mammalian populations. More research is needed to elucidate the epidemiology of MPXV and the role of Gambian rats and other species.     

The Role of Selection in Shaping Diversity of Natural M. tuberculosis Populations

Mycobacterium tuberculosis (M.tb), the cause of tuberculosis (TB), is estimated to infect a new host every second. While analyses of genetic data from natural populations of M.tb have emphasized the role of genetic drift in shaping patterns of diversity, the influence of natural selection on this successful pathogen is less well understood. We investigated the effects of natural selection on patterns of diversity in 63 globally extant genomes of M.tb and related pathogenic mycobacteria. We found evidence of strong purifying selection, with an estimated genome-wide selection coefficient equal to −9.5×10⁻⁴ (95% CI −1.1×10⁻³ to −6.8×10⁻⁴); this is several orders of magnitude higher than recent estimates for eukaryotic and prokaryotic organisms. We also identified different patterns of variation across categories of gene function. Genes involved in transport and metabolism of inorganic ions exhibited very low levels of non-synonymous polymorphism, equivalent to categories under strong purifying selection (essential and translation-associated genes). The highest levels of non-synonymous variation were seen in a group of transporter genes, likely due to either diversifying selection or local selective sweeps. In addition to selection, we identified other important influences on M.tb genetic diversity, such as a 25-fold expansion of global M.tb populations coincident with explosive growth in human populations (estimated timing 1684 C.E., 95% CI 1620–1713 C.E.). These results emphasize the parallel demographic histories of this obligate pathogen and its human host, and suggest that the dominant effect of selection on M.tb is removal of novel variants, with exceptions in an interesting group of genes involved in transportation and defense. We speculate that the hostile environment within a host imposes strict demands on M.tb physiology, and thus a substantial fitness cost for most new mutations. In this respect, obligate bacterial pathogens may differ from other host-associated microbes such as symbionts.