The Molecular Basis of Differentiation Wave Activity in Embryogenesis Bradly Alicea.

As development varies greatly across the tree of life, it may seem difficult to suggest a model that proposes a single mechanism for understanding collective cell behaviors and the coordination of tissue formation. Here we propose a mechanism called differentiation waves, which unify many disparate results involving developmental systems from across the tree of life. We demonstrate how a relatively simple model of differentiation proceeds not from function-related molecular mechanisms, but from so-called differentiation waves. A phenotypic model of differentiation waves is introduced, and its relation to molecular mechanisms is proposed. These waves contribute to a differentiation tree, which is an alternate way of viewing cell lineage and local action of the molecular factors. We construct a model of differentiation wave-related molecular mechanisms (genome, epigenome, and proteome) based on bioinformatic data from the nematode Caenorhabditis elegans. To validate this approach across different modes of development, we evaluate protein expression across different types of development by comparing Caenorhabditis elegans with several model organisms: fruit flies (Drosophila melanogaster), yeast (Saccharomyces cerevisiae), and mouse (Mus musculus). Inspired by gene regulatory networks, two Models of Interactive Contributions (fully-connected MICs and ordered MICs) are used to suggest potential genomic contributions to differentiation wave-related proteins. This, in turn, provides a framework for understanding differentiation and development.

A rapid host-protein test for differentiating bacterial from viral infection: Apollo diagnostic accuracy study.

Objectives: To determine the diagnostic accuracy of a rapid host-protein test for differentiating bacterial from viral infections in patients who presented to the emergency department (ED) or urgent care center (UCC). Methods: This was a prospective multicenter, blinded study. MeMed BV (MMBV), a test based on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-inducible protein-10 (IP-10), and C-reactive protein (CRP), was measured using a rapid measurement platform. Patients were enrolled from 9 EDs and 3 UCCs in the United States and Israel. Patients >3 months of age presenting with fever and clinical suspicion of acute infection were considered eligible. MMBV results were not provided to the treating clinician. MMBV results (bacterial/viral/equivocal) were compared against a reference standard method for classification of infection etiology determined by expert panel adjudication. Experts were blinded to MMBV results. They were provided with comprehensive patient data, including laboratory, microbiological, radiological and follow-up. Results: Of 563 adults and children enrolled, 476 comprised the study population (314 adults, 162 children). The predominant clinical syndrome was respiratory tract infection (60.5% upper, 11.3% lower). MMBV demonstrated sensitivity of 90.0% (95% confidence interval [CI]: 80.3-99.7), specificity of 92.8% (90.0%-95.5%), and negative predictive value of 98.8% (96.8%-99.6%) for bacterial infections. Only 7.2% of cases yielded equivocal MMBV scores. Area under the curve for MMBV was 0.95 (0.90-0.99). Conclusions: MMBV had a high sensitivity and specificity relative to reference standard for differentiating bacterial from viral infections. Future implementation of MMBV for patients with suspected acute infections could potentially aid with appropriate antibiotic decision-making.

Multifunctional metallic nanocomposite for overcoming the strength-ductility trade-off.

The actualization of high strength and ductility in alloys, in addition to providing strong, formable materials, can lead to reduced weights in practical applications. However, increasing strength typically comes at the cost of lowering the ductility and vice-versa, referred to as the strength-ductility trade-off. In this work, we investigate the thermo-mechanical response of a 3-element multifunctional NiTi-Nb nanocomposite material that overcomes this trade-off, as it exhibits a high strength of 980 MPa and an ultrahigh ductility of 58% at fracture. The remarkable properties are attributed to the underlying microstructure of Nb nanofibers dispersed in an NiTi matrix. Deformation is accommodated via the shape memory transformation of the active NiTi matrix in concert with elastoplastic deformation of Nb nanofibers embedded within the matrix. Consequently, the material exhibits multifunctionality and recovers deformation during heating via the reversion of the stress-induced martensitic transformation in the NiTi matrix. The high strength and high ductility of this 3-element nanocomposite material puts it amongst the best performing high-entropy alloys (HEAs) that are typically made up of five or more elements.

Prehospital Ultrasound: Nationwide Incidence from the NEMSIS Database.

OBJECTIVE: We sought to describe prehospital ultrasound (PHUS) use and trends in PHUS utilization over time using a national database. METHODS: Using the 2018 - 2021 National Emergency Medical Services Information System databases, we identified those EMS activations where PHUS was performed. We evaluated the association between year and number of PHUS exams performed using univariable and multivariable regression analysis. Analysis was performed on the overall group and various subgroups. RESULTS: In total, there were 148,709,000 EMS activations by 13,899 agencies over the 4 years. Of these, 3,291 unique activations (0.002%) involved PHUS, performed by 71 EMS agencies (0.5%). The annual rate of ultrasound evaluations per 1 million EMS activations significantly increased over the study period: 5.2 in 2018, 14.8 in 2019, 18.6 in 2020, and 38.9 in 2021 (p < 0.01). The number of agencies performing PHUS each year increased over the study period from 11 in 2018 to 54 in 2021 (p < 0.05). Each year after 2018 had an increased odds of PHUS use demonstrated with logistic regression (p < 0.01). PHUS was used in each US census region, and paramedics performed most of the PHUS exams (75.5%). We identified 1,060 out-of-hospital cardiac arrest, 820 trauma, and 427 respiratory PHUS cases. These three cohorts accounted for 70.1% of all PHUS cases. CONCLUSION: Prehospital ultrasound use in the United States increased significantly over the study period, but remains exceedingly rare. The performance of PHUS was recorded throughout the United States, with paramedics performing the majority of PHUS studies included in this database.

Macroevolution, differentiation trees, and the growth of coding systems.

An open process of evolution of multicellular organisms is based on the rearrangement and growth of the program of differentiation that underlies biological morphogenesis. The maintenance of the final (adult) stable non-equilibrium state (stasis) of a developmental system determines the direction of the evolutionary process. This state is achieved via the sequence of differentiation events representable as differentiation trees. A special type of morphogenetic code, acting as a metacode governing gene expression, may include electromechanical signals appearing as differentiation waves. The excessive energy due to the incorporation of mitochondria in eukaryotic cells resulted not only in more active metabolism but also in establishing the differentiation code for interconnecting cells and forming tissues, which fueled the evolutionary process. The "invention" of "continuing differentiation" distinguishes multicellular eukaryotes from other organisms. The Janus-faced control, involving both top-down control by differentiation waves and bottom-up control via the mechanical consequences of cell differentiations, underlies the process of morphogenesis and results in the achievement of functional stable final states. Duplications of branches of the differentiation tree may be the basis for continuing differentiation and macroevolution, analogous to gene duplication permitting divergence of genes. Metamorphoses, if they are proven to be fusions of disparate species, may be classified according to the topology of fusions of two differentiation trees. In the process of unfolding of morphogenetic structures, microevolution can be defined as changes of the differentiation tree that preserve topology of the tree, while macroevolution represents any change that alters the topology of the differentiation tree.

Pharmacological Inhibition of PTEN Rescues Dopaminergic Neurons by Attenuating Apoptotic and Neuroinflammatory Signaling Events.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta resulting in an irreversible and a debilitating motor dysfunction. Though both genetic and idiopathic factors are implicated in the disease etiology, idiopathic PD comprise the majority of clinical cases and is caused by exposure to environmental toxicants and oxidative stress. Fyn kinase activation has been identified as an early molecular signaling event that primes neuroinflammatory and neurodegenerative events associated with dopaminergic cell death. However, the upstream regulator of Fyn activation remains unidentified. We investigated whether the lipid and tyrosine phosphatase PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) could be the upstream regulator of Fyn activation in PD models as PTEN has been previously reported to contribute to Parkinsonian pathology. Our findings, using bioluminescence resonance energy transfer (BRET) and immunoblotting, indicate for the first time that PTEN is a critical early stress sensor in response to oxidative stress and neurotoxicants in in vitro models of PD. Pharmacological attenuation of PTEN activity rescues dopaminergic neurons from neurotoxicant-induced cytotoxicity by modulating Fyn kinase activation. Our findings also identify PTEN's novel roles in contributing to mitochondrial dysfunction which contribute to neurodegenerative processes. Interestingly, we found that PTEN positively regulates interleukin-1ß (IL-1ß) and the transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Taken together, we have identified PTEN as a disease course altering pharmacological target that may be further validated for the development of novel therapeutic strategies targeting PD.

RRx-001: a chimeric triple action NLRP3 inhibitor, Nrf2 inducer, and nitric oxide superagonist.

RRx-001 is a shape shifting small molecule with Fast Track designation for the prevention/amelioration of chemoradiation-induced severe oral mucositis (SOM) in newly diagnosed Head and Neck cancer. It has been intentionally developed or "engineered" as a chimeric single molecular entity that targets multiple redox-based mechanisms. Like an antibody drug conjugate (ADC), RRx-001 contains, at one end a "targeting" moiety, which binds to the NLRP3 inflammasome and inhibits it as well as Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of Nrf2, and, at the other end, a conformationally constrained, dinitro containing 4 membered ring, which fragments under conditions of hypoxia and reduction to release therapeutically active metabolites i.e., the payload. This "payload", which is delivered specifically to hypoperfused and inflamed areas, includes nitric oxide, nitric oxide related species and carbon-centered radicals. As observed with ADCs, RRx-001 contains a backbone amide "linker" attached to a binding site, which correlates with the Fab region of an antibody, and to the dinitroazetidine payload, which is microenvironmentally activated. However, unlike ADCs, whose large size impacts their pharmacokinetic properties, RRx-001 is a nonpolar small molecule that easily crosses cell membranes and the blood brain barrier (BBB) and distributes systemically. This short review is organized around the de novo design and in vivo pro-oxidant/pro-inflammatory and antioxidant/anti-inflammatory activity of RRx-001, which, in turn, depends on the reduced to oxidized glutathione ratio and the oxygenation status of tissues.

Response to Comment on "Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice".

We have replicated our original finding of elevated cleaved caspase-1 in mouse brains and neuroprotection by an NLRP3 inflammasome inhibitor in two mouse models of Parkinson's disease.

NoRCEL's Engagement in Africa: The AstroScience Exploration Network (ASEN).

Abstract The AstroScience Exploration Network (ASEN) is the latest innovative initiative from the Network of Researchers on the Chemical Emergence of Life (NoRCEL). Materializing on the vibrancy of the African continent, recognizing its people as a key asset, and building on specific strategic advantages, ASEN will funnel the appetite for scientific knowledge through an educational hub that paves the way for the Global South to come to the fore in new global endeavors and will eventually help build a variety of career paths in a diversifying economy.

Embodied cognitive morphogenesis as a route to intelligent systems.

The embryological view of development is that coordinated gene expression, cellular physics and migration provides the basis for phenotypic complexity. This stands in contrast with the prevailing view of embodied cognition, which claims that informational feedback between organisms and their environment is key to the emergence of intelligent behaviours. We aim to unite these two perspectives as embodied cognitive morphogenesis, in which morphogenetic symmetry breaking produces specialized organismal subsystems which serve as a substrate for the emergence of autonomous behaviours. As embodied cognitive morphogenesis produces fluctuating phenotypic asymmetry and the emergence of information processing subsystems, we observe three distinct properties: acquisition, generativity and transformation. Using a generic organismal agent, such properties are captured through models such as tensegrity networks, differentiation trees and embodied hypernetworks, providing a means to identify the context of various symmetry-breaking events in developmental time. Related concepts that help us define this phenotype further include concepts such as modularity, homeostasis and 4E (embodied, enactive, embedded and extended) cognition. We conclude by considering these autonomous developmental systems as a process called connectogenesis, connecting various parts of the emerged phenotype into an approach useful for the analysis of organisms and the design of bioinspired computational agents.

A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation.

Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1ß and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology.

RICT: Rotating image computed tomography with a one-to-one reversible image rotation algorithm.

BACKGROUND: The Mueller, Siddon and Joseph weighting algorithms are frequently used for projection and back-projection, which are relatively complicated when they are implemented in computer code. OBJECTIVE: This study aims to reduce the actual complexity of the projection and back-projection. METHODS: First, we neglect the exact shape of the pixel, so that its shadow is a rectangle projecting precisely to a detector bin, which implies that all the pixel weights are exactly 1 for each ray through them, otherwise are exactly 0. Next, a one-to-one reversible image rotation algorithm (RIRA) is proposed to compute the projection and back-projection, where two one-to-one mapping lists namely, U and V, are used to store the coordinates of a rotated pixel and its corresponding new coordinates, respectively. For each 2D projection, the projection is simply the column sum in each orientation according to the lists U and V. For each 2D back-projection, it is simply to arrange the projection to the corresponding column element according to the lists U and V. Thus, there is no need for an interpolation in the projection and back-projection. Last, a rotating image computed tomography (RICT) based on RIRA is proposed to reconstruct the image. RESULTS: Experiments show the RICT reconstructs a good image that is close to the result of filtered back-projection (FBP) method according to the RMSE, PSNR and MSSIM values. What's more, our weight, projection and back-projection are much easier to be implemented in computer code than the FBP method. CONCLUSION: This study demonstrates that the RIRA method has potential to be used to simplify many computed tomography image reconstruction algorithms.

Time to Antiarrhythmic and Association with Return of Spontaneous Circulation in the United States.

INTRODUCTION: Recent clinical trials have failed to identify a benefit of antiarrhythmic administration during cardiac arrest. However, little is known regarding the time to administration of antiarrhythmic drugs in clinical practice or its impact on return of spontaneous circulation (ROSC). We utilized a national EMS registry to evaluate the time of drug administration and association with ROSC. METHODS: We utilized the 2018 and 2019 NEMSIS datasets, including all non-traumatic, adult 9-1-1 EMS activations for cardiac arrests with initial shockable rhythm and that received an antiarrhythmic. We calculated the time from 9-1-1 call to administration of antiarrhythmic. We excluded cases with erroneous time stamps. Stratified by initial antiarrhythmic (amiodarone and lidocaine), we created a mixed-effect logistic regression model evaluating the association between every 5-minute increase in time to antiarrhythmic and ROSC. We modeled EMS agency as a random intercept and adjusted for confounders. RESULTS: There were 449,630 adults, non-traumatic cardiac arrests identified with 11,939 meeting inclusion criteria. 9,236 received amiodarone and 1,327 received lidocaine initially. The median time in minutes to initial dose for amiodarone was 19.9 minutes (IQR 15.8-25.6) and for lidocaine was 19.5 minutes (IQR 15.2-25.4). Increasing time to initial antiarrhythmic was associated with decreased odds of ROSC for both amiodarone (aOR 0.9; 95% CI 0.9-0.94) and lidocaine (aOR 0.9; 95% CI 0.8-0.97). CONCLUSION: Time to administration of anti-arrhythmic medication varied, but most patients received the first dose of anti-arrhythmic drug more than 19 minutes after the initial 9-1-1 call. Longer time to administration of an antiarrhythmic in patients with an initial shockable rhythm was associated with decreased ROSC rates.

Mechanisms of NLRP3 activation and pathology during neurodegeneration.

Inflammasomes are multiprotein complexes that are mainly present in resident and infiltrating immune cells in the central nervous system. Inflammasomes function as intracellular sensors of immunometabolic stress, infection and changes in the local microenvironment. Inflammasome assembly in response to these 'danger signals', triggers recruitment and cluster-dependent activation of caspase-1 and the subsequent proteolytic activation of inflammatory cytokines such as interleukin-1ß and interleukin-18. This is typically followed by a form of inflammatory cell death through pyroptosis. Since the discovery of inflammasomes in 2002, they have come to be recognized as central regulators of acute and chronic inflammation, a hallmark of progressive neurological diseases. Indeed, over the last decade, extensive inflammasome activation has been found at the sites of neuropathology in all progressive neurodegenerative diseases. Disease-specific misfolded protein aggregates which accumulate in neurodegenerative diseases, such as alpha synuclein or beta amyloid, have been found to be important triggers of NLRP3 inflammasome activation in the central nervous system. Together, these discoveries have transformed our understanding of how chronic inflammation is triggered and sustained in the central nervous system, and how it can contribute to neuronal death and disease progression in age-related neurodegenerative diseases. Therapeutic strategies around inhibition of NLRP3 activation in the central nervous system are already being evaluated to determine their effectiveness to slow progressive neurodegeneration. This review summarizes current understanding of inflammasomes in the most prevalent neurodegenerative diseases and discusses current knowledge gaps and inflammasome inhibition as a therapeutic strategy.

Inflammasome Activation in Parkinson's Disease.

Chronic sterile inflammation and persistent immune activation is a prominent pathological feature of Parkinson's disease (PD). Inflammasomes are multi-protein intracellular signaling complexes which orchestrate inflammatory responses in immune cells to a diverse range of pathogens and host-derived signals. Widespread inflammasome activation is evident in PD patients at the sites of dopaminergic degeneration as well as in blood samples and mucosal biopsies. Inflammasome activation in the nigrostriatal system is also a common pathological feature in both neurotoxicant and α-synuclein models of PD where dopaminergic degeneration occurs through distinct mechanisms. The NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome has been shown to be the primary driver of inflammatory neurotoxicity in PD and other neurodegenerative diseases. Chronic NLRP3 inflammasome activation is triggered by pathogenic misfolded α-synuclein aggregates which accumulate and spread over the disease course in PD. Converging lines of evidence suggest that blocking inflammasome activation could be a promising therapeutic strategy for disease modification, with both NLRP3 knockout mice and CNS-permeable pharmacological inhibitors providing robust neuroprotection in multiple PD models. This review summarizes the current evidence and knowledge gaps around inflammasome activation in PD, the pathological mechanisms by which persistent inflammasome activation can drive dopaminergic degeneration and the therapeutic opportunities for disease modification using NLRP3 inhibitors.

An assessment of solvent residue contaminants related to cannabis-based products in the South African market.

Organic solvents are used for manufacturing herbal medicines and can be detected as residues of such processing in the final products. It is important for the safety of consumers to control these solvent residues. South African cannabis-based product samples were analysed for solvent residue contaminants as classified by the United States Pharmacopeia (USP), chapter 467. The origin of these samples ranged anywhere from crude extract, product development samples, and market ready final products. Samples were submitted to a contract laboratory over a period of 2 years from 2019 to 2021. To date, no data of this kind exist in South Africa specifically relating to cannabis-based medicinal, recreational, or complementary products. A total of 279 samples were analysed in duplicate by full evaporation headspace gas-chromatography mass-spectrometry and the results are reported in an anonymised format. The results showed an alarming 37% sample solvent residue failure rate with respect to adherence to USP 467 specification. It is important to ensure regulation is enforced to control product quality. The South African public need to be educated about the risks associated with cannabis-based products.

Focused assessment with sonography for trauma in predicting early surgical intervention in hemodynamically unstable children with blunt abdominal trauma.

OBJECTIVES: The predictive accuracy and clinical role of the focused assessment with sonography for trauma (FAST) exam in pediatric blunt abdominal trauma are uncertain. This study investigates the performance of the emergency department (ED) FAST exam to predict early surgical intervention and subsequent free fluid (FF) in pediatric trauma patients. METHODS: Pediatric level 1 trauma patients ages 0 to 15 years with blunt torso trauma at a single trauma center were retrospectively reviewed. After stratification by initial hemodynamic (HD) instability, the association of a positive FAST with (1) early surgical intervention, defined as operative management (laparotomy or open pericardial window) or angiography within 4 hours of ED arrival and (2) presence of FF during early surgical intervention was determined. RESULTS: Among 508 salvageable pediatric trauma patients with an interpreted FAST exam, 35 (6.9%) had HD instability and 98 (19.3%) were FAST positive. A total of 42 of 508 (8.3%) patients required early surgical intervention, and the sensitivity and specificity of FAST predicting early surgical intervention were 59.5% and 84.3%, respectively. The specificity and positive predictive value of FF during early surgical intervention in FAST-positive HD unstable patients increased from 50% and 90.9% at 4 hours after ED arrival to 100% and 100% at 2 hours after ED arrival, respectively. CONCLUSIONS: In this large series of injured children, a positive FAST exam improves the ability to predict the need for early surgical intervention, and accuracy is greater for FF in HD unstable patients 2 hours after arrival to the ED.

Employing newly developed plastic bubble wrap technique for biofuel production from diatoms cultivated in discarded plastic waste.

Algal culturing in photobioreactors for biofuel and other value-added products is a challenge globally specifically due to expensive closed or open photobioreactors associated with the high cost, problems of water loss and contamination. Among the wide varieties of microalgae, diatoms have come out as potential source for crude oil in the form of Diafuel™ (biofuel from diatoms). However, culturing diatoms at large scale hypothesized as diatom solar panels for biofuel production is still facing a need for facile and economical production of value-added products. The aim of this work was to culture diatom (microalgae) in a closed system by sealing the reactor rim tightly with very cheap priced and used plastic bubble wrap material which is generally discarded in a lodging and transportation of goods. To optimize it, different plastic wraps discarded from a plastic industry were tested first for their permeability to gases and impermeability to water loss. It was found that among different varieties of plastic bubble wraps, low density polyethylene (LDPE) bubble wrap material which was used to seal glass containers as photobioreactors allowed harvest of maximum Diafuel™ (37%), lipid (35 µgmL-1), highest cell count (1152 × 102 cells mL-1), maximum CO2 absorbance (0.084) with almost no water loss and nutrient uptake for 40 days of experiments. This was due to its permeability to gases and impermeability to water. To check usability of such LDPE bubble wrap on other microalgae it was therefore tested on the red-green microalgae Haematococcus pluvialis, which showed scope to be scaled up for astaxanthin production using discarded bubble wrap packing material. This study thus would open up a new way for decreasing plastic disposal and with reuse for sustainable development and application of diatom in biofuel production which could find applications in environmental and industrial sectors.

Data-Theoretical Synthesis of the Early Developmental Process.

Biological development is often described as a dynamic, emergent process. This is evident across a variety of phenomena, from the temporal organization of cell types in the embryo to compounding trends that affect large-scale differentiation. To better understand this, we propose combining quantitative investigations of biological development with theory-building techniques. This provides an alternative to the gene-centric view of development: namely, the view that developmental genes and their expression determine the complexity of the developmental phenotype. Using the model system Caenorhabditis elegans, we examine time-dependent properties of the embryonic phenotype and utilize the unique life-history properties to demonstrate how these emergent properties can be linked together by data analysis and theory-building. We also focus on embryogenetic differentiation processes, and how terminally-differentiated cells contribute to structure and function of the adult phenotype. Examining embryogenetic dynamics from 200 to 400 min post-fertilization provides basic quantitative information on developmental tempo and process. To summarize, theory construction techniques are summarized and proposed as a way to rigorously interpret our data. Our proposed approach to a formal data representation that can provide critical links across life-history, anatomy and function.

Environmental neurotoxicants and inflammasome activation in Parkinson's disease - A focus on the gut-brain axis.

Inflammasomes are multi-protein complexes expressed in immune cells that function as intracellular sensors of environmental, metabolic and cellular stress. Inflammasome activation in the brain, has been shown to drive neuropathology and disease progression by multiple mechanisms, making it one of the most attractive therapeutic targets for disease modification in Parkinson's Disease (PD). Extensive inflammasome activation is evident in the brains of people with PD at the sites of dopaminergic degeneration and synuclein aggregation. While substantial progress has been made on validating inflammasome activation as a therapeutic target for PD, the mechanisms by which inflammasome activation is triggered and sustained over the disease course remain poorly understood. A growing body of evidence point to environmental and occupational chemical exposures as possible triggers of inflammasome activation in PD. The involvement of the gastrointestinal system and gut microbiota in PD pathophysiology is beginning to be elucidated, especially the profound link between gut dysbiosis and immune activation. While large cohort studies confirmed specific changes in the gut microbiota in PD patients compared to age-matched healthy controls, recent research suggest that synuclein pathology could be initiated in the gastrointestinal tract. In this review, we present a summarized perspective on current understanding on inflammasome activation and the gut-brain-axis link during PD pathophysiology. We discuss multiple environmental toxicants that are implicated as the etiological agents in causing idiopathic PD and their mechanistic underpinnings during neuroinflammatory events. We additionally present future directions that needs to address the research questions related to the gut-microbiome-brain mechanisms in PD.