Human Biome Research Articles

Elucidating the Molecular Basis of 14-3-3 Interaction with α-Synuclein: Insights from Molecular Dynamics Simulations and the Design of a Novel Protein-Protein Interaction Inhibitor.

Parkinson's disease is a widespread age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the midbrain along with the appearance of protein aggregates, termed as "Lewy bodies" in the surviving neuronal cells. The components of Lewy bodies include proteins such as α-synuclein, 14-3-3, Parkin, and LRRK2, along with other cellular organelles, which, in their native state, perform a plethora of vital biological functions within the human biome. Formation of these aggregates renders these components inactive, thereby interfering with homeostasis. In this regard, the current study attempts to investigate the complexation behavior of all human-based 14-3-3 isoforms with α-synuclein via a combination of classical and enhanced sampling techniques and thereby determine the causality of these protein-protein interactions. The study indicated that upon complexation, the aggregation propensity of both 14-3-3 and α-synuclein increases, and this increment is propelled by the interfacial residues on either protein. Furthermore, mutagenesis studies revealed that Lys214 of 14-3-3 (henceforth termed K214A) is crucial for the formation of this binary complex. Principal component analysis combined with clustering studies unveiled the stability of these complexes in terms of their conformational distribution across the entire MD trajectory. For K214A, these clustered states were sparsely located, thereby making the transitions between them slightly difficult. Dynamic cross-correlation maps (DCCM) revealed the role of residues in the range 80-130 of 14-3-3 having a potential allosteric role in driving this complexation process. Finally, a novel peptide-based supramolecular inhibitor was designed, which exhibited higher proficiency in limiting the 14-3-3/α-synuclein interaction compared to the previous inhibitor model. It was also revealed that the presence of this inhibitor induces structural rigidity in α-synuclein, making changes in its conformations extremely difficult, as observed through Umbrella Sampling studies. Based on available information, the current study provides an insight into the molecular-level understanding of protein-protein interactions underlying Parkinson's disease and adds on to the methods of devising novel therapeutic approaches to treat the same.

Jaguar conservation in the American continent: the role of protected landscape and human-impacted biomes

Introduction: Worldwide, expanding human activities continue to be a threat to many large-bodied species, including jaguars. As these activities continue, it is critical to understand how home range sizes will be impacted by human-modified landscapes. Objective: To evaluate the importance of protected and unprotected land on home-range size across their range. Methods: We used home range data from 117 jaguars in several habitat protection categories and human biome types. We used a Generalized Linear Mixed Model to test home range and spatial overlap with conservation categories and human biomes. Results: Most home-ranges were in Jaguar Conservation Units (62 %), followed by Protected Areas (21 %), Indigenous People's Lands (10 %) and Jaguar Movement Corridors (3 %), where 76 % of the jaguars lived inside one the first three conservation types. However, outside of conserved land, Rangeland, Cropland, Seminatural land and other human biomes were also important (24 % of the individuals). Jaguars in Rangeland, Cropland and Seminatural land had the largest home ranges. Conclusions: Although conservation land was dominant, human-impacted lands appear to play a considerable role in satisfying the spatial requirements of jaguars.

Phages in the Gut Ecosystem.

Phages, short for bacteriophages, are viruses that specifically infect bacteria and are the most abundant biological entities on earth found in every explored environment, from the deep sea to the Sahara Desert. Phages are abundant within the human biome and are gaining increasing recognition as potential modulators of the gut ecosystem. For example, they have been connected to gastrointestinal diseases and the treatment efficacy of Fecal Microbiota Transplant. The ability of phages to modulate the human gut microbiome has been attributed to the predation of bacteria or the promotion of bacterial survival by the transfer of genes that enhance bacterial fitness upon infection. In addition, phages have been shown to interact with the human immune system with variable outcomes. Despite the increasing evidence supporting the importance of phages in the gut ecosystem, the extent of their influence on the shape of the gut ecosystem is yet to be fully understood. Here, we discuss evidence for phage modulation of the gut microbiome, postulating that phages are pivotal contributors to the gut ecosystem dynamics. We therefore propose novel research questions to further elucidate the role(s) that they have within the human ecosystem and its impact on our health and well-being.

Transient Contingencies: Body as Ecology

This paper proposes an understanding of the human body as a plural object. Drawing on the ideas of Bennet, Merleau–Ponty, and Wilson, it envisions the body as a complex ecology in which the human biome, the billions of microbial communities that symbiotically live within our bodies, act as a dynamic system of flows and feedbacks within its environments. This body's spatial experiences are not fixed and static, but continuous, fluid, and permeable, in search of novel experiences and homeostasis. By re–imagining what it means to occupy space, we can re–experience our lives as intimately interwoven with the natural world, catalyzing new biophilia, as our body–ecology seeks contentment with “interiors” outside of itself, at home in a dynamic planetary biosphere.

Unravelling the consequences of the bacteriophages in human samples

Bacteriophages are abundant in human biomes and therefore in human clinical samples. Although this is usually not considered, they might interfere with the recovery of bacterial pathogens at two levels: 1) by propagating in the enrichment cultures used to isolate the infectious agent, causing the lysis of the bacterial host and 2) by the detection of bacterial genes inside the phage capsids that mislead the presence of the bacterial pathogen. To unravel these interferences, human samples (n = 271) were analyzed and infectious phages were observed in 11% of blood culture, 28% of serum, 45% of ascitic fluid, 14% of cerebrospinal fluid and 23% of urine samples. The genetic content of phage particles from a pool of urine and ascitic fluid samples corresponded to bacteriophages infecting different bacterial genera. In addition, many bacterial genes packaged in the phage capsids, including antibiotic resistance genes and 16S rRNA genes, were detected in the viromes. Phage interference can be minimized applying a simple procedure that reduced the content of phages up to 3 logs while maintaining the bacterial load. This method reduced the detection of phage genes avoiding the interference with molecular detection of bacteria and reduced the phage propagation in the cultures, enhancing the recovery of bacteria up to 6 logs.

Integrated Pathways of Candida albicans Revealing Potential Targets and Key Factors Accountable for Pathogenicity

Candida albicans is one of the most opportunistic commensal fungus of human biome found normally in gastrointestinal cavity of healthy humans. Its dimorphic character provides the easy switching of yeast to filamentous form. However, in immunocompromised patients, blood-stream infections often cause death, despite the use of anti-fungal therapies. Its dimorphic and highly adaptive properties make it even more pathogenic in nature. The hyphal growth causes virulence in Candida. There are many different pathways or factors responsible for the same in Candida albicans. It is thus paramount to see the relationship between the pathways and the key factors of pathogenicity. The common factors can be used to inhibit more than a single pathway at the same time. In the present work, systems biology approach has been employed to summarize all the pathways and common factors leading to yeast to hyphal transition in Candida. The study provides new and potential targets essential for antifungal drug discovery which is highly required against drug resistance.

Evaluation of Glyphosate Ecotoxicity and Biodegradability in the Municipal Wastewaters

Glyphosate (G) is a broad-spectrum systemic organophosphate herbicide being widely used to control weeds in agricultural fields and urban areas. Its safety for both human health and aquatic biomes is a subject of wide debate. This study was aimed at evaluating the removal efficiency and ecotoxicity of G based herbicide (GBH) Klinik® (Nufarm, Austria) added to the raw municipal wastewater (WW) in a lab-scale model column system. The effect of oxide ceramics as a filtering medium (treatment „B”), as well as activated sludge and nutrients (treatment „C”) was compared with the control columns, which contained only WW (treatment „A”). After 72h treatment of WW spiked with 100 mg/L G, the lowest G concentration was detected in the treatment „B”, i.e., 79.4±0.6 mg/L. Treatments „A” and „C” resulted in the remaining G concentrations of 83.3±3.8 and 89.6±3.7 mg/l, respectively. The second addition of 100 mg/L G to the columns followed by 72h incubation also showed the advantage of oxide ceramics. Most probably, this effect could be explained by coupled sorption and biodegradation processes. Experiments were accompanied by microbiological (colony forming units; biological oxygen demand) and ecotoxicological (Daphtoxkit F magna, MicroBioTests) testing. The results indicated that WW-derived microorganisms resist the presence of GBH in the tested concentration range of G, i.e., up to 300 mg/L. As for Daphnia magna, the 24-h EC50 for the GBH Klinik® under standard conditions and in raw WW was found to be 22 mg/L and 6 mg/L G, respectively.

Identification, isolation, and cloning of the full-length sequence of a gene encoding trypsin inhibitor-like protein (TIL) secreted by the intestinal parasitic nematode Strongyloides ratti

BackgroundIntestinal nematodes may interact with the intestinal mucosal host cells through molecules they produced actively in the host environment. Many excretory/secretory products (ESP) of the intestinal nematodes are considered as interesting candidates to be examined in vitro on their tolerance-inducing activities. Nematode-derived protease inhibitors are believed to have multiple, specific abilities for the host immunomodulation, playing on various immune effector mechanisms. Among the previously identified 500 ESP from Strongyloides ratti, trypsin inhibitor-like (Sra-TIL) peptides were detected in high concentration in the ESP of the parasitic female (pF). The aim is to identify interesting tolerance-inducing proteins belonging to the longtime adapted human biome which may be potentially applied to moderate inflammatory immune reactions.ResultsIn the present study, the full-length cDNA (from the parasitic female) and gDNA of the ~ 1605 bp Sra-til is identified and isolated by polymerase chain reaction (PCR), subsequent to cluster/EST analysis via alignment and BLAST search. gDNA and RNA were extracted from infective third stage larvae (iL3) and pF respectively, and the cDNA was synthesized.Then, the Sra-til was cloned and sequenced. The genomic organization analysis revealed that introns were absent in the Sra-til gene structure. Sequence analyses of both nucleotide and predicted protein sequences were investigated using different bioinformatic tools. The predicted architecture of the translated amino acid sequence showed the presence of a signal peptide for secretion. The architecture of Sra-TIL was Sra-TIL = TIL, EGF (epidermal growth factor) × 6). Phylogenetic analysis of the deduced amino acid sequence showed how related this novel Strongyloides protein to TIL orthologs from other nematodes.ConclusionThe full-length Sra-til gene which encodes an interesting ESP candidate, secreted from pF, was identified, isolated, cloned, and then sequenced. Both nucleotide and amino acid sequences were analyzed by various bioinformatic tools. The predicted innovative structural advantages of Sra-TIL polypeptides secreted from a parasitic intestinal stage of S. ratti nematode is probably reflective of the abundance of different biological functions, including the protection against host proteases, host immunomodulation via proliferation induction of the damaged intestinal cells as well as wound healing properties.

Attenuation of Pathogenicity in Candida albicans by Application of Polyphenols

Candida albicans is one of the most pathogenic and opportunistic class of fungi. Its emergence disturbs the human biome and can create serious damage in immunocompromised conditions. Hyphal growth and biofilm formation are mainly the core factors leading to progression of pathogenicity in C. albicans. The drug resistance towards azoles has created a demand of new novel pharmacologically active compounds. Although there are several pathways and factors known for causing pathogenicity there is none single connected pathway known for the whole mechanism such as SAP5, N-myrstyltransferase, Erg11 and Efg1 proteins. In the present study we have focussed on all the pathways and sorted major factors contributing in more than one pathways. The plant based polyphenols that have been studied here are non-toxic and more efficient as compared to the marketed azoles. These selected polyphenols were found to be capable of causing cell death of C. albicans up to 20% and inhibiting hyphal growth up to 90% as compared to Fluconazole. Biologically the polyphenols have been found to be more active on glyoxylate pathway.

Restraining Pathogenicity in Candida albicans by Taxifolin as an Inhibitor of Ras1-pka Pathway.

Candida albicans is one of the most virulent and opportunistic fungal strains. In the present scenario, majority metabolic imbalances and unsuccessful treatments of some severe diseases including cancer, diabetes, HIV, psoriasis are because of invasive Candida emergence. Being a beneficial integral part of human biome, its elimination is not possible. The major pathogenicity characteristics in Candida involve hyphal growth, biofilm formation, HSP90 down regulation and genetic modifications. Ras1-pka pathway initiated by HSP90 down regulation is important for hyphal growth and has been focused in the present study. The principle transcriptional factors that induce hyphal growth causing invasiveness and virulence through this pathway have been identified as Tec1 and Rfg1. In the present study, taxifolin, a naturally occurring polyphenol, has been identified as inhibitor for both the transcriptional factors in parallel.

Comorbidity: Reconsidering the Unit of Analysis.

In this short essay, I wish to briefly discuss smoking, polypharmacy, the human biome and multispecies relations, and biomedicalization as a means of stretching the common ways we think about comorbidity. My intent is to expand our thinking about comorbidity and multimorbidity beyond the individual as a unit of analysis, to reframe comorbidity in relation to trajectories of risk, and to address comorbid states of our own making when the treatment of one health problem results in the experience of additional health problems. I do so as a corrective to what I see as an overly narrow focus on comorbidity as co-occurring illnesses within a single individual, and as a complement to critical medical anthropological assessments of synergistic comorbid conditions (syndemics) occurring in structurally vulnerable populations living in environments of risk exposed to macro and micro pathogenic agents.

Policy and regulations in light of the human body as a ‘superorganism’ containing multiple, intertwined symbiotic relationships

AbstractThe human body is now understood to exist as an ecosystem that includes an abundance of life, called the human biome. For purposes of understanding and treating disease, the biome of the human ‘superorganism’ can be divided into three parts: human, microbial, and more complex organisms such as worms and protists. This paper examines medical progress with biome restorative practices, including fecal microbiota transplants and helminthic therapy, which have proven in some cases more effective and more economical at treating a wide range of diseases than pharmaceutical-based approaches. The regulatory and policy hurdles responsible in part for this limited use of these restorative practices are examined. More importantly, new approaches are encouraged which might reverse the general lack of interest for these restorative practices seen in the medical and biomedical research communities. Such approaches include the regulation of benign helminths as dietary supplements and the establishment of an Insti...

Food safety and the hygiene misnomer.

From a food safety perspective, effective standards of hygiene and cleanliness throughout the food chain are understood to be key factors in reducing the incidence of foodborne disease. Therefore, it is difficult to postulate that we could ever be too clean from the point of view of controlling microbiological hazards in foods. Whist interactions within the human biome are highly complex and many pathways remain to be understood, it is important that views that we might be ‘too clean’ are not allowed to overrule application of food hygiene practices either in the food industry or in the home.

Biomes and human distribution during the last ice age

AbstractAimOur research attempts to provide an explicit explanation of human–biome interactions during the last glacial period and how these have influenced current human population genetics at the global scale. Publications to date have not addressed this topic.LocationWorld‐wide.MethodsUsing climate, terrain, hydrographic, fossil pollen and plant‐macrofossil data we developed a model of the distribution of biomes during climate deteriorations of the last glacial period. Subsequently, we analysed current human genetic diversity, the origins of genetic lineages and Palaeolithic human sites in relation to the inferred biomes.ResultsOur analyses indicated that: (1) current human Y‐DNA diversity, the places of origin of human Y‐DNA lineages and the distribution of Palaeolithic human settlements are best explained by distance from savanna and dry woodland during a series of glacial maxima, and (2) during periods of relatively benign climate conditions, humans dispersed through areas of high primary productivity while avoiding dense forest cover.Main conclusionsIn a metapopulation of Palaeolithic humans, the biome of savanna and dry woodland supported source populations and other biomes acted as sinks. Present‐day genetic, phenotypical and linguistic differences are largely related to discontinuity of and impeded migration between human source populations during glacial periods, rather than simply geographical distance, and in the post‐glacial period there has not been enough time for displacements and admixture of human populations to completely blur these differences.

Microbial metagenomics in the Baltic Sea: Recent advancements and prospects for environmental monitoring.

Metagenomics refers to the analysis of DNA from a whole community. Metagenomic sequencing of environmental DNA has greatly improved our knowledge of the identity and function of microorganisms in aquatic, terrestrial, and human biomes. Although open oceans have been the primary focus of studies on aquatic microbes, coastal and brackish ecosystems are now being surveyed. Here, we review so far published studies on microbes in the Baltic Sea, one of the world’s largest brackish water bodies, using high throughput sequencing of environmental DNA and RNA. Collectively the data illustrate that Baltic Sea microbes are unique and highly diverse, and well adapted to this brackish-water ecosystem, findings that represent a novel base-line knowledge necessary for monitoring purposes and a sustainable management. More specifically, the data relate to environmental drivers for microbial community composition and function, assessments of the microbial biodiversity, adaptations and role of microbes in the nitrogen cycle, and microbial genome assembly from metagenomic sequences. With these discoveries as background, prospects of using metagenomics for Baltic Sea environmental monitoring are discussed.

A model for the induction of autism in the ecosystem of the human body: the anatomy of a modern pandemic?

BackgroundThe field of autism research is currently divided based on a fundamental question regarding the nature of autism: Some are convinced that autism is a pandemic of modern culture, with environmental factors at the roots. Others are convinced that the disease is not pandemic in nature, but rather that it has been with humanity for millennia, with its biological and neurological underpinnings just now being understood.ObjectiveIn this review, two lines of reasoning are examined which suggest that autism is indeed a pandemic of modern culture. First, given the widely appreciated derailment of immune function by modern culture, evidence that autism is strongly associated with aberrant immune function is examined. Second, evidence is reviewed indicating that autism is associated with ‘triggers’ that are, for the most part, a construct of modern culture. In light of this reasoning, current epidemiological evidence regarding the incidence of autism, including the role of changing awareness and diagnostic criteria, is examined. Finally, the potential role of the microbial flora (the microbiome) in the pathogenesis of autism is discussed, with the view that the microbial flora is a subset of the life associated with the human body, and that the entire human biome, including both the microbial flora and the fauna, has been radically destabilized by modern culture.ConclusionsIt is suggested that the unequivocal way to resolve the debate regarding the pandemic nature of autism is to perform an experiment: monitor the prevalence of autism after normalizing immune function in a Western population using readily available approaches that address the well-known factors underlying the immune dysfunction in that population.

Biome depletion in conjunction with evolutionary mismatches could play a role in the etiology of neurofibromatosis 1

Neurofibromatosis 1 (NF1) arises de novo in a striking 30–50% of cases, pointing toward an environmental etiology, though none has been clearly identified. The Biome Depletion Theory posits that the absence of mutualistic and commensal organisms within the human body coupled with modern lifestyle alterations may have profoundly deleterious effects, inclusive of immunologic derangement that is thought to result in allergy, atopy, and numerous autoimmune diseases. Biome depletion has been implicated as a factor in the etiology of both multiple sclerosis and autism spectrum disorders; biome reconstitution, i.e. replenishment of the biome with certain keynote species, is being used in the treatment of these and other autoimmune states. Neurofibromatosis 1 has been associated with allergy, various autoimmune states, multiple sclerosis, and autism. Recent research has posited that NF1, multiple sclerosis and autism may all arise from disturbances in the neural crest during gestation. This paper hypothesizes that there is indirect evidence that a highly inflammatory uterine state may precipitate epigenetic changes in vulnerable NF-related genes in the course of fetal development. The etiology of NF1 may lie in the absence of immunomodulation by commensal and mutualistic species once ubiquitously present in the environment, as well as through adoption of a modern lifestyle that contributes to chronic inflammation. Replenishment of helminths and other missing organisms to the human biome prior to conception as well as addressing nutritional status, psychological stress, and environmental exposures may prevent the development of NF1. ©Donna L. Beales.

Individualist Biocentrism vs. Holism Revisited

While holist views such as ecocentrism have considerable intuitive appeal, arguing for the moral considerability of ecological wholes such as ecosystems has turned out to be a very difficult task. In the environmental ethics literature, individualist biocentrists have persuasively argued that individual organisms—but not ecological wholes—are properly regarded as having a good of their own . In this paper, I revisit those arguments and contend that they are fatally flawed. The paper proceeds in five parts. First, I consider some problems brought about by climate change for environmental conservation strategies and argue that these problems give us good pragmatic reasons to want a better account of the welfare of ecological wholes. Second, I describe the theoretical assumptions from normative ethics that form the background of the arguments against holism. Third, I review the arguments given by individualist biocentrists in favour of individualism over holism. Fourth, I review recent work in the philosophy of biology on the units of selection problem, work in medicine on the human biome, and work in evolutionary biology on epigenetics and endogenous viral elements. I show how these developments undermine both the individualist arguments described above as well as the distinction between individuals and wholes as it has been understood by individualists. Finally, I consider five possible theoretical responses to these problems.

Decreased Breastfeeding as One Factor on a Short List That Causes Pandemics of Allergic and Autoimmune Disease

Postindustrial society is plagued with pandemics of noninfectious, immune related illnesses. These diseases, which include allergic, autoimmune, and neuroinflammatory diseases, are not found in preindustrial societies, and are apparently caused by a limited number of environmental factors. These factors, essentially incompatible with human genetics, are each associated with a wide range of immune diseases. The most influential of these factors is a loss of diversity from the ecosystem of the human body, a condition termed "biome depletion." This state affects all postindustrial humans during and after fetal development, and remains the strongest challenge for modern medicine to overcome in the field of immunology. Fortunately, progress is being made. On the other hand, other factors associated with pandemics of allergic and autoimmune disease are within the control of each individual rather than the medical establishment. These factors include unrequited or chronic psychological stress, vitamin D deficiency, and substitution of breast milk with infant formula. Decreased breastfeeding in particular has a profound effect on immunity, probably through multiple mechanisms that involve increased stress levels, alterations of the human biome, and direct modulation of the immune system by mechanisms that remain largely uncharacterized. Given the synergism of these factors that adversely affect immunity in postindustrial culture, the importance of avoiding as many of these factors as possible is emphasized.

Herpesviruses and the microbiome

The focus of this article will be to examine the role of common herpesviruses as a component of the microbiome of atopic patients and to review clinical observations suggesting that atopic patients might be predisposed to more severe and atypical herpes-related illness because their immune response is biased toward a TH2 cytokine profile. Human populations are infected with 8 herpesviruses, including herpes simplex virus HSV1 and HSV2 (also termed HHV1 and HHV2), varicella zoster virus (VZV or HHV3), EBV (HHV4), cytomegalovirus (HHV5), HHV6, HHV7, and Kaposi sarcoma-associated herpesvirus (termed KSV or HHV8). Herpesviruses are highly adapted to lifelong infection of their human hosts and thus can be considered a component of the human "microbiome" in addition to their role in illness triggered by primary infection. HSV1 and HSV2 infection and reactivation can present with more severe cutaneous symptoms termed eczema herpeticum in the atopic population, similar to the more severe eczema vaccinatum, and drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) is associated with reactivation of HSV6 and possibly other herpesviruses in both atopic and nonatopic patients. In this review evidence is reviewed that primary infection with herpesviruses may have an atypical presentation in the atopic patient and conversely that childhood infection might alter the atopic phenotype. Reactivation of latent herpesviruses can directly alter host cytokine profiles through viral expression of cytokine-like proteins, such as IL-10 (EBV) or IL-6 (cytomegalovirus and HHV8), viral encoded and secreted siRNA and microRNAs, and modulation of expression of host transcription pathways, such as nuclear factor κB. Physicians caring for allergic and atopic populations should be aware of common and uncommon presentations of herpes-related disease in atopic patients to provide accurate diagnosis and avoid unnecessary laboratory testing or incorrect diagnosis of other conditions, such as drug allergy or autoimmune disease. Antiviral therapy and vaccines should be administered promptly when indicated clinically.