Natural Milieu Research Articles

COMÉRCIO E MEIO GEOGRÁFICO

Trade has always been a traditional topic of study in geography, present in different approaches. In this work, commerce is interpreted from the perspective of technique, approaching the technical phenomenon geographically, that is, through the geographical milieu and its manifestations. This article aims to propose an interpretation of trade through geography from the category of geographical milieu. Based on Milton Santos' proposal for the periodization of geographical space, we relate the natural milieu and exchanges, the technical milieu and traditional commerce, reaching the current period with the emergence of the technical-scientific-informational milieu and its corresponding form of commerce, the e-commerce. Keywords: geographical space; technical-scientific-informational milieu; e-commerce.

Spatio-temporal interplay between ecosystem services and urbanization in the Yangtze River Economic Belt: A new perspective for considering the scarcity effect

The expeditious trajectory of urbanization has profound ramifications on the configuration and functioning of the natural milieu. Given the constrained opulence of natural capital and its indispensable bestowal of ecosystem services in different regions, meticulous contemplation of the relationship between urbanization and the ecosystem service scarcity value (ESSV) while formulating decisions is imperative. This study focuses on the Yangtze River Economic Belt (YREB), where ESSV is quantified by combining the dynamic changes in market supply and demand factors. The influence of supply and demand changes on the ESSV is discussed and analyzed in four scenarios. Subsequently, a multidimensional urbanization comprehensive evaluation index system was established to explore the spatiotemporal interactive response mode between ESSV and urbanization. Our findings manifest a notably augmented ESSV in the YREB from 1990 to 2020, particularly prominent between 2000 and 2010. Moreover, the growth in public goods services outpaced that in private goods services within the same period. Demand-driven scarcity has emerged as the foremost determinant of ESSV. Urbanization levels gradually increased from 1990 to 2020, with a uniform allocation of heightened ESSV and urbanization throughout the region. The urbanization level of YREB, as a whole, exhibited conspicuous spatial heterogeneity, with the downstream region significantly surpassing the middle and upper reaches, and the downstream Yangtze River Delta city cluster and the middle reaches of the Chengdu-Chongqing city cluster notably outpacing that in the surrounding region. The coupling coordination degree (CCD) between the ESSV and urbanization in the YREB develops in a harmonious direction during the study period, accompanied by palpable spatial disparities. The area of unbalanced development gradually decreased, and the area proportion of the coordinated development type of ESSV and urbanization increased continuously. Overall, this study elucidates regional disparities in the reciprocal relationship between the ESSV and urbanization in the YREB, thereby unveiling the extent of incongruity between regional urbanization and the ecosystem. It serves to identify the juncture at which ecological sustainability and urbanization converge harmoniously, thus offering novel insights in achieving comprehensive, high-caliber, and synchronized development in the YREB.

Andai-Andai Folk Tale: A Tool to Promote Eco-Social Values among Children in Kedurang Community

Folk tales serve as a conduit for imparting knowledge concerning the natural environment and social mores to children. The 'Andai-Andai' folk tales within the context of Kedurang assumes a pivotal role in instilling ecological and societal principles in the succeeding generation. This study seeks to investigate the prevalence of the 'Andai-Andai' folk tales and its efficacy in instilling social acumen among students in Kedurang, Bengkulu. The research corpus comprises 'Andai-Andai' folk tales titled "The Clever Orphan," "The Promise of the Buffalo," and "The Buffalo and Beteri." The findings reveal a scarcity in the transmission of 'Andai-Andai' folk tales to the younger demographic. The 'Andai-Andai' folk tales epitomize commendable ecological and social values instilled in children from an early age. The monarch depicted in the 'Andai-Andai' folk tales emerges as a figure characterized by elevated social empathy, fostering community welfare and exemplifying effective leadership. Similarly, the character of Beteri embodies compassion towards others, serving as an exemplar of virtue and beauty. Furthermore, the orphan's portrayal depicts filial devotion towards his grandmother alongside devout religious observance. Additionally, the 'Andai-Andai' folk tales encapsulate the natural milieu of Kedurang, as evidenced by references to elements such as rice fields, buffalo, forests, villages, and rivers. The study findings underscore the significance of preserving 'Andai-Andai' folk tales and highlight community ardor towards this endeavor, recognizing these stories as repositories of environmental knowledge and moral values indispensable for posterity.

The Briquetage of the Seille proto-industrial salt extraction during the European Iron Age

A pluri-disciplinary research project, devoted to the study of the « Briquetage de la Seille », a huge complex of salt production sites dating to the Iron Age and located in Lorraine, has been carried out from 2001 to 2017. Extensive geophysical surveys have revealed the internal structure of the workshops, which cover up to several tens of hectares. Archaeo-environmental studies have provided evidence of a strong impact of such a « proto-industrial » activity on the natural milieu. The field survey has revealed substantial evidence of Iron Age funerary features in the immediate vicinity of the salt production workshops. Analysis of the individuals present within these cemeteries indicates they most likely represent the social groups which controlled the salt-producing community.

Pro-Environmental Transformation of Cultural Institutions through Sustainable Infrastructural Projects: A Case Study of Poznan

The aim of the article is to elucidate pro-environmental solutions and activities, consonant with the tenets of sustainability and enduring developmental paradigms, implemented within the infrastructural purview of the cultural institutions situated in Poznan—a municipality located in western Poland. A diagnostic scrutiny was executed encompassing the entirety of municipal cultural entities, constituting a cumulative assemblage of 15 establishments, all of which were extended invitations to participate in this investigation. Interrogations were directed towards ascertaining their strategic, environmentally conscientious determinations vis à vis the construction, renovation, or modernization of edifices during the temporal expanse of 2021 and 2022. Ultimately, responses germane to the posed inquiries were proffered by 7 institutions, as the remaining entities refrained from financial investments during the stipulated timeframe. The discerned outcomes illuminate the manifold pro-environmental measures and endeavors embraced by these institutions within the domain of infrastructural initiatives. These initiatives pertain to ecological considerations, safeguarding the natural milieu, and fortifying sustainability, encompassing facets such as energy and water conservation, the abatement of water and air contaminants, recycling endeavors, the utilization of renewable materials, the afforestation of vicinities, and the mitigation of the ostensibly designated “heat island effect”, among sundry others. These initiatives are not only significant for the current ecological situation worldwide, but they also appear to be crucial for the better future of the next generations.

Exploring a Solvent Dependent Strategy to Control Self-Assembling Behavior and Cellular Interaction in Laminin-Mimetic Short Peptide based Supramolecular Hydrogels.

Self-assembled hydrogels, fabricated through diverse non-covalent interactions, have been extensively studied in regenerative medicines. Inspired from bioactive functional motifs of ECM protein, short peptide sequences have shown remarkable abilities to replicate the intrinsic features of the natural extracellular milieu. In this direction, we have fabricated two short hydrophobic bioactive sequences derived from the laminin protein i. e., IKVAV and YIGSR. Based on the substantial hydrophobicity of these peptides, we selected a co-solvent approach as a suitable gelation technique that included different concentrations of DMSO as an organic phase along with an aqueous solution containing 0.1 % TFA. These hydrophobic laminin-based bioactive peptides with limited solubility in aqueous physiological environment showed significantly enhanced solubility with higher DMSO content in water. The enhanced solubility resulted in extensive intermolecular interactions that led to the formation of hydrogels with a higher-order entangled network along with improved mechanical properties. Interestingly, by simply modulating DMSO content, highly tunable gels were accessed in the same gelator domain that displayed differential physicochemical properties. Further, the cellular studies substantiated the potential of these laminin-derived hydrogels in enhancing cell-matrix interactions, thereby reinforcing their applications in tissue engineering.

DNP-assisted solid-state NMR enables detection of proteins at nanomolar concentrations in fully protonated cellular milieu.

With the sensitivity enhancements conferred by dynamic nuclear polarization (DNP), magic angle spinning (MAS) solid state NMR spectroscopy experiments can attain the necessary sensitivity to detect very low concentrations of proteins. This potentially enables structural investigations of proteins at their endogenous levels in their biological contexts where their native stoichiometries with potential interactors is maintained. Yet, even with DNP, experiments are still sensitivity limited. Moreover, when an isotopically-enriched target protein is present at physiological levels, which typically range from low micromolar to nanomolar concentrations, the isotope content from the natural abundance isotopes in the cellular milieu can outnumber the isotope content of the target protein. Using isotopically enriched yeast prion protein, Sup35NM, diluted into natural abundance yeast lysates, we optimized sample composition. We found that modest cryoprotectant concentrations and fully protonated environments support efficient DNP. We experimentally validated theoretical calculations of the limit of specificity for an isotopically enriched protein in natural abundance cellular milieu. We establish that, using pulse sequences that are selective for adjacent NMR-active nuclei, proteins can be specifically detected in cellular milieu at concentrations in the hundreds of nanomolar. Finally, we find that maintaining native stoichiometries of the protein of interest to the components of the cellular environment may be important for proteins that make specific interactions with cellular constituents.

Where sports performance meets reproductive rights: hormonal contraception

Rational To discuss the use of hormonal contraception (HC) in elite women’s competitive sports from an anti-doping perspective because 1) it changes the natural female hormonal milieu; 2) is used to manipulate the menstrual cycle with performance enhancement intent; 3) even though lowering endogenous testosterone levels, some HCs contain testosterone-like androgenic compounds with potential performance-enhancing effects. Results A complex interaction between rapidly advancing sports-relevant biomedical scientific discoveries, societal changes concerning sex and gender, and a zero-tolerance anti-doping ideology, leads to contentious results, jeopardizing the premises defining and protecting contemporary elite sport in general and that of women in particular. Discussion and conclusions This is in part because of the two out of three criteria for inclusion on the World Anti-Doping Agency’s List of forbidden substances and methods: i) actual or potential for performance enhancement, ii) actual or potential for health risk, and iii) counter to the Spirit of Sport concept. These criteria would suffice for the inclusion of HC on the List, especially in their androgenic form. The fact that they are not is good for women’s reproductive rights but also illustrates the arbitrariness of the administration of WADA’s Prohibited List of substances and methods in elite sports.

Tooth-derived stem cells integrated biomaterials for bone and dental tissue engineering.

Recent years have seen the emergence of tissue engineering strategies as a means to overcome some of the limits of conventional medical treatment. A biomaterial with tailored physio-chemical characteristics is used in this sophisticated method to transport stem cells and growth factors/bioactive substances, or to attract local endogenous cells, enabling new tissue formation. Biomaterials might serve as a biomimetic structure inspired by the natural milieu, assisting the cells in establishing their natural relationships. Such a method would benefit from having ready access to an abundant reservoir of stem cells with strong tissue regeneration capacity, in addition to using biological compatible material to promote new tissue creation. Teeth may have a plethora of self-renewing, multipotent mesenchymal stem cell (MSC) populations. Recent advancements and promising directions for cell transplantation and homing techniques using dental MSCs for tissue regeneration are discussed in this review paper. Overall, this research paints a picture of the present landscape of new approaches to using tooth-derived MSCs in conjunction with biomaterials and bioactive substances for tissue regeneration.

Nanoarchitectonic approaches for measuring the catalytic behavior of a membrane anchored enzyme. From Langmuir-Blodgett to a novel Langmuir-Schaefer based nanofilm building device

Self-organized lipid monolayers at the air-water interface (Langmuir films, LF) are commonly used for measuring the catalytic properties of membrane-bound enzymes. This methodology allows to provide a consistent flat topography molecular density, packing defects and thickness. The aim of the present work was to show the methodological advantages of using the horizontal transfer method (Langmuir-Schaefer) with respect to the vertical transfer method (Langmuir-Blodgett) when mounting a device to measure catalytic activity of membrane enzymes. Based on the results obtained we can conclude that it is possible to prepare stable Langmuir-Blodgett (LB) and Langmuir-Schaefer (LS) films from Bovine Erythrocyte Membranes (BEM) preserving the catalytic activity of its native Acetylcholinesterase (BEA). In comparison, the LS films showed Vmax values more similar to the enzyme present in the vesicles of natural membranes. In addition, it was much easier to produce large amounts of transferred areas with the horizontal transfer methodology. It was possible to decrease the time required to mount an assay with numerous activity points, such as building activity curves as a function of substrate concentration. The present results show that LSBEM provides a proof of concept for the development of biosensors based on transferred purified membrane for the screening of new products acting on an enzyme embedded on its natural milieu. In the case of BEA, the application of these enzymatic sensors could have medical interest, providing drug screening tools for the treatment of Alzheimer's disease.

Improving Whole Tomato Transformation for Prostate Health: Benign Prostate Hypertrophy as an Exploratory Model.

It is well-established that the beneficial properties of single phytonutrients can be better attained when they are taken with the complex of the molecules present in their natural milieu. Tomato, the fruit providing the most comprehensive complex of prostate-health-preserving micronutrients, has been shown to be superior to its single-nutrient counterparts in decreasing the incidence of age-related prostate diseases. Herein, we describe a novel tomato food supplement enriched with olive polyphenols, containing cis-lycopene concentrations far exceeding those present in industry-produced tomato commodities. The supplement, endowed with antioxidant activity comparable to that of N-acetylcysteine, significantly reduced, in experimental animals, the blood levels of prostate-cancer-promoting cytokines. In prospective, randomized, double-blinded, placebo-controlled studies performed on patients affected by benign prostatic hyperplasia, its uptake significantly improved urinary symptoms and quality of life. Therefore, this supplement can complement and, in some cases, be an alternative to current benign prostatic hyperplasia management. Furthermore, the product suppressed carcinogenesis in the TRAMP mouse model of human prostate cancer and interfered with prostate cancer molecular signaling. Thus, it may offer a step forward in exploring the potential of tomato consumption to delay or prevent the onset of age-related prostate diseases in high-risk individuals.

Impact of the natural hormonal milieu on ventral striatal responses to appetitive cigarette smoking cues: A prospective longitudinal study

BackgroundThe female sex hormones estradiol (E) and progesterone (P) galvanize the ventral striatal reward pathway. E elevates ventral striatal dopamine and accelerates drug-cued reinstatement, while P has opposing ‘protective’ effects on drug-related behavior. We hypothesize that women may exhibit greater ventral striatal responses to smoking cues (SCs) during the late follicular phase of the menstrual cycle (MC) when E is high and unimpeded by P, and reduced responses during the late luteal phase when P is high. MethodsTo test our hypothesis, 24 naturally cycling cigarette-dependent women completed functional magnetic resonance (fMRI) sessions over the course of 3 MCs at select time points to reflect the early follicular (low E and P; LEP, control condition), late follicular (high E, low P; HE) and mid-luteal (high E, high P; HEP) MC phases. During fMRI sessions (counterbalanced by phase), women were exposed to a SC versus nonSC audio-visual clip. Ovulation was verified for each MC, and hormone levels were acquired prior to sessions. ResultsContrasts within conditions showed that ventral striatal brain responses to SCs versus nonSCs were negligible during LEP and greater during HE (p=0.009) and HP (p=0.016). Contrasts across conditions showed that HE and HEP had greater responses than LEP (p=0.005), and HE had greater responses than HEP (p=0.049). ConclusionsResults support and extend our retrospective cross-sectional study of the influence of the hormonal milieu on SC reactivity. Results are clinically relevant as they may guide novel, hormonally-informed and immediately translatable treatment strategies that can potentially reduce relapse in naturally cycling women.

Sacred Forests, Modes of Transmission of Cultural Knowledge and Security Geopolitics of Monarchs and Dignitaries Among the Bamiléké of West Cameroon

Many authors have written on problematic of natural environment in Bantu’s lands in general and in Bamiléké people in particular. In fact, those “sacred” environments represent for the population in this area, a base of spiritual and cultural life because of a relation existing between natural milieu and divine. Place of highest spiritual connotation, sacred forests are presented in this paper in various forms in accordance with attributes its takes. However, this paper present in a socio historical point of view, the conditions in which natural milieu favoring transmission of knowledge and power to monarchs of Bamilékés kingdoms in western Cameroun.

Anthropogenic impact on the shores and the bottom of the Jebriyan bay in the Northwestern part of the Black Sea


 
 
 
 The Jebriyan Bay is located in the northern part of the Kiliya Danube Delta, at a junction of the delta cone and the indigenous coast. This is a zone of very high anthropogenic impact on the Danube Biosphere Reserve. The two opposite shores of this bay are fundamentally different. Along the northern shore, the Northwest coastal sand sediment flows discharge from the Cape of the Great Fontanne to the Jebriyan Bay. That is why the northern coast of the bay is made up of sandy forms of coastal topography (marine accumulative terrace and spit). The southern coast is deltaic; composed of a mixture of muddy, siltstone and sandy sediments. The area of the bay is limited to isobaths –11 m and is about 80 km2. The bottom of the bay has a gentle relief, made up of smooth outlines, with an average depth of 6.2 m. The shape of the transverse profile of the underwater slope is mostly convex. The natural system of the bay was affected by fishing, recreation, shipping and industrial sand production on coastal accumulative landforms. Coastal fishing uses a system of fixed bottom seines and small motorized floating equipment. Recreational facilities are designed to serve about 350 thousand people during the warm period each year. The impact of shipping was expressed in the construction and operation of the seaport of Ust-Dunaysk, together with suitable canal and the technical canal between the sea and the branch of the delta breakthrough the system of the large Ochakov branch. The ladle port had an area of about 1.5 km2, a maximal depth of 16 m, and an average depth of 13.7 m. The trough was connected to the Ochakov branch of the Danube Delta by a technical canal with a depth of 4 m. Vessels could enter the harbor of Ust-Danube through an access navigation channel with a depth of 11–12 m and a bottom width of 125 m. The port was used for the transshipment of large containers, general forest cargo from ocean vessels (displacement of 60–100 thousand tons) on regular sea lines from the countries of Southeast Asia to the Black Sea, to the Danube and further to the countries of Central Europe and to the ports of the North and the Baltic Seas. But it was unfortunate that the port construction site did not last as expected. Between 1980–2010 the harbor and approach canal of Ust-Dunaysk were filled with Danube river sediments. The example of Jebriyan Bay has shown that when executing any type of sustainable nature management project, it is very important to take into account the natural milieu.
 
 
 

In silico trials to design potent inhibitors against matrilysin (MMP-7)

The study deals with structure-based rational drug design against the chief zinc-rely endopeptidase called matrilysin (MMP-7) that is involved in inflammatory and metastasis process of several carcinomas. Hyperactivated matrilysin of human was targeted, because of its hydrolytic actions on extracellular matrix (ECM) protein components constitutes fibrillar collagens, gelatins, fibronectins and it also activates zymogen forms of vital matrix metalloproteinases (gelatinase A-MMP-2 and B-MMP-9) responsible for ECM destruction in many cancers. In the present work, e-pharmacophores were generated for the respective five co-crystal structures of human matrilysin by mapping ligand’s pharmacophoric features. During the lead-optimization campaign, the five e-pharmacophores-based shape screening against an in-house library of >21 million compounds created a dataset of 5000 structural analogs. The subsequent three different docking strategies, including rigid-receptor docking, quantum-polarized-ligand docking, induced-fit docking and free energy binding calculations resulted four leads as novel and potent MMP-7 binders. These four leads were observed with good pharmacological features and good receiver operating characteristics curve metrics (ROC: 0.93) in post-docking evaluations against five existing co-crystal inhibitors and 1000 decoy molecules with MMP-7. Moreover, stability and dynamics behavior of matrilysin-lead1 complex and matrilysin-cocrystal ligand (TQJ) complex were analyzed in natural physiological milieu of 1000 ns or 1 µs molecular dynamics simulations. Lead1-MMP-7 complex was found with an average Cα root-mean-square deviation (RMSD) of 2.35 Å, average ligand root-mean-square fluctuations (RMSF) of 0.66 Å and the strong metallic interactions with E220, a key residue for proteolytic action thereby hinders ECM proteolysis that in turn can halt metastatic cancerous condition. Communicated by Ramaswamy H. Sarma

Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform

Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell carcinoma (ccRCC) and is a confounding factor for therapy selection. Most approaches to evaluate ITH are limited by two-dimensional ex vivo tissue analyses. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can noninvasively assess the spatial landscape of entire tumors in their natural milieu. To assess the potential of DCE-MRI, we developed a vertically integrated radiogenomics colocalization approach for multi-region tissue acquisition and analyses. We investigated the potential of spatial imaging features to predict molecular subtypes using histopathologic and transcriptome correlatives. We report the results of a prospective study of 49 patients with ccRCC who underwent DCE-MRI prior to nephrectomy. Surgical specimens were sectioned to match the MRI acquisition plane. RNA sequencing data from multi-region tumor sampling (80 samples) were correlated with percent enhancement on DCE-MRI in spatially colocalized regions of the tumor. Independently, we evaluated clinical applicability of our findings in 19 patients with metastatic RCC (39 metastases) treated with first-line antiangiogenic drugs or checkpoint inhibitors. DCE-MRI identified tumor features associated with angiogenesis and inflammation, which differed within and across tumors, and likely contribute to the efficacy of antiangiogenic drugs and immunotherapies. Our vertically integrated analyses show that angiogenesis and inflammation frequently coexist and spatially anti-correlate in the same tumor. Furthermore, MRI contrast enhancement identifies phenotypes with better response to antiangiogenic therapy among patients with metastatic RCC. These findings have important implications for decision models based on biopsy samples and highlight the potential of more comprehensive imaging-based approaches.

‘What are people for?’: Ecologists and the Articulation of the Built Environment

This article revisits previously overlooked exchanges between pre-eminent figures in British architecture and ecology, William Holford, Julian Huxley, and Max Nicholson, which were incorporated in one of the earliest uses of the term ‘built environment’ in 1964. By examining how an energy-entropy interpretation of the ecosystem had shaped their views on the natural, human-made, and psychosocial milieu, I will consider the way cybernetics conditioned the articulation of the built environment. Contextualising their exchanges in the socio-cultural climate of the early 1960s, I trace an almost concurrent environmental turn made by architecture and ecology. Moreover, the exchange between architecture and ecology has engendered an environmental conception that prioritised the transformative and reciprocal relationship between humans and what surrounds them. In this effort, I pay particular attention to a co-evolutionary view of the technosphere, biosphere, and political sphere formulated by Nicholson. I also discuss the infiltration of eugenic and technocratic views in this reconceptualisation of the environment. Despite the peculiarities of these theories, their conceptualisation of the environment had pointed towards an important question in employing the ecosystemic metaphor: what are people for?

The Cultural Constituents of the urban environment; the impact on the patterns and nature behavior (University space as a model)

Human's relationship with the environment is strong and mutually beneficial, with thedevelopment of this relationship, a person develops and increases his awareness. The urban environment isa natural, physical, social and cultural milieu that a human lives in it, and get from him the life Constituents.As well as it is a product of human interaction with it, so the urban environment represents what has animpact on human behavior. It effects on human physiology and psychology then represented the relationshipconceptually, socially, and physically. the Cultural Constituents of the urban environment plays a criticaland essential role in user behavior, because they are part of the project they must be included in making thedesign decision as well as in treatment of urban spaces. on the other side, the comprehensive behavioralstudies are still few in this field, especially those studies that are based on ecological behavioral trend andthrough observing of behavior in the urban environment .The current study seeks to draw out a theoreticalmodel for developing ecological behavior measures, to evaluate the role of Cultural Constituents indetermining patterns and nature of human behavior through the experimental approach. Through theprevious literature has been identified the main research problem is represented ) There is a lack ofknowledge in the distribution of behavioral patterns in urban environments that have a high aestheticquality, also there are few objective measures that can be used as an indicator to evaluate the aestheticquality of the urban environment before its development and presenting urban designs in urban space andspecial organization (.According to the research problem, the goals and hypothesis of the research weredetermined, and an inductive experimental approach was defined theoretical and practical axes, also theresearch samples were identified (ten urban spaces in University of Babylon) were observing during (2018-2019),furthermore survey questionnaire sent to the experts In architecture, urban design and psychologyfield .Finally, the results were analyzed and the research found that aesthetic quality plays an important andmajor role in determining patterns and nature of behavior.

ETMM-08 METABOLIC REGULATION OF THE EPIGENOME DRIVES LETHAL INFANTILE EPENDYMOMA

Ependymomas are malignant glial tumours that occur throughout the central nervous system. Of the nine distinct molecular subgroups of ependymoma, Posterior Fossa A (PFA), is the most prevalent, occurring in the hindbrain of infants and young children. Lacking highly recurrent somatic mutations, PFAs are thought to be a largely epigenetically driven entity, defined by hypomethylation at the histone 3 lysine 27 residue. Previous transcriptional analysis of PFAs revealed an enrichment of hypoxia signaling genes. Thus, we hypothesized that hypoxic signaling, in combination with a unique metabolic milieu, drive PFA oncogenesis through epigenetic regulation. In this study, we identified that PFA cells control the availability of specific metabolites under hypoxic conditions, resulting in diminished H3K27 trimethylation and increased H3K27 acetylation in vitro and in vivo. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. Furthermore, perturbation of key metabolic pathways is sufficient to inhibit growth of PFA primary cultures in vitro. PFA cells sequester s-adenosylmethionine while upregulating EZHIP, a polycomb repressive complex 2 (PRC2) inhibitor, resulting in decreased H3K27 trimethylation. Furthermore, hypoxia fine-tunes the abundance of alpha-ketoglutarate and acetyl-CoA to fuel demethylase and acetyltransferase activity. Paradoxically, a genome-wide CRISPR knockout screen identified the core components of PRC2 as uniquely essential in PFAs. Our findings suggest that PFAs thrive in a narrow “Goldilocks” zone, whereby they must maintain a unique epigenome and deviation to increased or decreased H3K27 trimethylation results in diminished cellular fitness. Previously, we showed that PFAs have a putative cell of origin arising in the first trimester of development. Using single-cell RNAseq and metabolomics, we demonstrate that PFAs resemble the natural metabolic-hypoxic milieu of normal development. Therefore, targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

Influence of the natural hormonal milieu on brain and behavior in women who smoke cigarettes: Rationale and methodology

Women experience more severe health consequences from smoking, have greater difficulty quitting, and respond less favorably to nicotine replacement therapy than men. The influence of fluctuating ovarian hormones, specifically estradiol (E) and progesterone (P), on brain and behavioral responses during exposure to smoking reminders (i.e., cues) may be a contributing factor. Results from our laboratory suggest that women in the late follicular phase of their menstrual cycle (MC) have enhanced smoking cue (SC) vulnerabilities and reduced functional connectivity in neurocircuitry underlying cognitive control, potentially placing them at greater risk for continued smoking and relapse. The primary aim of this study is to examine and link hormonal status with brain and behavioral responses to SCs over the course of three monthly MCs in naturally cycling women who are chronic cigarette smokers. This longitudinal, counterbalanced study collects brain and behavioral responses to SCs at three time points during a woman's MC. Participants complete psychological and physical examinations, biochemical hormonal verification visits, and at least three laboratory/neuroimaging scan visits. The scan visits include a 10-min SC task during blood oxygen level-dependent (BOLD) data acquisition and are timed to occur during the early follicular phase (low E and P), late follicular phase (high E, unopposed by P), and mid-luteal phase (high P, high E). The primary outcomes include brain responses to SCs (compared to non-SCs), subjective craving, E and P hormone levels, and behavioral responses to SCs. This study addresses a critical gap in our knowledge: namely, the impact of the natural hormonal milieu on brain and behavioral responses to SCs, a powerful relapse trigger. Additionally, this study will provide a roadmap for human sex differences researchers who are obliged to consider the often confounding cyclic hormonal fluctuations of women.