Epigenetic Trajectories of Aging and Reprogramming

The epigenetic landscape is remodeled with age, bringing about widespread consequences for cell function. With the revolutionary discoveries by Yamanaka and Takahashi, as well as those that built on this work, the transcription factors Oct4, Sox2, KLF4, and C-Myc (OSKM) can be expressed in a variety of cells, including fibroblasts, to make iPSCs. Once cells are reprogrammed, they show an erasure of epigenetic remodeling, suggesting an avenue to reverse aging. It has been recently shown that ectopic expression of three factors, OSK, can restore vision in mouse glaucoma model and reduces epigenetic age. It is not known the path epigenetic remodeling takes or whether all three factors, OSK, are required to remodel the epigenetic landscape. We hypothesize that during reprogramming, cells will reverse along a similar path they took during aging and eventually reverse along that path they took during differentiation. Alternatively, it may also be possible that cells take entirely new paths to reach a state of partial reprogramming or pluripotency. We used DNA methylation and RNA-seq as a multi-omics approach to map the trajectories cells make during aging, differentiation, and reprogramming. In human fibroblasts and hepatocytes, we tested the three-factor OSK mix, as well as pairwise factors OS, OK, and SK and individual Oct4, Sox2, and KLF4 for their effect on cell trajectories. This study provides a dynamic model for epigenetic changes in aging, differentiation, and reprogramming and highlights barriers and bottlenecks throughout the process.

Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases

The sugars streptose and dihydrohydroxystreptose (DHHS) are unique to the bacteria Streptomyces griseus and Coxiella burnetii respectively. Streptose forms the central moiety of the antibiotic streptomycin, whilst DHHS is found in the O-antigen of the zoonotic pathogen C. burnetii. Biosynthesis of these sugars has been proposed to follow a similar path to that of TDP-rhamnose, catalysed by the enzymes RmlA/RmlB/RmlC/RmlD. Streptose and DHHS biosynthesis unusually require a ring contraction step that might be performed by the orthologues of RmlC or RmlD. Genome sequencing of S. griseus and C. burnetii proposed the StrM and CBU1838 proteins respectively as RmlC orthologues. Here, we demonstrate through both coupled and direct observation studies that both enzymes can perform the RmlC 3'',5'' double epimerisation activity; and that this activity supports TDP-rhamnose biosynthesis in vivo. We demonstrate that proton exchange is faster at the 3'' position than the 5'' position, in contrast to a previously studied orthologue. We solved the crystal structures of CBU1838 and StrM in complex with TDP and show that they form an active site highly similar to previously characterised enzymes. These results further support the hypothesis that streptose and DHHS are biosynthesised using the TDP pathway and are consistent with the ring contraction step being performed on a double epimerised substrate, most likely by the RmlD paralogue. This work will support the determination of the full pathways for streptose and DHHS biosynthesis.

The Role of Religious Experiences and Religious Institutions: Comparing Peter L. Berger’s and Hans Joas’ Approach to Religion

Hans Joas (born 1948) has repeatedly criticized Peter L. Berger (1929–2017) for placing religious experiences in the cognitive realm, where it runs the risk of being “contaminated” by secularization and pluralism. Instead, Joas has proposed to locate religious experiences in the “deeper layers” of the human person, where it is protected against mere cognitive reductionism and against contamination by secularization and pluralism. Despite his critique, Joas follows a similar path of Berger, as he explains the phenomenon of religion from an inductive point of view that originates in the experiential realm. This article demonstrates how Joas’ approach operates on a similar methodology like the one of Berger and ultimately results in similar theoretical conclusions despite their differing theoretical foundations. Moreover, this article illuminates an implicit methodological similarity between Joas and Berger that, on the one hand, differs from one of the taken-for-granted methodologies in the discipline of sociology (of religion), and, on the other hand, strongly influences the disposition of religious institutions in their definition of religion.

WESTERNIZATION, ASIANIZATION AND AFRICANIZATION THE WORLD BETWEEN 1500 AND 2100

Until 1800, China and India were the dominant powers of the world, when they are overtaken by the powers of Western Europe, and after 1900 they will be overtaken by the USA, then by Russia and Japan. Now it is time for the Chinese continent to re-assert itself, and after 2050 India will have a similar path and after the end of the demographic explosion in Africa predicted towards the end of the 21st century, it will also become one of the world's rulers, thus proving that the West is only a tab in the history of the movement of wealth on Earth.

New Town, New Townspeople: Transforming Gatchina in the 1790s

On 11 November 1796, only five days after the death of Catherine II, her son and successor Paul released a decree naming two of his villages, Pavlovsk and Gatchina, towns. In an odd way, given their fraught relationship, this act echoed his mother’s past practice. She founded several hundred new towns to serve as new administrative centers for her newly formed provinces. Paul’s actions are more obscure, tied not to administrative needs but perhaps instead to a desire to glorify his own landholdings—or if not to glorify at least to increase the economic prosperity of his lands. The end results, however, followed a similar path: new towns needed new courts and new schools, new town seals and new town plans, and above all new townspeople. This article examine the process by which Gatchina, the village, was transformed into Gatchina, the town. In particular, it will focus on the establishment there of new merchant and meshchanin corporations, and of a town ratusha to oversee their management. Many of the new town’s new townspeople came from elsewhere to register there; as a result, they not only built up the town in numbers but also created a Russian space within what was an imperial periphery. This transformation shows both an effort at social organization and engineering and also the limits of those efforts when faced with individual desires.

Exporting Spanishness: The Role of Netflix in Shaping How the World Imagines Spain

The worldwide leader in streaming television, Netflix exercises significant influence over what viewers watch through algorithms and the shaping of communities based on a set of culturally determined preferences, or ‘taste communities’. Furthermore, its reputation for producing noteworthy and boundary-pushing original television content creates the expectation that Netflix will follow a similar path in Spain, where viewers represent diverse backgrounds. This essay argues that as a company based in the US creating original shows for broadcast to a global audience, Netflix sidesteps many of the thorny issues surrounding contemporary Spanish national identity and the country’s multicultural ‘ethnoscape’ to focus on genres and storylines that have proved successful on the platform. In this way, the streaming company offers locally produced content that appeals to existing global taste communities. Their made-in-Spain original dramas - Las chicas del cable, La casa de papel and Élite - present common themes such as socio-economic inequality, social mobility and female friendship, and settings that resonate with a local audience while remaining accessible and relevant globally. In this way, Netflix influences how Spain is portrayed to a global audience while maintaining a local presence.

Pandemics and the role of culture

Pandemics creep up on us slowly, and without our suspecting, while we are distracted. Likewise, human experience shows that they recede gradually and without our noticing. For those in the eye of its storm—those that experience their devastating impact firsthand without the hope of an end in sight—they touch and shape their daily lives and their societies, in big and small ways. History shows, that across millennia, pandemics throw a harsh light on existing cleavages in societies and shortcomings in their organization; fuel deliberation, agitation, and the search for new ideas; and accelerate or bring about change. There is no reason to believe the effect of the pandemic that is presently affecting every continent will not follow a similar path.