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Design files for molds for microfluidic modules (used for fabrication of two-layer polydimethylsiloxane (PDMS) devices). LabVIEW scripts for operating microfluidic devices for automated cell culture under dynamically changing media compositions., JT was supported by a Grant from the Swiss National Science Foundation (Marie-Heim Voegtlin Fellowship, PMPDP3_171383). This work was also supported by the European Research Council under the European Union's Horizon 2020 research and innovation program Grant 723106 (to SJM), a Swiss National Science Foundation NRP (National Research Program) 78 Covid-19 Grant 198412 (to SJM).

Summary Cell populations can be strikingly heterogeneous, composed of multiple cellular states, each exhibiting stochastic noise in its gene expression. A major challenge is to disentangle these two types of variability and to understand the dynamic processes and mechanisms that control them. Embryonic stem cells (ESCs) provide an ideal model system to address this issue because they exhibit heterogeneous and dynamic expression of functionally important regulatory factors. We analyzed gene expression in individual ESCs using single-molecule RNA-FISH and quantitative time-lapse movies. These data discriminated stochastic switching between two coherent (correlated) gene expression states and burst-like transcriptional noise. We further showed that the “2i” signaling pathway inhibitors modulate both types of variation. Finally, we found that DNA methylation plays a key role in maintaining these metastable states. Together, these results show how ESC gene expression states and dynamics arise from a combination of intrinsic noise, coherent cellular states, and epigenetic regulation., Graphical Abstract, Highlights • smFISH in ESCs reveals two transcriptional states and highly stochastic expression • Live-cell expression dynamics reveal the in situ transition rates between states • DNA methylation regulates state-switching dynamics • “2i” signaling inhibitors impact both gene expression noise and state transitions, Using single-molecule RNA-FISH and quantitative time-lapse movies, Singer et al. discriminate two primary sources of gene expression heterogeneity in embryonic stem cells: random switching between correlated gene expression states and burst-like transcriptional noise. Perturbing specific signaling pathways modulates both processes, and DNA methylation is key to maintaining these states.

High-throughput combinatorial RNAi demonstrates that many duplicated genes in C. elegans can retain redundant functions for more than 80 million years, Background Systematic analyses of loss-of-function phenotypes have been carried out for most genes in Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster. Although such studies vastly expand our knowledge of single gene function, they do not address redundancy in genetic networks. Developing tools for the systematic mapping of genetic interactions is thus a key step in exploring the relationship between genotype and phenotype. Results We established conditions for RNA interference (RNAi) in C. elegans to target multiple genes simultaneously in a high-throughput setting. Using this approach, we can detect the great majority of previously known synthetic genetic interactions. We used this assay to examine the redundancy of duplicated genes in the genome of C. elegans that correspond to single orthologs in S. cerevisiae or D. melanogaster and identified 16 pairs of duplicated genes that have redundant functions. Remarkably, 14 of these redundant gene pairs were duplicated before the divergence of C. elegans and C. briggsae 80-110 million years ago, suggesting that there has been selective pressure to maintain the overlap in function between some gene duplicates. Conclusion We established a high throughput method for examining genetic interactions using combinatorial RNAi in C. elegans. Using this technique, we demonstrated that many duplicated genes can retain redundant functions for more than 80 million years of evolution. This provides strong support for evolutionary models that predict that genetic redundancy between duplicated genes can be actively maintained by natural selection and is not just a transient side effect of recent gene duplication events.

Mutations in lin-35, the worm ortholog of a mammalian tumor suppressor gene, and other synMuv B genes result in an increased sensitivity to RNAi and enhanced somatic transgene silencing., Background Genome-wide RNA interference (RNAi) screening is a very powerful tool for analyzing gene function in vivo in Caenorhabditis elegans. The effectiveness of RNAi varies from gene to gene, however, and neuronally expressed genes are largely refractive to RNAi in wild-type worms. Results We found that C. elegans strains carrying mutations in lin-35, the worm ortholog of the tumor suppressor gene p105Rb, or a subset of the genetically related synMuv B family of chromatin-modifying genes, show increased strength and penetrance for many germline, embryonic, and post-embryonic RNAi phenotypes, including neuronal RNAi phenotypes. Mutations in these same genes also enhance somatic transgene silencing via an RNAi-dependent mechanism. Two genes, mes-4 and zfp-1, are required both for the vulval lineage defects resulting from mutations in synMuv B genes and for RNAi, suggesting a common mechanism for the function of synMuv B genes in vulval development and in regulating RNAi. Enhanced RNAi in the germline of lin-35 worms suggests that misexpression of germline genes in somatic cells cannot alone account for the enhanced RNAi observed in this strain. Conclusion A worm strain with a null mutation in lin-35 is more sensitive to RNAi than any other previously described single mutant strain, and so will prove very useful for future genome-wide RNAi screens, particularly for identifying genes with neuronal functions. As lin-35 is the worm ortholog of the mammalian tumor suppressor gene p105Rb, misregulation of RNAi may be important during human oncogenesis.

A report on the joint Keystone Symposia on Systems and Biology and Proteomics and Bioinformatics, Keystone, USA, 8-13 April 2005.

China’s medical assistance to Africa has attracted relatively little attention from scholars compared to other forms of assistance such as economic and political. “A Historical Study of China’s Medical Assistance in Post-Colonial Tanzania” examines the implications of Chinese assistance in the development of Tanzania’s health sector under the discourse of South-South cooperation. Through the use of archival and other documentary sources collected in Tanzania, China, and Switzerland, as well as oral histories, this study explores how China’s medical assistance reflected the Southern agenda of promoting self-reliance and lessening the dominance of Northern countries in medical aid and knowledge in the South. It illuminates social, economic, and political contexts that gave birth to China’s medical assistance in Tanzania. The study shows that, after the Arusha Declaration of 1967, the Tanzanian government adopted Chinese health policies such as free health care, the institutionalisation of traditional medicine, and rural health care. It argues that the adoption of Chinese health policies contested the conceptions of the production and transmission of knowledge from the North “core” to the South “periphery”. Consequently, the practices of Chinese health policies in Tanzania signal the realisation of knowledge production and exchange from the periphery to the periphery. Indeed, as the study shows, the independent Tanzanian government aspired to become self-dependent. Such endeavours grew in the mid-1960s, following its diplomatic rifts with traditional donors of the North. Under idealistic motives of Southern solidarity, it perceived Chinese aid as a bridge to self-reliance, and indeed, this was the “vision” of the Chinese government as is evident in its foreign aid principles. In the same vein, the Chinese-funded health projects, such as the medical team program, were expected to build the capacity of Tanzania’s health sector through medical knowledge production and exchanges with local medical workers. The Chinese-sponsored pharmaceutical industries were planned to maintain the local production of pharmaceuticals and ensure imports, while traditional Chinese medicine research and treatment projects were expected to boost medical knowledge among local researchers and practitioners. Nevertheless, this study argues that China’s medical assistance to post-colonial Tanzania was hampered by several drawbacks, which affected its efficiency and sustainability, hence failed to realise the country’s anticipated self-reliance. Contrary to the government’s expectations, the assistance created unforeseen dependences on Chinese medical doctors, pharmaceutical raw materials, traditional Chinese medicine, and pharmaceutical technicians sent from China. Findings of this study show that most of the medical projects declined in the absence of Chinese assistance. Such circumstances warrant the conclusion that despite the merits of China’s aid, especially in counteracting the dominance of medical aid and knowledge from the North, its assistance hardly functioned as a sustainable solution to health challenges that faced the Tanzanian government. Admittedly, the medical assistance functioned as a soft way of securing allies during the Cold War era and a vital tool in maintaining China’s political and economic interests.

The tropical Small Island Developing States (SIDS) typically contribute little to global climate change, yet they are among the countries most vulnerable to sea level rises, variations in temperature, fluctuations in rainfall, and extreme weather events. With high population density and limited natural resources, they are also susceptible to the challenges of sustainable natural resource management. The Republic of Mauritius is one of four SIDS in the Indian Ocean, and one of six SIDS that are also members of the African Union. In 2008 the Mauritian government launched a programme called Maurice Ile Durable (MID, or Sustainable Mauritius) with the intention of turning Mauritius into a world and SIDS model of sustainable development. This chapter deploys MID as a lens through which to examine debates about environment and development in Mauritius. MID’s remit included environment, employment, education, and equity, but its main priority was energy efficiency. This chapter contrasts the narrow focus of Mauritian government actors firstly with the critiques of environmentalists – who called for greater emphasis on the preservation of biodiversity and mitigation of climate change – and secondly with the interpretations of marginalised urban citizens, many of whom came to see MID in particularly – and consequently the concept of sustainable development in general – in terms of energy efficiency and economic development rather than (also) environmental sustainability. It suggests that MID could have been more effective if environmental sustainability had been foregrounded, and more inclusive if economic development had been more equitably distributed.

[This corrects the article DOI: 10.1016/j.crmeth.2022.100244.]., (© 2022 The Author(s).)