Members of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in human cancer, but how they suppress tumorigenesis is currently unclear. Here, we use Drosophila neuroblasts to demonstrate that the SWI/SNF component Osa (ARID1) prevents tumorigenesis by ensuring correct lineage progression in stem cell lineages. We show that Osa induces a transcriptional program in the transit-amplifying population that initiates temporal patterning, limits self-renewal, and prevents dedifferentiation. We identify the Prdm protein Hamlet as a key component of this program. Hamlet is directly induced by Osa and regulates the progression of progenitors through distinct transcriptional states to limit the number of transit-amplifying divisions. Our data provide a mechanistic explanation for the widespread tumor suppressor activity of SWI/SNF. Because the Hamlet homologs Evi1 and Prdm16 are frequently mutated in cancer, this mechanism could well be conserved in human stem cell lineages. PAPERCLIP:

Background: India first detected SARS-CoV-2, causal agent of COVID-19 in late January 2020, imported from Wuhan, China. From March 2020 onwards, the importation of cases from countries in the rest of the world followed by seeding of local transmission triggered further outbreaks in India. Methods: We used ARTIC protocol-based tiling amplicon sequencing of SARS-CoV-2 (n=104) from different states of India using a combination of MinION and MinIT sequencing from Oxford Nanopore Technology to understand how introduction and local transmission occurred. Results: The analyses revealed multiple introductions of SARS-CoV-2 genomes, including the A2a cluster from Europe and the USA, A3 cluster from Middle East and A4 cluster (haplotype redefined) from Southeast Asia (Indonesia, Thailand and Malaysia) and Central Asia (Kyrgyzstan). The local transmission and persistence of genomes A4, A2a and A3 was also observed in the studied locations. The most prevalent genomes with patterns of variance (confined in a cluster) remain unclassified, and are here proposed as A4-clade based on its divergence within the A cluster. Conclusions: The viral haplotypes may link their persistence to geo-climatic conditions and host response. Multipronged strategies including molecular surveillance based on real-time viral genomic data is of paramount importance for a timely management of the pandemic.

The gene for Parkin, an E3 ubiquitin ligase, is mutated in some familial forms of Parkinson's disease, a severe neurodegenerative disorder. A homozygous mutant of the Drosophila ortholog of human parkin is viable but results in severe motoric impairment including an inability to fly, female and male sterility, and a decreased life span. We show here that a double mutant of the genes for Parkin and the metal-responsive transcription factor 1 (MTF-1) is not viable. MTF-1, which is conserved from insects to mammals, is a key regulator of heavy metal homeostasis and detoxification and plays additional roles in other stress conditions, notably oxidative stress. In contrast to the synthetic lethality of the double mutant, elevated expression of MTF-1 dramatically ameliorates the parkin mutant phenotype, as evidenced by a prolonged life span, motoric improvement including short flight episodes, and female fertility. At the cellular level, muscle and mitochondrial structures are substantially improved. A beneficial effect is also seen with a transgene encoding human MTF-1. We propose that Parkin and MTF-1 provide complementary functions in metal homeostasis, oxidative stress and other cellular stress responses. Our findings also raise the possibility that MTF-1 gene polymorphisms in humans could affect the severity of Parkinson's disease.Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disorder and the most common age-related movement disorder (10,13,43,59). Many molecular aspects of PD pathogenesis still need to be clarified. Extensive studies point to oxidative stress as a major contributor to the disease (28). Besides the gene for Parkin, an E3 ubiquitin ligase, four other genes, PINK1, DJ1, UCHL1, and ␣-synuclein, have been implicated in rare, early-onset, familial forms of PD, whereas LRRK2 is predominantly responsible for late-onset PD (20,57,70). Much effort has gone into the development of animal models of PD, including models in the fly Drosophila melanogaster. In the studies presented here, we use a strain in which the ortholog of the human parkin gene has been disrupted by the insertion of a P-element transposon into the coding region (24,48).In mammals, the proteins PINK1 and Parkin cooperate to ensure proper quality control of mitochondria, and Parkin is particularly important for autophagy of faulty mitochondria (reviewed in references 8 and 73). In agreement with this notion, Parkin deficient flies suffer from mitochondrial malfunction (24, 45, 48), which distorts muscle structure and causes severe locomotor defects and an inability to fly (24, 48). Furthermore, both male and female parkin-null Drosophila mutants are sterile (52), exhibit an increased sensitivity to multiple stresses (including oxidative stress), and have a reduced life span (23, 48).Maintenance of metal homeostasis is an essential requirement for the proper functioning of all organisms. An adequate supply of essential trace metals, such as copper and zinc, is important, whereas an excess can be highly t...

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