Functional compartmentalization of Rad9 and Hus1 reveals diverse assembly of the 9-1-1 complex components during the DNA damage response in Leishmania

The Rad9-Rad1-Hus1 (9-1-1) complex is a key component in the coordination of DNA damage sensing, cell cycle progression and DNA repair pathways in eukaryotic cells. This PCNA-related trimer is loaded onto RPA-coated single stranded DNA and interacts with ATR kinase to mediate effective checkpoint signaling to halt the cell cycle and to promote DNA repair. Beyond these core activities, mounting evidence suggests that a broader range of functions can be provided by 9-1-1 structural diversification. The protozoan parasite Leishmania is an early-branching eukaryote with a remarkably plastic genome, which hints at peculiar genome maintenance mechanisms. Here, we investigated the existence of homologs of the 9-1-1 complex subunits in L. major and found that LmRad9 and LmRad1 associate with chromatin in response to replication stress and form a complex in vivo with LmHus1. Similar to LmHus1, LmRad9 participates in telomere homeostasis and in the response to both replication stress and double strand breaks. However, LmRad9 and LmHus1-deficient cells present markedly opposite phenotypes, which suggest their functional compartmentalization. We show that some of the cellular pool of LmRad9 forms an alternative complex and that some of LmHus1 exists as a monomer. We propose that the diverse assembly of the Leishmania 9-1-1 subunits mediates functional compartmentalization, which has a direct impact on the response to genotoxic stress

Towards a formalism for mapping the spacetimes of massive compact objects: Bumpy black holes and their orbits

Observations have established that extremely compact, massive objects are common in the universe. It is generally accepted that these objects are black holes. As observations improve, it becomes possible to test this hypothesis in ever greater detail. In particular, it is or will be possible to measure the properties of orbits deep in the strong field of a black hole candidate (using x-ray timing or with gravitational-waves) and to test whether they have the characteristics of black hole orbits in general relativity. Such measurements can be used to map the spacetime of a massive compact object, testing whether the object's multipoles satisfy the strict constraints of the black hole hypothesis. Such a test requires that we compare against objects with the ``wrong'' multipole structure. In this paper, we present tools for constructing bumpy black holes: objects that are almost black holes, but that have some multipoles with the wrong value. The spacetimes which we present are good deep into the strong field of the object -- we do not use a large r expansion, except to make contact with weak field intuition. Also, our spacetimes reduce to the black hole spacetimes of general relativity when the ``bumpiness'' is set to zero. We propose bumpy black holes as the foundation for a null experiment: if black hole candidates are the black holes of general relativity, their bumpiness should be zero. By comparing orbits in a bumpy spacetime with those of an astrophysical source, observations should be able to test this hypothesis, stringently testing whether they are the black holes of general relativity. (Abridged)Comment: 16 pages + 2 appendices + 3 figures. Submitted to PR

African League Against Rheumatism (AFLAR) preliminary recommendations on the management of rheumatic diseases during the COVID-19 pandemic

Objectives To develop recommendations for the management of rheumatic and musculoskeletal diseases (RMDs) during the COVID-19 pandemic. Method A task force comprising of 25 rheumatologists from the 5 regions of the continent was formed and operated through a hub-and-spoke model with a central working committee (CWC) and 4 subgroups. The subgroups championed separate scopes of the clinical questions and formulated preliminary statements of recommendations which were processed centrally in the CWC. The CWC and each subgroup met by several virtual meetings, and two rounds of voting were conducted on the drafted statements of recommendations. Votes were online-delivered and recommendations were pruned down according to predefined criteria. Each statement was rated between 1 and 9 with 1–3, 4–6 and 7–9 representing disagreement, uncertainty and agreement, respectively. The levels of agreement on the statements were stratified as low, moderate or high according to the spread of votes. A statement was retired if it had a mean vote below 7 or a ‘low’ level of agreement. Results A total of 126 initial statements of recommendations were drafted, and these were reduced to 22 after the two rounds of voting. Conclusions The preliminary statements of recommendations will serve to guide the clinical practice of rheumatology across Africa amidst the changing practices and uncertainties in the current era of COVID-19. It is recognized that further updates to the recommendations will be needed as more evidence emerges

Genetic diversity and connectivity of southern right whales (Eubalaena australis) found in the Brazil and Chile-Peru wintering grounds and the South Georgia (Islas Georgias del Sur) feeding ground

As species recover from exploitation, continued assessments of connectivity and population structure are warranted to provide information for conservation and management. This is particularly true in species with high dispersal capacity, such as migratory whales, where patterns of connectivity could change rapidly. Here we build on a previous long-term, large-scale collaboration on southern right whales (Eubalaena australis) to combine new (nnew) and published (npub) mitochondrial (mtDNA) and microsatellite genetic data from all major wintering grounds and, uniquely, the South Georgia (Islas Georgias del Sur: SG) feeding grounds. Specifically, we include data from Argentina (npub mtDNA/microsatellite=208/46), Brazil (nnew mtDNA/microsatellite=50/50), South Africa (nnew mtDNA/microsatellite=66/77, npub mtDNA/microsatellite=350/47), Chile-Peru (nnew mtDNA/microsatellite=1/1), the Indo-Pacific (npub mtDNA/microsatellite=769/126), and SG (npub mtDNA/microsatellite=8/0, nnew mtDNA/microsatellite=3/11) to investigate the position of previously unstudied habitats in the migratory network: Brazil, SG and Chile-Peru. These new genetic data show connectivity between Brazil and Argentina, exemplified by weak genetic differentiation and the movement of one genetically identified individual between the South American grounds. The single sample from Chile-Peru had a mtDNA haplotype previously only observed in the Indo-Pacific and had a nuclear genotype that appeared admixed between the Indo-Pacific and South Atlantic, based on genetic clustering and assignment algorithms. The SG samples were clearly South Atlantic, and were more similar to the South American than the South African wintering grounds. This study highlights how international collaborations are critical to provide context for emerging or recovering regions, like the SG feeding ground, as well as those that remain critically endangered, such as Chile-Peru

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH