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Background Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA and/or DNA damage-response inhibitor (DDRi) therapies. Methods We used a multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies and mechanistic studies to assess SLFN11 as a potential biomarker for stratification of patients treated with several DDA and/or DDRi in the preclinical and clinical setting. Results SLFN11 protein associated with both preclinical and patient treatment response to DDA, but not to non-DDA or DDRi therapies, such as WEE1 inhibitor or olaparib in breast cancer. SLFN11-low/absent cancers were identified across different tumour types tested. Combinations of DDA with DDRi targeting the replication-stress response (ATR, CHK1 and WEE1) could re-sensitise SLFN11-absent/low cancer models to the DDA treatment and were effective in upper gastrointestinal and genitourinary malignancies. Conclusion SLFN11 informs on the standard of care chemotherapy based on DDA and the effect of selected combinations with ATR, WEE1 or CHK1 inhibitor in a wide range of cancer types and models.

Ritualistic male–male combat is exhibited by several snake species, and is accepted as a given natural history trait for king cobras. However, there are no detailed accounts of combat behavior in king cobras in the primary literature, despite this understanding and anecdotal reporting (e.g., via social media posts). The recent taxonomic split of the king cobra species complex has increased our overall understanding of king cobras, but has narrowed the applicability of accepted knowledge across the four novel species. Here, we document three direct and indirect observations of ritualistic male–male combat in the newly revised northern king cobra (Ophiophagus hannah) in Thailand during the 2019 breeding season. We provide detailed accounts of each combat event and the implications that these observations have for our understanding of male–male combat, particularly among king cobra species and the northern king cobra specifically. Following the recent taxonomic split of the king cobra complex, it is important to provide new information and context to behaviors and natural history linked to each new species. We therefore provide detailed observations of ritualistic male–male combat of the newly described northern king cobra (Ophiophagus hannah). Observations were all made in Thailand during the 2019 breeding season and provide important information to further our understanding of male–male combat in snakes and the northern king cobra specifically.

Although the final size of plant organs is influenced by environmental cues, it is generally accepted that the primary size determinants are intrinsic factors that regulate and coordinate cell proliferation and cell expansion. Here, we show that optimal proteasome function is required to maintain final shoot organ size in Arabidopsis (Arabidopsis thaliana). Loss of function of the subunit regulatory particle AAA ATPase (RPT2a) causes a weak defect in 26S proteasome activity and leads to an enlargement of leaves, stems, flowers, fruits, seeds, and embryos. These size increases are a result of increased cell expansion that compensates for a reduction in cell number. Increased ploidy levels were found in some but not all enlarged organs, indicating that the cell size increases are not caused by a higher nuclear DNA content. Partial loss of function of the regulatory particle non-ATPase (RPN) subunits RPN10 and RPN12a causes a stronger defect in proteasome function and also results in cell enlargement and decreased cell proliferation. However, the increased cell volumes in rpn10-1 and rpn12a-1 mutants translated into the enlargement of only some, but not all, shoot organs. Collectively, these data show that during Arabidopsis shoot development, the maintenance of optimal proteasome activity levels is important for balancing cell expansion with cell proliferation rates.

Fanconi anemia (FA) is a recessive disorder characterized by congenital abnormalities, progressive bone-marrow failure, and cancer susceptibility. Cells from FA patients are hypersensitive to agents that produce DNA crosslinks and, after treatment with these agents, have pronounced chromosome breakage and other cytogenetic abnormalities. Eight FANC genes have been cloned, and the encoded proteins interact in a common cellular pathway. DNA-damaging agents activate the monoubiquitination of FANCD2, resulting in its targeting to nuclear foci that also contain BRCA1 and BRCA2/FANCD1, proteins involved in homology-directed DNA repair. Given the interaction of the FANC proteins with BRCA1 and BRCA2, we tested whether cells from FA patients (groups A, G, and D2) and mouse Fanca-/-cells with a targeted mutation are impaired for this repair pathway. We find that both the upstream (FANCA and FANCG) and downstream (FANCD2) FA pathway components promote homology-directed repair of chromosomal double-strand breaks (DSBs). The FANCD2 monoubiquitination site is critical for normal levels of repair, whereas the ATM phosphorylation site is not. The defect in these cells, however, is mild, differentiating them from BRCA1 and BRCA2 mutant cells. Surprisingly, we provide evidence that these proteins, like BRCA1 but unlike BRCA2, promote a second DSB repair pathway involving homology, i.e., single-strand annealing. These results suggest an early role for the FANC proteins in homologous DSB repair pathway choice.

Collective Identity, Oppression, and the Right to Self-Ascription argues that groups have an irreducibly collective right to determine the meaning of their shared group identity, and that such a right is especially important for historically oppressed groups. The author specifies this right by way of a modified discourse ethic, demonstrating that it can provide the foundation for a conception of identity politics that avoids many of its usual pitfalls. The focus throughout is on racial identity, which provides a test case for the theory. That is, it investigates what it would mean for racial identities to be self-ascribed rather than imposed, establishing the possible role racial identity might play in a just society. The book thus makes a unique contribution to both the field of critical theory, which has been woefully silent on issues of race, and to race theory, which often either presumes that a just society would be a raceless society, or focuses primarily on understanding existing racial inequalities, in the manner typical of so-called “non-ideal theory.”

Background Roost-site quality can significantly affect the individual fitness of shorebirds, but roost sites remain poorly described for many threatened species on the East Asian–Australasian Flyway. We studied roost-site selection of the globally endangered Spotted Greenshank ( Tringa guttifer ) in the Inner Gulf of Thailand, an area which supports approximately 24% of their global wintering population, during two non-breeding seasons (October 2014–May 2015 and December 2015–February 2016). Methods We measured nine variables associated with roost site characteristics including water depth, indicators of disturbance/predation risk, and associations with other shorebird species. We predicted that roost ponds with shallow water in proximity to foraging sites would receive higher usage than those further away. Results A total of 94 sites were measured of which 46 were used for roosts with 23 used repeatedly. All used sites were human-modified ponds, of which 44 were used for salt farming and two used for aquaculture. Roosts were on average 1.10 ± 0.78 (SE) km from foraging sites and 5.8 ± 2.4 cm deep. The most supported model indicated that roost sites were negatively associated with distance to foraging sites and positively associated with the presence of Grey Plover ( Pluvialis squatarola ) and water depth. Conclusions Traditional saltpans and other artificial wetlands near (< 1 km) mudflats serve as the primary high-tide roost habitat in the Inner Gulf of Thailand for this Spotted Greenshank population and perhaps seven other globally threatened or near-threatened species. Critically, all observed roost sites are on private land with no formal protection and thus will require creative public–private partnerships to manage sustainably.

Background The absence of the putative DNA/RNA helicase Schlafen11 (SLFN11) is thought to cause resistance to DNA-damaging agents (DDAs) and PARP inhibitors. Methods We developed and validated a clinically applicable SLFN11 immunohistochemistry assay and retrospectively correlated SLFN11 tumour levels to patient outcome to the standard of care therapies and olaparib maintenance. Results High SLFN11 associated with improved prognosis to the first-line treatment with DDAs platinum-plus-etoposide in SCLC patients, but was not strongly linked to paclitaxel–platinum response in ovarian cancer patients. Multivariate analysis of patients with relapsed platinum-sensitive ovarian cancer from the randomised, placebo-controlled Phase II olaparib maintenance Study19 showed SLFN11 tumour levels associated with sensitivity to olaparib. Study19 patients with high SLFN11 had a lower progression-free survival (PFS) hazard ratio compared to patients with low SLFN11, although both groups had the benefit of olaparib over placebo. Whilst caveated by small sample size, this trend was maintained for PFS, but not overall survival, when adjusting for BRCA status across the olaparib and placebo treatment groups, a key driver of PARP inhibitor sensitivity. Conclusion We provide clinical evidence supporting the role of SLFN11 as a DDA therapy selection biomarker in SCLC and highlight the need for further clinical investigation into SLFN11 as a PARP inhibitor predictive biomarker.

Available habitat and hence the global population of the Endangered giant nuthatch Sitta magna, restricted to lower montane habitats of south-western China, eastern Myanmar and northern Thailand, remains poorly quantified. Thailand is the only portion of the species’ range for which there is a population estimate. To obtain a more precise estimate of the Thai population and clarify the extent and characteristics of suitable habitat remaining, we conducted 335 point-count surveys at 67 points across eight localities during November 2019–February 2020. We estimated abundance and identified preferred habitat characteristics using N-mixture models, and created suitable habitat maps based on data from surveys and remote sensing. Our estimate for Thailand was 578 (95% CI 391–854) individuals based on a density of 3.7 (95% CI 2.5–5.5) individuals/km2 in 156 km2 of suitable habitat. The giant nuthatch prefers dry forest with a large amount of mature native or planted pine Pinus kesiya and with a large tree basal area and an open canopy. Our estimate of suitable habitat remaining was less than previously reported and thus the population has probably decreased, although most of this habitat is within protected areas. Habitats for the species in Thailand have a stronger level of protection than in Myanmar and China, although habitat in China remains unquantified. We recommend further research in Myanmar and China, which may hold the majority of available habitat for the giant nuthatch. For long-term management, detailed study of the association of the giant nuthatch with pine plantations is required.

Advocates for racial justice who are skeptical of racial integration frequently emphasize the disproportionate burdens that integration places on people of color, pointing, for example, to the fact that integration programs often focus on moving people of color into White communities, schools, and workplaces rather than the reverse. Despite renewed philosophical attention to the issue of racial integration, this concern about “one-way” integration has not been adequately addressed. This is surprising, since processes of gentrification have seen increasing numbers of White people moving into communities of color, reversing the mid-century trend of “White flight.” In this paper, I argue that, despite serious injustices associated with gentrification as it has unfolded, the trend holds some promise for a more equitable approach to integration, provided that it can be uncoupled from its role in initiating processes that lead to the displacement and exclusion of long-term residents. Resisting these effects, I argue, requires strong and effective democratic institutions at the city and neighborhood levels. With this in mind, I conclude with a brief review of some policy measures that might reinforce such institutions, focusing on community land trusts as a promising possibility for facilitating equitable racial integration.

BackgroundImproving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II.MethodsCB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques.ResultsCB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration.ConclusionsCB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.