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Polypharmacology drugs—compounds that inhibit multiple proteins—have many applications but are difficult to design. To address this challenge we have developed POLYGON, an approach to polypharmacology based on generative reinforcement learning. POLYGON embeds chemical space and iteratively samples it to generate new molecular structures; these are rewarded by the predicted ability to inhibit each of two protein targets and by drug-likeness and ease-of-synthesis. In binding data for >100,000 compounds, POLYGON correctly recognizes polypharmacology interactions with 82.5% accuracy. We subsequently generate de-novo compounds targeting ten pairs of proteins with documented co-dependency. Docking analysis indicates that top structures bind their two targets with low free energies and similar 3D orientations to canonical single-protein inhibitors. We synthesize 32 compounds targeting MEK1 and mTOR, with most yielding >50% reduction in each protein activity and in cell viability when dosed at 1–10 μM. These results support the potential of generative modeling for polypharmacology. Polypharmacology drugs are compounds designed to inhibit multiple protein targets. Here, authors use recent advances in AI to rapidly generate polypharmacology compounds against any pair of protein targets, experimentally validating numerous compounds targeting MEK1 and mTOR.

Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions. First, fundamental cellular processes are perturbed by systematic combinatorial knockouts across tumor lineages, identifying 1,805 synthetic lethal interactions (95% unreported). Interactions are then analyzed by hierarchical pooling, revealing that half segregate reliably by tissue type or biomarker status (51%) and a substantial minority are penetrant across lineages (34%). Interactions converge on 49 multigene systems, including MAPK signaling and BAF transcriptional regulatory complexes, which become essential on disruption of polymerases. Some 266 interactions translate to robust biomarkers of drug sensitivity, including frequent genetic alterations in the KDM5C/6A histone demethylases, which sensitize to inhibition of TIPARP (PARP7). SCHEMATIC offers a context-aware, data-driven approach to match genetic alterations to targeted therapies. A framework combining combinatorial CRISPR knockout in breast, lung and oropharyngeal cancer in vitro models with public data identifies synthetic lethal interactions, such as perturbed KDM5C sensitizing cells to PARP7 inhibition.

Cell-cycle control is accomplished by cyclin-dependent kinases (CDKs), motivating extensive research into CDK targeting small-molecule drugs as cancer therapeutics. Here we use combinatorial CRISPR/Cas9 perturbations to uncover an extensive network of functional interdependencies among CDKs and related factors, identifying 43 synthetic-lethal and 12 synergistic interactions. We dissect CDK perturbations using single-cell RNAseq, for which we develop a novel computational framework to precisely quantify cell-cycle effects and diverse cell states orchestrated by specific CDKs. While pairwise disruption of CDK4/6 is synthetic-lethal, only CDK6 is required for normal cell-cycle progression and transcriptional activation. Multiple CDKs (CDK1/7/9/12) are synthetic-lethal in combination with PRMT5, independent of cell-cycle control. In-depth analysis of mRNA expression and splicing patterns provides multiple lines of evidence that the CDK-PRMT5 dependency is due to aberrant transcriptional regulation resulting in premature termination. These inter-dependencies translate to drug–drug synergies, with therapeutic implications in cancer and other diseases.

Common carp ( Cyprinus carpio ; hereafter carp) is a highly invasive freshwater fish that has colonised river basins across the world causing ecological degradation. In regulated rivers, restoration of natural flow regimes to rehabilitate aquatic ecosystems is a primary focus of environmental management, yet some actions (e.g., environmental water delivery or artificial floodplain inundations) may have unintended consequences including favouring carp. We developed a stochastic population model to represent carp population responses to hydrology and management actions. The model uses current understanding of carp life history, including different survival rates of early life-stages for a range of habitat types, to estimate population responses to various flow/inundation scenarios. Using case studies from two major regions of a large, regulated dryland river, we demonstrate that large natural floods and prolonged droughts accounted for the greatest amplitude of projected carp population increases and declines, respectively. Within-channel flow pulses and small floods, which are a primary focus of environmental flows, appeared to have little influence on long-term carp population trajectories. Artificial inundations generated by floodplain infrastructure, however, caused significant carp recruitment compared to baseline scenarios. Large natural floodplain inundations also maintained high carp biomasses and thus likely high impacts on natural ecological values. The carp population model captures the response of carp to flows and artificial floodplain inundation and will inform environmental managers on the likely trade-offs between achieving restoration of natural ecological values and suppressing a globally invasive fish.

PurposeVarious classification systems describe fractures of the acetabulum and pelvis separately. Horizontal shear fractures involve the pelvic ring and both acetabula and have not been previously described. The aim of this study is to describe the horizontal shear fracture of the pelvis.MethodsAt a level 1 trauma centre over 10 years from December 2008 to December 2018, 1242 patients had pelvic and acetabular fractures. Six patients had horizontal shear fractures, comprising 0.5% of all pelvic and acetabular fractures. Demographic, clinical and radiological data was collected. Clinical outcomes were pain and mobility level, sciatic nerve symptoms, further acetabular or pelvic surgery, or total hip arthroplasty. Radiological outcomes included fracture displacement, implant migration, femoral head osteonecrosis, and post-traumatic arthritis. Outcomes were assessed at a minimum 12 month follow-up.ResultsThe median patient age was 35 years. Five of six shear fractures were due to motorcycle crashes. No mortalities occurred. At follow-up, three patients reported pain, two patients had difficulty mobilising associated with traumatic sciatic nerve injury, and one patient underwent total hip arthroplasty for femoral head osteonecrosis. No fracture displacement or implant migration occurred. The Matta arthritis grade was excellent or good in all except one hip. Median follow-up time was 1.8 (range 1.1–7.8) years.ConclusionThe horizontal shear fracture of the pelvis is a high-energy injury characterised by separation of the anterior and posterior pelvic ring through the acetabula. Good outcomes can be achieved with open reduction and internal fixation of displaced fractures.

Carp are a highly successful invasive fish species, now widespread, abundant and considered a pest in south-eastern Australia. To date, most management effort has been directed at reducing abundances of adult fish, with little consideration of population growth through reproduction. Environmental water allocations are now an important option for the rehabilitation of aquatic ecosystems, particularly in the Murray–Darling Basin. As carp respond to flows, there is concern that environmental watering may cause floodplain inundation and provide access to spawning habitats subsequently causing unwanted population increase. This is a management conundrum that needs to be carefully considered within the context of contemporary river flow management (natural, environmental, irrigation). This paper uses a population model to investigate flow-related carp population dynamics for three case studies in the Murray–Darling Basin: (1) river and terminal lakes; (2) wetlands and floodplain lakes; and (3) complex river channel and floodplain system. Results highlight distinctive outcomes depending on site characteristics. In particular, the terminal lakes maintain a significant source carp population regardless of river flow; hence any additional within-channel environmental flows are likely to have little impact on carp populations. In contrast, large-scale removal of carp from the lakes may be beneficial, especially in times of extended low river flows. Case studies 2 and 3 show how wetlands, floodplain lakes and the floodplain itself can now often be inundated for several months over the carp spawning season by high volume flows provided for irrigation or water transfers. Such inundations can be a major driver of carp populations, compared to within channel flows that have relatively little effecton recruitment. The use of a population model that incorporates river flows and different habitats for this flow-responsive species, allows for the comparison of likely population outcomes for differing hydrological scenarios to improve the management of risks relating to carp reproduction and flows.

Migratory life cycles and population structure of 2 putatively diadromous Australian fishes were examined using otolith chemistry (87Sr/86Sr) and genetics (microsatellites and mitochondrial deoxyribonucleic acid [mtDNA]). Australian whitebait (Lovettia sealii) is widely considered to be one of only a few anadromous fish species in the southern hemisphere. The congolli or tupong (Pseudaphritis urvillii) is reported to undertake an unusual form of sexually segregated catadromous migration, where females switch habitats between marine and freshwater, while males remain in marine or estuarine environments. Sr-isotope profiles of L. sealii showed this species does not move into fully freshwater habitats during its life cycle, suggesting it should be considered semianadromous or estuarine-dependent, rather than truly anadromous. This life-history strategy is unique among the Galaxiidae. Lovettia sealii is regionally divided into at least 3 well differentiated genetic stocks: northern and southern Tasmanian coasts and mainland Australia. Sr-isotope profiles of P. urvillii showed that females are catadromous, with the early life history spent in the marine environment and a single migratory transition from marine to freshwater occurring at an early point in the life history. Lack of bidirectional adult migration between freshwater and the sea suggests that female P. urvillii are semelparous, returning to the marine habitat to mate with resident males after an extended period of freshwater residence. Pseudaphritis exhibit weak genetic structure across their mainland range. An isolation-by-distance relationship describes the genetic structure of this species, a pattern it shares with several other nearshore-restricted catadromous fishes.

Background COVID-19 revealed and broadened existing disparities in large cities. This article interprets the early impacts of COVID-19 on food insecurity (FI) in the Chicago and New York City (NYC) metropolitan areas for Black, Indigenous, and People of Color (BIPOC) and provides a study using a Social Determinants of Health (SDOH) framework. Methods A cross-sectional survey adapted from the National Food Access and COVID Research Team (NFACT) was deployed in Chicago ( N  = 680) and in NYC ( N  = 525) during summer 2020 and oversampled for race, ethnicity, and socioeconomic status. Multivariate binary logistic regression generated adjusted odds ratios (aOR) and 95% CIs for FI and select SDOH variables, which was conducted on each dataset. Results The prevalence of FI in NYC increased to 66.8% (from 57.8%) and in Chicago to 44.8% (from 41.0%). While higher income protected against FI before, protection was diminished or eliminated since COVID-19. FI declined for households with children in NYC while odds increased and became significant in Chicago. Respondents with chronic health conditions experienced increased odds of FI since COVID. In Chicago, this variable had the highest odds of FI. Respondents with depression or anxiety had increased odds of FI. In NYC, depression had the highest odds of FI. Females in NYC were protected against FI. Hispanics in NYC lost protection against FI from before to since COVID-19. Conclusions Results support the observed rise of FI for BIPOC and its association with health status. The analysis has multifaceted, structural policy implications for reducing FI in urban centers.

Neurological abnormalities in phenylketonuria were described before dietary treatment became possible. These included tremor, clumsiness, epilepsy, spastic paraparesis and occasionally extrapyramidal features. Neurological deterioration after childhood was recognised. Patients with neurological deterioration described recently have been late diagnosed or intellectually impaired or both. No early diagnosed patient who was well treated and of good intellectual outcome has yet shown neurological deterioration after stopping diet but it may happen. The fascinating links between pathology, magnetic resonance imaging appearances, magnetic resonance spectroscopy results and clinical features are not yet clearly understood. Patients must understand the possible risks of stopping diet and make their choice. All patients need help, support and follow-up regardless of the choices they make over continuing diet.