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This paper deals with the history of the following problem: \"Can an arbitrary rectangle be dissected into 3 non-rectangular congruent regions?\" We present a new elementary proof that the answer is indeed no.

Ancient DNA makes it possible to observe natural selection directly by analysing samples from populations before, during and after adaptation events. Here we report a genome-wide scan for selection using ancient DNA, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 bc, including 163 with newly reported data. The new samples include, to our knowledge, the first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones, and who we show were members of the population that was the source of Europe’s first farmers. We also report a transect of the steppe region in Samara between 5600 and 300 bc , which allows us to identify admixture into the steppe from at least two external sources. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height. The first genome-wide scan for selection using ancient DNA, based on data from 230 West Eurasians dating between to 6500 and 300 bc and including new data from 163 individuals among which are 26 Neolithic Anatolians, provides a direct view of selection on loci associated with diet, pigmentation and immunity. Selection pressures deduced from ancient DNA This study uses ancient DNA as a window on a crucial period of human evolution — the arrival of farming in Europe around 8,500 years ago. Genome-wide scanning data was obtained from 230 West Eurasians from between 6500 BC and 300 BC, including samples from 26 Anatolian Neolithic individuals, representing the first genome-wide ancient DNA from the eastern Mediterranean. The authors find evidence of selection on loci associated with diet, pigmentation and immunity. The strongest signal of selection is at the allele responsible for lactase persistence, supporting the view that an appreciable frequency of lactase persistence in Europe only dates to the past four thousand years.

Dysfunctional endothelium causes more disease than any other cell type. Systemically administered RNA delivery to nonliver tissues remains challenging, in large part because there is no high-throughput method to identify nanoparticles that deliver functional mRNA to cells in vivo. Here we report a system capable of simultaneously quantifying how >100 lipid nanoparticles (LNPs) deliver mRNA that is translated into functional protein. Using this system (named FIND), we measured how >250 LNPs delivered mRNA to multiple cell types in vivo and identified 7C2 and 7C3, two LNPs that efficiently deliver siRNA, single-guide RNA (sgRNA), and mRNA to endothelial cells. The 7C3 delivered Cas9 mRNA and sgRNA to splenic endothelial cells as efficiently as hepatocytes, distinguishing it from LNPs that deliver Cas9 mRNA and sgRNA to hepatocytes more than other cell types. These data demonstrate that FIND can identify nanoparticles with novel tropisms in vivo.

Now, 25 years after the coup that crushed Salvador Allende, something new to worry about. The Chilean electorate looks set to endorse one of Allende's party colleagues, Ricardo Lagos, in tomorrow's presidential primaries. \"If the Socialists win the presidency, this country will be back in the same situation we had before the 1973 coup,\" lamented Mr [PEDRO] Alvarez, a supporter of Augusto Pinochet who now runs his own salmon- smoking business on the island of Chiloe. Mr Lagos, the man appointed as Allende's ambassador to the Soviet Union, knows very well that people such as Mr Alvarez represent a significant minority among those whose vote he may need in December.

Aim Fires can severely impact aquatic fauna, especially when attributes of soil, topography, fire severity and post‐fire rainfall interact to cause substantial sedimentation. Such events can cause immediate mortality and longer‐term changes in food resources and habitat structure. Approaches for estimating fire impacts on terrestrial species (e.g. intersecting fire extent with species distributions) are inappropriate for aquatic species as sedimentation can carry well downstream of the fire extent, and occur long after fire. Here, we develop an approach for estimating the spatial extent of fire impacts for aquatic systems, across multiple catchments. Location Southern Australian bioregions affected by the fires in 2019–2020 that burned >10 million ha of temperate and subtropical forests. Methods We integrated an existing soil erosion model with fire severity mapping and rainfall data to estimate the spatial extent of post‐fire sedimentation threat in waterways and in basins and the potential exposure of aquatic species to this threat. We validated the model against field observations of sedimentation events after the 2019–20 fires. Results While fires overlapped with ~27,643 km of waterways, post‐fire sedimentation events potentially occurred across ~40,449 km. In total, 55% (n = 85) of 154 basins in the study region may have experienced substantial post‐fire sedimentation. Ten species—including six Critically Endangered—were threatened by post‐fire sedimentation events across 100% of their range. The model increased the estimates for potential impact, compared to considering fire extent alone, for >80% of aquatic species. Some species had distributions that did not overlap with the fire extent, but that were entirely exposed to post‐fire sedimentation threat. Conclusions Compared with estimating the overlap of fire extent with species' ranges, our model improves estimates of fire‐related threats to aquatic fauna by capturing the complexities of fire impacts on hydrological systems. The model provides a method for quickly estimating post‐fire sedimentation threat after future fires in any fire‐prone region, thus potentially improving conservation assessments and informing emergency management interventions.

Background Predicting hospital length of stay (LoS) for patients with COVID-19 infection is essential to ensure that adequate bed capacity can be provided without unnecessarily restricting care for patients with other conditions. Here, we demonstrate the utility of three complementary methods for predicting LoS using UK national- and hospital-level data. Method On a national scale, relevant patients were identified from the COVID-19 Hospitalisation in England Surveillance System (CHESS) reports. An Accelerated Failure Time (AFT) survival model and a truncation corrected method (TC), both with underlying Weibull distributions, were fitted to the data to estimate LoS from hospital admission date to an outcome (death or discharge) and from hospital admission date to Intensive Care Unit (ICU) admission date. In a second approach we fit a multi-state (MS) survival model to data directly from the Manchester University NHS Foundation Trust (MFT). We develop a planning tool that uses LoS estimates from these models to predict bed occupancy. Results All methods produced similar overall estimates of LoS for overall hospital stay, given a patient is not admitted to ICU (8.4, 9.1 and 8.0 days for AFT, TC and MS, respectively). Estimates differ more significantly between the local and national level when considering ICU. National estimates for ICU LoS from AFT and TC were 12.4 and 13.4 days, whereas in local data the MS method produced estimates of 18.9 days. Conclusions Given the complexity and partiality of different data sources and the rapidly evolving nature of the COVID-19 pandemic, it is most appropriate to use multiple analysis methods on multiple datasets. The AFT method accounts for censored cases, but does not allow for simultaneous consideration of different outcomes. The TC method does not include censored cases, instead correcting for truncation in the data, but does consider these different outcomes. The MS method can model complex pathways to different outcomes whilst accounting for censoring, but cannot handle non-random case missingness. Overall, we conclude that data-driven modelling approaches of LoS using these methods is useful in epidemic planning and management, and should be considered for widespread adoption throughout healthcare systems internationally where similar data resources exist.

Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment. Amino acids availability is normally a limitation for protein synthesis and can determine cancer progression and therapy response. Here, the authors show that MYC-associated cancer has a dependency on tryptophan not because of translation regulation, but Indole 3-Pyruvate synthesis.

Suicidality in childhood and adolescence is of increasing concern. The aim of this paper was to review the published literature identifying key psychosocial risk factors for suicidality in the paediatric population. A systematic two-step search was carried out following the PRISMA statement guidelines, using the terms ‘suicidality, suicide, and self-harm’ combined with terms ‘infant, child, adolescent’ according to the US National Library of Medicine and the National Institutes of Health classification of ages. Forty-four studies were included in the qualitative synthesis. The review identified three main factors that appear to increase the risk of suicidality: psychological factors (depression, anxiety, previous suicide attempt, drug and alcohol use, and other comorbid psychiatric disorders); stressful life events (family problems and peer conflicts); and personality traits (such as neuroticism and impulsivity). The evidence highlights the complexity of suicidality and points towards an interaction of factors contributing to suicidal behaviour. More information is needed to understand the complex relationship between risk factors for suicidality. Prospective studies with adequate sample sizes are needed to investigate these multiple variables of risk concurrently and over time.

Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5–13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1–13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84–1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3–4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. Eli Lilly and Company.

Evapotranspiration (ET) is a crucial part of commercial grapevine production in California, and the partitioning of this quantity allows the separate assessment of soil and vine water and energy fluxes. This partitioning has an important role in agriculture since it is related to grapevine stress, yield quality, irrigation efficiency, and growth. Satellite remote sensing-based methods provide an opportunity for ET partitioning at a subfield scale. However, medium-resolution satellite imagery from platforms such as Landsat is often insufficient for precision agricultural management at the plant scale. Small, unmanned aerial systems (sUAS) such as the AggieAir platform from Utah State University enable ET estimation and its partitioning over vineyards via the two-source energy balance (TSEB) model. This study explores the assessment of ET and ET partitioning (i.e., soil water evaporation and plant transpiration), considering three different resistance models using ground-based information and aerial high-resolution imagery from the Grape Remote sensing Atmospheric Profile and Evapotranspiration eXperiment (GRAPEX). We developed a new method for temperature partitioning that incorporated a quantile technique separation (QTS) and high-resolution sUAS information. This new method, coupled with the TSEB model (called TSEB-2TQ), improved sensible heat flux (H) estimation, regarding the bias, with around 61% and 35% compared with the H from the TSEB-PT and TSEB-2T, respectively. Comparisons among ET partitioning estimates from three different methods (Modified Relaxed Eddy Accumulation—MREA; Flux Variance Similarity—FVS; and Conditional Eddy Covariance—CEC) based on EC flux tower data show that the transpiration estimates obtained from the FVS method are statistically different from the estimates from the MREA and the CEC methods, but the transpiration from the MREA and CEC methods are statistically the same. By using the transpiration from the CEC method to compare with the transpiration modeled by different TSEB models, the TSEB-2TQ shows better agreement with the transpiration obtained via the CEC method. Additionally, the transpiration estimation from TSEB-2TQ coupled with different resistance models resulted in insignificant differences. This comparison is one of the first for evaluating ET partitioning estimation from sUAS imagery based on eddy covariance-based partitioning methods.