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Birds exhibit an enormous variety of beak shapes. Such remarkable variation, however, has distracted research from other important aspects of their skull evolution, the nature of which has been little explored. Key aspects of avian skull variation appear to be qualitatively similar to those of mammals, encompassing variation in the degree of cranial vaulting, cranial base flexure, and the proportions and orientations of the occipital and facial regions. The evolution of these traits has been studied intensively in mammals under the Spatial Packing Hypothesis (SPH), an architectural constraint so-called because the general anatomical organization and development of such skull parts makes them evolve predictably in response to changes in relative brain size. Such SPH predictions account for the different appearances of skull configurations across species, either in having longer or shorter faces, and caudally or ventrally oriented occiputs, respectively. This pattern has been morphometrically and experimentally proven in mammals but has not been examined in birds or other tetrapods, and so its generality remains unknown. We explored the SPH in an interspecific sample of birds using three dimensional geometric morphometrics. Our results show that the dominant trend of evolutionary variation in the skull of crown-group birds can be predicted by the SPH, involving concomitant changes in the face, the cranial vault and the basicranium, and with striking similarities to craniofacial variation among mammals. Although craniofacial variation is significantly affected by allometry, these allometric effects are independent of the influence of the SPH on skull morphology, as are any effects of volumetric encephalization. Our results, therefore, validate the hypothesis that a general architectural constraint underlies skull homoplasy evolution of cranial morphology among avian clades, and possibly between birds and mammals, but they downplay encephalization and allometry as the only factors involved.

The earliest known crown-group lepidosaurs are known from the Middle Triassic; however, their stem group is poorly sampled, with only a few representative fossils found. This is partly due to the small size and delicate bones of early stem-lepidosaurs (= non-lepidosaurian lepidosauromorphs), which make both preservation in the fossil record and subsequent discovery less likely. The Middle Jurassic lepidosauromorph Marmoretta oxoniensis Evans is re-examined using high-resolution µCT scanning to reveal parts of the skull anatomy that were previously unknown. These include a squamosal, postorbital, more complete parietal, pterygoids, and an articulated posterior section of the mandible. Some differences between this and other Marmoretta specimens were identified as a result, such as the arrangement of palatal teeth and the shape of the parabasisphenoid. The status of Marmoretta as a stem lepidosaur or stem squamate has been debated. To evaluate this, we tested the phylogenetic position of Marmoretta by including our new data in an adapted phylogenetic character matrix. We recover Marmoretta as a stem-lepidosaur and sister to Fraxinisaura rozynekae. Our findings support the hypothesis that both taxa belonged to a clade of non-lepidosaurian lepidosauromorphs that co-existed with lepidosaurs into the Middle Jurassic.

Macrolides are among the most widely prescribed antibiotics, particularly for bacterial lung infections, due to their favorable safety, oral bioavailability, and spectrum of activity against Gram-positive pathogens such as Streptococcus pneumoniae, the most common cause of bacterial pneumonia. Their utility against Gram-negative bacteria is extremely limited and does not include the Enterobacteriaceae or other ESKAPE pathogens. With the increasing development of resistance to current therapies and the lack of safe, oral options to treat Gram-negative infections, extended-spectrum macrolides have the potential to provide valuable treatment options. While the bacterial ribosome, the target of macrolides, is highly conserved across Gram-positive and Gram-negative bacteria, traditional macrolides do not possess the proper physicochemical properties to cross the polar Gram-negative outer membrane and are highly susceptible to efflux. As with most natural product-derived compounds, macrolides are generally prepared through semisynthesis, which is limited in scope and lacks the ability to make the drastic physicochemical property changes necessary to overcome these hurdles.By using a fully synthetic platform technology to greatly expand structural diversity, novel macrolides were prepared with a focus on lowering the MW and increasing the polarity to achieve a physicochemical property profile more similar to that of traditional Gram-negative drug classes. In addition to the removal of lipophilic groups, a critical structural feature for obtaining Gram-negative activity in the macrolide class proved to be the introduction of small secondary or tertiary amines to yield polycationic species potentially capable of self-promoted uptake. Within the azithromycin-like 15-membered azalides, potent activity was seen when small alkyl amines were introduced at the 6'-position of desosamine. The biggest gains, however, were made by replacing the entire C10-C13 fragment of the macrolactone ring with commercially available or readily synthesized 1,2-aminoalcohols, leading to 13-membered azalides. The introduction of a tethered basic amine at the C10-position and systematic optimization of substitution and tether length and flexibility ultimately provided new macrolides that for the first time exhibit clinically relevant antibacterial activity against multi-drug resistant Gram-negative bacteria. A retrospective computational analysis of >1800 fully synthetic macrolides prepared during this effort identified key drivers and optimum ranges for improving permeability and avoiding efflux. In contrast to standard Gram-negative drugs which generally have MWs below 600 and clogD7.4 values below 0, we found that the ideal ranges for Gram-negative macrolides were MW between 600 and 720 and cLogD7.4 between -1 and 3. A total charge of between 2.5 and 3 was also required to provide optimal permeability and efflux avoidance. Thus, Gram-negative macrolides occupy a unique physicochemical property space that lies between traditional Gram-negative drug classes and Gram-positive macrolides.

Background The present study aims to evaluate the effects of ouabain on memory and neurotrophic parameters in the brains of rats. Methods Wistar rats received an intracerebroventricular (ICV) injection of ouabain or artificial cerebrospinal fluid (aCSF). Seven and 14 days after ICV administration, the animals were subjected to the open-field and splash tests. Furthermore, the pro-BDNF, BDNF, TrkB, and CREB were assessed in the frontal cortex and hippocampus of the rats, in both seven and 14 days after ICV injection. The memory of the animals was tested by novel object recognition test (NOR) and inhibitory avoidance task (IA), only 14 days after ICV administration. Results Ouabain increased locomotion and exploration in the animals seven days after its administration; however, 14 days after ICV, these behavioral parameters return to the basal level. Seven days after ouabain administration increased grooming behavior in the splash test; on the other hand, seven days after ouabain injection decreased the grooming behavior, which is considered an anhedonic response. Besides, ouabain decreased recognition index in the NOR and decreased aversive memory in the IA, when compared to the control group. The levels of pro-BDNF and BDNF decreased in the frontal cortex seven days after ouabain; but its receptor (TrkB) and CREB decreased seven and 14 days after ouabain, in both cerebral structures evaluated. Conclusion Ouabain-induced animal model of BD is an excellent model to assess memory alteration, observed in bipolar patients. Besides, the memory impairment induced by ouabain seems to be related to BDNF signaling pathway alterations.

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. Significance: Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design. This article is highlighted in the In This Issue feature, p. 521

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration., Defective protein quality control is a key feature of neurodegeneration. Here, the authors show that mutations in Nemf/NEMF, a component of the Ribosome-associated Quality Control complex, have a neurodegenerative effect in mice and may underlie neuromuscular disease in seven unrelated families.

It is known that bipolar disorder has a multifactorial aetiology where the interaction between genetic and environmental factors is responsible for its development. Because of this, epigenetics has been largely studied in psychiatric disorders. The present study aims to evaluate the effects of histone deacetylase inhibitors on epigenetic enzyme alterations in rats or mice submitted to animal models of mania induced by dextro-amphetamine or sleep deprivation, respectively. Adult male Wistar rats were subjected to 14 days of dextro-amphetamine administration, and from the eighth to the fourteenth day, the animals were treated with valproate and sodium butyrate in addition to dextro-amphetamine injections. Adult C57BL/6 mice received 7 days of valproate or sodium butyrate administration, being sleep deprived at the last 36 hr of the protocol. Locomotor and exploratory activities of rats and mice were evaluated in the open-field test, and histone deacetylase, DNA methyltransferase, and histone acetyltransferase activities were assessed in the frontal cortex, hippocampus, and striatum. Dextro-amphetamine and sleep deprivation induced hyperactivity and increased histone deacetylase and DNA methyltransferase activities in the animal's brain. Valproate and sodium butyrate were able to reverse hyperlocomotion induced by both animal models, as well as the alterations on histone deacetylase and DNA methyltransferase activities. There was a positive correlation between enzyme activities and number of crossings for both models. Histone deacetylase and DNA methyltransferase activities also presented a positive correlation between theirselves. These results suggest that epigenetics can play an important role in BD pathophysiology as well as in its treatment.

Transcriptional control is exerted primarily through the binding of transcription factor proteins to regulatory elements in DNA. By virtue of eukaryotic DNA being complexed with histones, transcription factor binding to DNA alters or eliminates histone-DNA contacts, leading to increased accessibility of the DNA region to nuclease enzymes. This hypersensitivity to nuclease digestion has been used to define DNA binding events and regulatory elements across genomes, and to compare these attributes between cell types or conditions. These approaches make it possible to define the regulatory elements in a genome as well as to predict the regulatory networks of transcription factors and their target genes in a given cell state. As these chromatin accessibility assays are increasingly used, it is important to consider how to analyze the resulting data to avoid artifactual results or misinterpretation. In this review, we focus on some of the key technical and computational caveats associated with plant chromatin accessibility data, including strategies for sample preparation, sequencing, read mapping, and downstream analyses.

We report severe acute respiratory syndrome coronavirus 2 antibody positivity among market and city bus depot workers in Lima, Peru. Among 1285 vendors from 8 markets, prevalence ranged from 27% to 73%. Among 488 workers from 3 city bus depots, prevalence ranged from 11% to 47%. Self-reported symptoms were infrequent. National Institute of Allergy and Infectious Diseases Revisión por pares

In most trawl fisheries, drag forces tend to close the meshes in large areas of diamond mesh codends, negatively affecting their selective potential. In the Barents Sea deep-water shrimp (Pandalus borealis) trawl fishery, selectivity is based on a sorting grid followed by a diamond mesh codend. However, the retention of juvenile fish as well as undersized shrimp is still a problem. In this study, we estimated the effect of applying different codend modifications, each aimed at affecting codend mesh openness and thereby selectivity. Changing from a 4-panel to a 2-panel construction of the codend did not affect size selectivity. Shortening the lastridge ropes of a 4-panel codend by 20% resulted in minor reductions for juvenile fish bycatch, but a 45% reduction of undersized shrimp was observed. Target-size catches of shrimp were nearly unaffected. When the codend mesh circumference was reduced while simultaneously shortening the lastridge ropes, the effect on catch efficiency for shrimp or juvenile fish bycatch was marginal compared to a 4-panel codend design with shortened lastridge ropes.

Summary The fossil record is the primary source of information on how biodiversity has varied in deep time, providing unique insight on the long-term dynamics of diversification and their drivers. However, interpretations of fossil record diversity patterns have been much debated, with a traditional focus on global diversity through time. Problems arise because the fossil record is spatially and temporally patchy, so ‘global’ diversity estimates actually represent the summed diversity across a set of geographically and environmentally distinct regions that vary substantially in number and identity through time. Furthermore, a focus on global diversity lumps the signal of ecological drivers at local and regional scales with the signal of global-scale processes, including variation in the distribution of environments and in provincialism (the extent of subdivision into distinct biogeographic regions). These signals cannot be untangled by studying global diversity measures alone. These conceptual and empirical concerns necessitate a shift away from the study of ‘biodiversity through time’ and towards the study of ‘biodiversity across time and space’. Spatially explicit investigations, including analyses of local- and regional-scale datasets, are central to achieving this and allow analysis of geographic scale, location and the environmental parameters directly experienced by organisms. So far, research in this area has revealed the stability of species richness variation among environments through time, and the potential climatic and Earth-system drivers of changing biodiversity. Ultimately, this research program promises to address key questions regarding the assembly of biodiversity, and the contributions of local-, regional- and global-scale processes to the diversification of life on Earth.

Staphylococcus aureus (S. aureus) causes gastrointestinal illness worldwide. Disinfectants are used throughout the food chain for pathogenic bacteria control. We investigated S. aureus bioavailability in swine Mandibular lymph node tissue (MLT) and pork sausage meat (PSM), established susceptibility values for S. aureus to disinfectants, and determined the multilocus sequence type of MRSA strains. Antimicrobial and disinfectant susceptibility profiles were determined for 164 S. aureus strains isolated from swine feces (n = 63), MLT (n = 49) and PSM (n = 52). No antimicrobial resistance (AMR) was detected to daptomycin, nitrofurantoin, linezolid, and tigecycline, while high AMR prevalence was determined to erythromycin (50.6%), tylosin tartrate (42.7%), penicillin (72%), and tetracycline (68.9%). Methicillin-resistant S. aureus (MRSA) strains, ST398 (n = 6) and ST5 (n = 1), were found in the MLT and PSM, 4 MRSA in MLT and 3 MRSA strains in the PSM. About 17.5% of feces strains and 41.6% of MLT and PSM strains were resistant to chlorhexidine. All strains were susceptible to triclosan and benzalkonium chloride, with no cross-resistance between antimicrobials and disinfectants. Six MRSA strains had elevated susceptibilities to 18 disinfectants. The use of formaldehyde and tris(hydroxylmethyl)nitromethane in DC&R was not effective, which can add chemicals to the environment. Didecyldimethylammonium chloride and benzyldimethylhexadecylammonium chloride were equally effective disinfectants. ST398 and ST5 MRSA strains had elevated susceptibilities to 75% of the disinfectants tested. This study establishes susceptibility values for S. aureus strains from swine feces, mandibular lymph node tissue, and commercial pork sausage against 24 disinfectants. Since it was demonstrated that S. aureus and MRSA strains can be found deep within swine lymph node tissue, it may be beneficial for the consumer if raw swine lymph node tissue is not used in uncooked food products and pork sausage.

BackgroundThe origin of powered avian flight was a locomotor innovation that expanded the ecological potential of maniraptoran dinosaurs, leading to remarkable variation in modern birds (Neornithes). The avian sternum is the anchor for the major flight muscles and, despite varying widely in morphology, has not been extensively studied from evolutionary or functional perspectives. We quantify sternal variation across a broad phylogenetic scope of birds using 3D geometric morphometrics methods. Using this comprehensive dataset, we apply phylogenetically informed regression approaches to test hypotheses of sternum size allometry and the correlation of sternal shape with both size and locomotory capabilities, including flightlessness and the highly varying flight and swimming styles of Neornithes.ResultsWe find evidence for isometry of sternal size relative to body mass and document significant allometry of sternal shape alongside important correlations with locomotory capability, reflecting the effects of both body shape and musculoskeletal variation. Among these, we show that a large sternum with a deep or cranially projected sternal keel is necessary for powered flight in modern birds, that deeper sternal keels are correlated with slower but stronger flight, robust caudal sternal borders are associated with faster flapping styles, and that narrower sterna are associated with running abilities. Correlations between shape and locomotion are significant but show weak explanatory power, indicating that although sternal shape is broadly associated with locomotory ecology, other unexplored factors are also important.ConclusionsThese results display the ecological importance of the avian sternum for flight and locomotion by providing a novel understanding of sternum form and function in Neornithes. Our study lays the groundwork for estimating the locomotory abilities of paravian dinosaurs, the ancestors to Neornithes, by highlighting the importance of this critical element for avian flight, and will be useful for future work on the origin of flight along the dinosaur-bird lineage.

International audience; Teleost fishes comprise one-half of all vertebrate species and possess a duplicated genome. This whole-genome duplication (WGD) occurred on the teleost stem lineage in an ancient common ancestor of all living teleosts and is hypothesized as a trigger of their exceptional evolutionary radiation. Genomic and phylogenetic data indicate that WGD occurred in the Mesozoic after the divergence of teleosts from their closest living relatives but before the origin of the extant teleost groups. However, these approaches cannot pinpoint WGD among the many extinct groups that populate this 50- to 100-million-y lineage, preventing tests of the evolutionary effects of WGD. We infer patterns of genome size evolution in fossil stem-group teleosts using high-resolution synchrotron X-ray tomography to measure the bone cell volumes, which correlate with genome size in living species. Our findings indicate that WGD occurred very early on the teleost stem lineage and that all extinct stem-group teleosts known so far possessed duplicated genomes. WGD therefore predates both the origin of proposed key innovations of the teleost skeleton and the onset of substantial morphological diversification in the clade. Moreover, the early occurrence of WGD allowed considerable time for postduplication reorganization prior to the origin of the teleost crown group. This suggests at most an indirect link between WGD and evolutionary success, with broad implications for the relationship between genomic architecture and large-scale evolutionary patterns in the vertebrate Tree of Life.

The Middle Jurassic witnessed the early diversification of mammal groups, including the stem-mammalian clade, Docodonta. Recent discoveries in China indicate docodontans exhibited ecomorphological diversity akin to small-bodied mammals living >100 million years later, in the Cenozoic. Our understanding of the emergence of this ecological diversity is hindered by a lack of Middle Jurassic fossil material from other parts of the world. The two partial postcranial skeletons of Borealestes described here come from the Kilmaluag Formation, Scotland. These are the most complete Mesozoic mammaliaform skeletons currently known from the UK, and among the best preserved in Europe. As an early member of Docodonta, Borealestes provides key anatomical information for understanding the clade's evolution, and the emergence of mammaliaform ecomorphological diversity. Using digital reconstructions from micro-CT and synchrotron scans, we describe the postcranial anatomy of Borealestes and provide an updated phylogenetic analysis incorporating cranial and postcranial characters. We find Borealestes species form a sister group to a clade comprising Agilodocodon and Microdocodon. To complement observational analyses of the skeleton, we carry out principal components analyses using 3D landmarks on a comparative dataset of 42 extant mammal taxa. Our results indicate Borealestes lacked specializations for derived locomotor behaviour. We detect some similarity in the humerus between Borealestes and Ornithorhynchus. Borealestes is morphologically intermediate between the robust morphology of fossorial and semi-fossorial/semi-aquatic Haldanodon and Docofossor, and the gracile morphology for scansorial Agilodocodon and Microdocodon. We suggest ecological diversity in Docodonta may arise from an unspecialized basal bauplan, of which Borealestes may be representative.

Plant-eating dinosaurs evolved varied feeding strategies. A new study demonstrates convergent evolution of their skulls and teeth towards two distinct functional optima, one resembling advanced mammalian herbivory and the other echoing herbivory in birds and other reptiles.

PURPOSE The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non–small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations. METHODS We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). RESULTS From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/ KRAS, 18 had STK11/ TP53, and seven had STK11/ KRAS/ TP53. Patients with STK11/ KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/ TP53 (4.3 months; log-rank P = .043), and STK11/ KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/ KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/ TP53 (28.3 months; log-rank P < .001), and STK11/ KRAS/ TP53 (22 months; log-rank P = .025). CONCLUSION Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis.

Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.

PURPOSE Biomarkers that can predict response to anti–programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell–inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors. METHODS KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1–positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell–inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points. RESULTS ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell–inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports. CONCLUSION A T-cell–-inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti–PD-1 therapies across a broad spectrum of cancers.

Purpose: Clinical responses with programmed death (PD-1) receptor–directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition. Patients and Methods: We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3–5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/106 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti–PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.

Birds show tremendous ecological disparity in spite of strong biomechanical constraints imposed by flight. Modular skeletal evolution is generally accepted to have facilitated this, with distinct body regions showing semi-independent evolutionary trajectories. However, this hypothesis has received little scrutiny. We analyse evolutionary modularity and ecomorphology using three-dimensional data from across the entire skeleton in a phylogenetically broad sample of extant birds. We find strongly modular evolution of skeletal element sizes within body regions (head, trunk, forelimb and hindlimb). However, element shapes show substantially less modularity, have stronger relationships to ecology, and provide evidence that ecological adaptation involves coordinated evolution of elements across different body regions. This complicates the straightforward paradigm in which modular evolution facilitated the ecological diversification of birds. Our findings suggest the potential for undetected patterns of morphological evolution in even well-studied groups, and advance the understanding of the interface between evolutionary integration and ecomorphology.

VERNALIZATION INSENSITIVE 3-LIKE (VIL) proteins are PHD-finger proteins that recruit the repressor complex Polycomb Repressive Complex 2 (PRC2) to the promoters of target genes. Most known VIL targets are flowering repressor genes. Here, we show that the tomato VIL gene CRAWLING ELEPHANT (CREL) promotes differentiation throughout plant development by facilitating the trimethylation of Histone H3 on lysine 27 (H3K27me3). We identified the crel mutant in a screen for suppressors of the simple-leaf phenotype of entire (e), a mutant in the AUX/IAA gene ENTIRE/SlIAA9, involved in compound-leaf development in tomato. crel mutants have increased leaf complexity, and suppress the ectopic blade growth of e mutants. In addition, crel mutants are late flowering, and have delayed and aberrant stem, root and flower development. Consistent with a role for CREL in recruiting PRC2, crel mutants present altered H3K27me3 modifications at a subset of PRC2 targets throughout the genome. Our results uncover a wide role for CREL in plant and organ differentiation in tomato and suggest that CREL is required for targeting PRC2 activity to, and thus silencing, a specific subset of polycomb targets.Author summaryPlants form organs continuously throughout their lives, and the number and shape of their organs is determined in a flexible manner according to the internal and external circumstances. Alongside this flexibility, plants maintain basic developmental programs to ensure proper functioning. Among the ways by which plants achieve flexible development is by tuning the pace of their maturation and differentiation, at both the plant and organ levels. One of the ways plants regulate the rate of maturation and differentiation is by changing gene expression. Here, we identified a gene that promotes plant and organ maturation and differentiation. This gene, CRAWLING ELEPHANT (CREL) acts by bringing a repressing complex to target genes. We show the importance of CREL in multiple developmental processes and in the expression of multiple genes throughout the tomato genome.

Organisms comprise multiple interacting parts, but few quantitative studies have analysed multi-element systems, limiting understanding of phenotypic evolution. We investigate how disparity of vertebral morphology varies along the axial column of mammalian carnivores — a chain of 27 subunits — and the extent to which morphological variation have been structured by evolutionary constraints and locomotory adaptation. We find that lumbars and posterior thoracics exhibit high individual disparity but low serial differentiation. They are pervasively recruited into locomotory functions and exhibit relaxed evolutionary constraint. More anterior vertebrae also show signals of locomotory adaptation, but nevertheless have low individual disparity and constrained patterns of evolution, characterised by low-dimensional shape changes. Our findings demonstrate the importance of the thoracolumbar region as an innovation enabling evolutionary versatility of mammalian locomotion. Moreover, they underscore the complexity of phenotypic macroevolution of multi-element systems and that the strength of ecomorphological signal does not have a predictable influence on macroevolutionary outcomes., Figueirido et al. use a 3D geometric morphometric approach to study functional among-species disparity in the vertebral column of Carnivora, as well as assessing the effect of different sampling methods on homology. Disparity is generally higher in more caudal regions, compared to more cranial regions, but recruitment for locomotor function is pervasive throughout the whole studied column.

RNA editing exerts critical impacts on numerous biological processes. While millions of RNA editings have been identified in humans, much more are expected to be discovered. In this work, we constructed Convolutional Neural Network (CNN) models to predict human RNA editing events in both Alu regions and non-Alu regions. With a validation dataset resulting from CRISPR/Cas9 knockout of the ADAR1 enzyme, the validation accuracies reached 99.5% and 93.6% for Alu and non-Alu regions, respectively. We ported our CNN models in a web service named EditPredict. EditPredict not only works on reference genome sequences but can also take into consideration single nucleotide variants in personal genomes. In addition to the human genome, EditPredict tackles other model organisms including bumblebee, fruitfly, mouse, and squid genomes. EditPredict can be used stand-alone to predict novel RNA editing and it can be used to assist in filtering for candidate RNA editing detected from RNA-Seq data.

Evolutionary variation in ontogeny played a central role in the origin of the avian skull. However, its influence in subsequent bird evolution is largely unexplored. We assess the links between ontogenetic and evolutionary variation of skull morphology in Strisores (nightbirds). Nightbirds span an exceptional range of ecologies, sizes, life-history traits and craniofacial morphologies constituting an ideal test for evo-devo hypotheses of avian craniofacial evolution. These morphologies include superficially ‘juvenile-like’ broad, flat skulls with short rostra and large orbits in swifts, nightjars and allied lineages, and the elongate, narrow rostra and globular skulls of hummingbirds. Here, we show that nightbird skulls undergo large ontogenetic shape changes that differ strongly from widespread avian patterns. While the superficially juvenile-like skull morphology of many adult nightbirds results from convergent evolution, rather than paedomorphosis, the divergent cranial morphology of hummingbirds originates from an evolutionary reversal to a more typical avian ontogenetic trajectory combined with accelerated ontogenetic shape change. Our findings underscore the evolutionary lability of cranial growth and development in birds, and the underappreciated role of this aspect of phenotypic variability in the macroevolutionary diversification of the amniote skull.

Earth’s largest biotic crisis occurred during the Permo–Triassic Transition (PTT). On land, this event witnessed a turnover from synapsid- to archosauromorph-dominated assemblages and a restructuring of terrestrial ecosystems. However, understanding extinction patterns has been limited by a lack of high-precision fossil occurrence data to resolve events on submillion-year timescales. We analyzed a unique database of 588 fossil tetrapod specimens from South Africa’s Karoo Basin, spanning ∼4 My, and 13 stratigraphic bin intervals averaging 300,000 y each. Using sample-standardized methods, we characterized faunal assemblage dynamics during the PTT. High regional extinction rates occurred through a protracted interval of ∼1 Ma, initially co-occurring with low origination rates. This resulted in declining diversity up to the acme of extinction near the Daptocephalus–Lystrosaurus declivis Assemblage Zone boundary. Regional origination rates increased abruptly above this boundary, co-occurring with high extinction rates to drive rapid turnover and an assemblage of short-lived species symptomatic of ecosystem instability. The “disaster taxon” Lystrosaurus shows a long-term trend of increasing abundance initiated in the latest Permian. Lystrosaurus comprised 54% of all specimens by the onset of mass extinction and 70% in the extinction aftermath. This early Lystrosaurus abundance suggests its expansion was facilitated by environmental changes rather than by ecological opportunity following the extinctions of other species as commonly assumed for disaster taxa. Our findings conservatively place the Karoo extinction interval closer in time, but not coeval with, the more rapid marine event and reveal key differences between the PTT extinctions on land and in the oceans.

Poor sleep quality can have harmful health consequences. Although many aspects of sleep are heritable, the understandings of genetic factors involved in its physiology remain limited. Here, we performed a genome-wide association study (GWAS) using the Pittsburgh Sleep Quality Index (PSQI) in a multi-ethnic discovery cohort (n = 2868) and found two novel genome-wide loci on chromosomes 2 and 7 associated with global sleep quality. A meta-analysis in 12 independent cohorts (100 000 individuals) replicated the association on chromosome 7 between NPY and MPP6. While NPY is an important sleep gene, we tested for an independent functional role of MPP6. Expression data showed an association of this locus with both NPY and MPP6 mRNA levels in brain tissues. Moreover, knockdown of an orthologue of MPP6 in Drosophila melanogaster sleep center neurons resulted in decreased sleep duration. With convergent evidence, we describe a new locus impacting human variability in sleep quality through known NPY and novel MPP6 sleep genes.

Docodonta are one of the earliest diverging groups of mammaliaforms, and their morphology provides key information on the transition between non-mammalian cynodonts and Mammalia. We describe the partial skulls of two docodontans Borealestes serendipitus and Borealestes cuillinensis sp. nov. from the Kilmaluag Formation (Middle Jurassic: Bathonian), Isle of Skye, Scotland. We visualize their cranial anatomy using laboratory and synchrotron X-ray micro-CT. The skulls belong to two partial skeletons, currently comprising the most complete Mesozoic mammal fossils reported from the British Isles. The associated upper and lower dentitions show that the lower dentition of Borealestes is not diagnostic to species level. We establish, B. cuillinensis, based on upper molar characters, and re-identify upper molars previously assigned to ‘Borealestes’ mussettae as belonging to B. cuillinensis. ‘Borealestes’ mussettae, based on distinctive lower molars, is found to be morphologically and phylogenetically distinct from Borealestes, necessitating assignment to a new genus, Dobunnodon gen. nov. The skulls of Borealestes retain many plesiomorphic features seen in Morganucodon but absent in more crownward mammaliaforms. Our study highlights that generic and species taxonomy of docodontans are more reliable when based on both upper and lower teeth, while lower molar morphology may underrepresent the true diversity of Mesozoic mammaliaforms.

Understanding how roots modulate development under varied irrigation or rainfall is crucial for development of climate resilient crops. We established a toolbox of tagged rice lines to profile translating mRNAs and chromatin accessibility within specific cell populations. We used these to study roots in a range of environments: plates in the lab, controlled greenhouse stress and recovery conditions, and outdoors in a paddy. Integration of chromatin and mRNA data resolves regulatory networks of: cycle genes in proliferating cells that attenuate DNA synthesis under submergence; genes involved in auxin signaling, the circadian clock, and small RNA regulation in ground tissue; and suberin biosynthesis, iron transporters, and nitrogen assimilation in endodermal/exodermal cells modulated with water availability. By applying a systems approach we identify known and candidate driver transcription factors of water deficit responses and xylem development plasticity. Collectively, this resource will facilitate genetic improvements in root systems for optimal climate resilience.

Several shrimp trawl fisheries use a Nordmore sorting grid to avoid bycatch of fish. However, small fish can pass through the grid. Therefore, the retention of juvenile fish often remains an issue during shrimp trawling. We investigated the vertical distribution of deepwater shrimp (Pandalus borealis) and dominant bycatch species at the point where the Nordmore grid section is installed. This was achieved using a separator frame which split the net vertically into three compartments of equal entry size. Our results showed that shrimp predominately follow the lower part of the trawl belly, whereas species such as redfish (Sebastes spp.), cod (Gadus morhua), polar cod (Boreogadus saida) and American plaice (Hippoglossoides platessoides) preferred the mid-section in the aft of the trawl. Haddock (Melanogrammus aeglefinus) primarily entered through the upper section of the trawl belly. Using these results, we predict that a vertical separation device installed forward of a 19 mm Nordmore grid combined with a 35 mm codend would result in a significant reduction in bycatch with only minor loss of shrimp., Norwegian Seafood Research Fund (FHF project) [901303]; UiT The Arctic University of Norway, We are grateful to the Norwegian Seafood Research Fund (FHF project number 901303) for funding the experiments. The publication charges for this article have been funded by a grant from the publication fund of UiT The Arctic University of Norway.

The gut of food-producing animals is a reservoir for foodborne pathogens. Thymol is bactericidal against foodborne pathogens but rapid absorption of thymol from the proximal gut precludes the delivery of effective concentrations to the lower gut where pathogens mainly colonize. Thymol-β-d-glucopyranoside is reported to be more resistant to absorption than thymol in everted jejunal segments and could potentially function as a prebiotic by resisting degradation and absorption in the proximal gut but being hydrolysable by microbial β-glycosidase in the distal gut. Previous in vitro studies showed bactericidal effects of thymol-β-d-glucopyranoside against Campylobacter, Escherichia coli, and Salmonella enterica serovar Typhimurium in the presence but not absence of intestinal microbes expressing β-glycosidase activity, indicating that hydrolysis was required to obtain antimicrobial activity. Presently, the oral administration of thymol-β-d-glucopyranoside was studied to examine the effects on intestinal carriage of Campylobacter, E. coli, and S. Typhimurium in swine. The effects of thymol-β-d-glucopyranoside or thymol on antimicrobial sensitivity of representative E. coli isolates and characterized Salmonella strains were also explored. Results from two in vivo studies revealed little antimicrobial effects of thymol-β-d-glucopyranoside on Campylobacter, E. coli, or S. Typhimurium in swine gut. These findings add credence to current thinking that hydrolysis and absorption of thymol-β-d-glucopyranoside and thymol may be sufficiently rapid within the proximal gut to preclude delivery to the distal gut. Antibiotic susceptibilities of selected bacterial isolates and strains were mainly unaffected by thymol. Further research is warranted to overcome obstacles, preventing the delivery of efficacious amounts of thymol-β-d-glucopyranoside to the lower gut.

In the Northeast Atlantic deep-water shrimp (Pandalus borealis) trawl fishery, the bycatch of juvenile fish and shrimp represents a problem. This study evaluated if inserting a 200 mm mesh size top-panel in the last three sections of the tapered upper belly section of the trawl could reduce bycatch of juveniles while maintaining the catch efficiency for deep-water shrimp. The bycatch species investigated were Greenland halibut (Reinhardtius hippoglossoides), redfish (Sebastes spp.) and polar cod (Boreogadus saida). The bycatch of Greenland halibut and the smallest polar cod was significantly reduced, while no effect was found for redfish. The large mesh panel did not lead to a significant loss of deep-water shrimp. The results of this study illustrate how a simple modification of a fishing gear can mitigate the bycatch problem in a shrimp fishery, without significant losses of the target species.

Pterosaurs were the first vertebrates to evolve powered flight1 and comprised one of the main evolutionary radiations in terrestrial ecosystems of the Mesozoic era (approximately 252–66 million years ago), but their origin has remained an unresolved enigma in palaeontology since the nineteenth century2–4. These flying reptiles have been hypothesized to be the close relatives of a wide variety of reptilian clades, including dinosaur relatives2–8, and there is still a major morphological gap between those forms and the oldest, unambiguous pterosaurs from the Upper Triassic series. Here, using recent discoveries of well-preserved cranial remains, microcomputed tomography scans of fragile skull bones (jaws, skull roofs and braincases) and reliably associated postcrania, we demonstrate that lagerpetids—a group of cursorial, non-volant dinosaur precursors—are the sister group of pterosaurs, sharing numerous synapomorphies across the entire skeleton. This finding substantially shortens the temporal and morphological gap between the oldest pterosaurs and their closest relatives and simultaneously strengthens the evidence that pterosaurs belong to the avian line of archosaurs. Neuroanatomical features related to the enhanced sensory abilities of pterosaurs9 are already present in lagerpetids, which indicates that these features evolved before flight. Our evidence illuminates the first steps of the assembly of the pterosaur body plan, whose conquest of aerial space represents a remarkable morphofunctional innovation in vertebrate evolution. Lagerpetids, bipedal archosaurs that are thought to be related to dinosaurs, are instead a sister group to pterosaurs, and although they have no obvious flight adaptations they share numerous synapomorphies with pterosaurs across the entire skeleton.

The Kilmaluag Formation on the Isle of Skye, Scotland, provides one of the richest Mesozoic vertebrate fossil assemblages in the UK, and is among the richest globally for Middle Jurassic tetrapods. Since its discovery in 1971, this assemblage has predominantly yielded small-bodied tetrapods, including salamanders, choristoderes, lepidosaurs, turtles, crocodylomorphs, pterosaurs, dinosaurs, non-mammalian cynodonts and mammals, alongside abundant fish and invertebrates. It is protected as a Site of Special Scientific Interest and by Nature Conservancy Order. Unlike contemporaneous localities from England, this assemblage yields associated partial skeletons, providing unprecedented new data. We present a comprehensive updated overview of the Kilmaluag Formation, including its geology and the fossil collections made to date, with evidence of several species occurrences presented here for the first time. We place the vertebrate faunal assemblage in an international context through comparisons with relevant contemporaneous localities from the UK, Europe, Africa, Asia and the US. This wealth of material reveals the Kilmaluag Formation as a vertebrate fossil assemblage of global significance, both in terms of understanding Middle Jurassic faunal composition and the completeness of specimens, with implications for the early evolutionary histories of mammals, squamates and amphibians.

Salmonella-contaminated lymph nodes (LN), when included into edible meat products, are a potential source of Salmonella foodborne disease. In this survey, ventral superficial cervical and mandibular LN were tested for the presence of Salmonella from two sow processing plants in the midwestern United States. Results indicate that both LN can be contaminated with Salmonella; mandibular LN have higher prevalence (p < 0.05) of Salmonella than cervical LN (16% vs. 0.91%), and the majority (>90%) of Salmonella isolates are pan-susceptible or resistant to one antimicrobial, while 9.78% of isolates were multi-drug-resistant (MDR-resistant to three or more classes of antimicrobials). Intervention methods to prevent foodborne disease could include elimination of these LN from pork products or inclusion of LN only into products that are destined for cooking. Integrated multi-faceted intervention methods need to be developed to reduce Salmonella in the food chain.

Damage incurred during the catch process is an indicator of the overall quality of fish and fish welfare. Because catch quality is difficult to improve once it has deteriorated, it is important to preserve quality during the catch process. Atlantic cod (Gadus morhua) is the most important species in the Barents Sea bottom trawl fishery. Bottom trawling is a non-benign fishing method, and it is therefore considered important to reduce damage imparted to fish during capture, and subsequently improve catch quality and fish welfare. In the present study, the levels of damage on cod captured with a new gear design were assessed in the Barents Sea bottom trawl fishery. Furthermore, this study investigated to what extent the compulsory sorting grid and diamond mesh codend configuration employed in the fishery is responsible for the damage incurred by cod during the capture process. In total, 750 cod captured over 25 hauls were evaluated for catch damage (marks, ecchymosis, exsanguination, and scale loss). The results showed that substituting the grid and codend configuration with a four-panel selective knotless section followed by a gentle codend increased the probability of cod having no catch damage by 6.00% (CI: 0.6%–11.41%). Moreover, the gentle codend led to a significant reduction in the severity of all catch damage categories.

The origin of herbivory in the Carboniferous was a landmark event in the evolution of terrestrial ecosystems, increasing ecological diversity in animals but also giving them greater influence on the evolution of land plants. We evaluate the effect of early vertebrate herbivory on plant evolution by comparing local species richness of plant palaeofloras with that of vertebrate herbivores and herbivore body size. Vertebrate herbivores became diverse and achieved a much greater range of body sizes across the Carboniferous–Permian transition interval. This coincides with an abrupt reduction in local plant richness that persists throughout the Permian. Time-series regression analysis supports a negative relationship of plant richness with herbivore richness but a positive relationship of plant richness with minimum herbivore body size. This is consistent with studies of present-day ecosystems in which increased diversity of smaller, more selective herbivores places greater predation pressures on plants, while a prevalence of larger bodied, less selective herbivores reduces the dominance of a few highly tolerant plant species, thereby promoting greater local richness. The diversification of herbivores across the Carboniferous–Permian boundary, along with the appearance of smaller, more selective herbivores like bolosaurid parareptiles, constrained plant diversity throughout the Permian. These findings demonstrate that the establishment of widespread vertebrate herbivory has structured plant communities since the late Palaeozoic, as expected from examination of modern ecosystems, and illustrates the potential for fossil datasets in testing palaeoecological hypotheses.

Plant species have evolved myriads of solutions to adapt to dynamic environments, including complex cell type development and regulation. To understand this diversity, we profiled tomato root cell type translatomes and chromatin accessibility. Using xylem differentiation in tomato, relative to Arabidopsis, examples of functional innovation, repurposing and conservation of transcription factors are described. Repurposing and innovation of genes are further observed within an exodermis regulatory network and illustrate its function. Translatome analyses of rice, tomato and Arabidopsis tissues suggest that root meristems are more conserved, and that the functions of constitutively expressed genes are more conserved than those of cell type/tissue-enriched genes. These observations suggest that higher-order properties of cell type and pan-cell type regulation are conserved between plants and animals.One Sentence SummaryPan-species cell type translatome and chromatin accessibility data reveal novelty, conservation and repurposing of gene function.

Osteocytes, cells embedded within the bone mineral matrix, inform on key aspects of vertebrate biology. In particular, a relationship between volumes of the osteocytes and bone growth and/or genome size has been proposed for several tetrapod lineages. However, the variation in osteocyte volume across different scales is poorly characterized and mostly relies on incomplete, two-dimensional information. In this study, we characterize the variation of osteocyte volumes in ray-finned fishes (Actinopterygii), a clade including more than half of modern vertebrate species in which osteocyte biology is poorly known. We use X-ray synchrotron micro-computed tomography (SRµCT) to achieve a three-dimensional visualization of osteocyte lacunae and direct measurement of their size (volumes). Our specimen sample is designed to characterize variation in osteocyte lacuna morphology at three scales: within a bone, among the bones of one individual and among species. At the intra-bone scale, we find that osteocyte lacunae vary noticeably in size between zones of organized and woven bone (being up to six times larger in woven bone), and across cyclical bone deposition. This is probably explained by differences in bone deposition rate, with larger osteocyte lacunae contained in bone that deposits faster. Osteocyte lacuna volumes vary 3.5-fold among the bones of an individual, and this cannot readily be explained by variation in bone growth rate or other currently observable factors. Finally, we find that genome size provides the best explanation of variation in osteocyte lacuna volume among species: actinopterygian taxa with larger genomes (polyploid taxa in particular) have larger osteocyte lacunae (with a ninefold variation in median osteocyte volume being measured). Our findings corroborate previous two-dimensional studies in tetrapods that also observed similar patterns of intra-individual variation and found a correlation with genome size. This opens new perspectives for further studies on bone evolution, physiology and palaeogenomics in actinopterygians, and vertebrates as a whole.

Significance Elongation factor Tu (EF-Tu) facilitates rapid and accurate selection of aminoacyl-tRNA (aa-tRNA) by the bacterial ribosome during protein synthesis. We show that EF-Tu dissociates from the ribosome as aa-tRNA navigates the accommodation corridor en route to peptide bond formation. We find that EF-Tu’s release from the ribosome during aa-tRNA selection can be reversible. We also demonstrate that new ternary complex formation, accompanied by futile cycles of GTP hydrolysis, can occur on aa-tRNA bound within the ribosome. These findings inform on the decoding mechanism, the contributions of EF-Tu to the fidelity of translation, and the potential consequences of reduced rates of peptide bond formation on cellular physiology., The substrate for ribosomes actively engaged in protein synthesis is a ternary complex of elongation factor Tu (EF-Tu), aminoacyl-tRNA (aa-tRNA), and GTP. EF-Tu plays a critical role in mRNA decoding by increasing the rate and fidelity of aa-tRNA selection at each mRNA codon. Here, using three-color single-molecule fluorescence resonance energy transfer imaging and molecular dynamics simulations, we examine the timing and role of conformational events that mediate the release of aa-tRNA from EF-Tu and EF-Tu from the ribosome after GTP hydrolysis. Our investigations reveal that conformational changes in EF-Tu coordinate the rate-limiting passage of aa-tRNA through the accommodation corridor en route to the peptidyl transferase center of the large ribosomal subunit. Experiments using distinct inhibitors of the accommodation process further show that aa-tRNA must at least partially transit the accommodation corridor for EF-Tu⋅GDP to release. aa-tRNAs failing to undergo peptide bond formation at the end of accommodation corridor passage after EF-Tu release can be reengaged by EF-Tu⋅GTP from solution, coupled to GTP hydrolysis. These observations suggest that additional rounds of ternary complex formation can occur on the ribosome during proofreading, particularly when peptide bond formation is slow, which may serve to increase both the rate and fidelity of protein synthesis at the expense of GTP hydrolysis.

Tetanurae is a special group of theropod dinosaurs that originated by the late Early Jurassic. It includes several early-diverging groups of generally large-bodied predators (megalosauroids, allosauroids, tyrannosauroid coelurosaurs) as well as morphologically disparate small-bodied coelurosaurs, including birds. Aspects of the evolutionary history of tetanurans remain contested, including the topology of their deep phylogenetic divergences (among Megalosauroidea, Allosauroidea and Coelurosauria). We report a new theropod, Yunyangosaurus puanensis gen. et sp. nov., based on a fragmentary specimen recovered from the Middle Jurassic Xintiangou Formation of Chongqing, southwestern China. It shares several features uniquely with some megalosauroids (the clade of megalosaurids + spinosaurids + piatnitzkysaurids), such as prominent rims around the anterior articular surfaces of cervical centra and bifurcated anterior dorsal neural spines (present in piatnitzkysaurids). Nevertheless, it also shows several features that are rare or absent among megalosauroids and more crownward tetanurans, including prominent spinopostyzgopophyseal laminae (also present in non-tetanurans and metriacanthosaurid allosauroids), flat anterior articular surfaces of the cervical centra (also present in piatnitzkysaurids and some earlier-diverging tetanurans), and the presence of a posterior pneumatic foramen or fossa (absent in most tetanurans, but sporadically present in some cervical vertebrae of piatnitzkysaurids). Yunyangosaurus therefore presents a combination of derived and apparently primitive character states that are not seen in other theropods. This suggests that patterns of morphological evolution associated with deep tetanuran divergences were more complex than currently recognized, with implications for understanding the character evolution in theropods.

Insular gigantism—evolutionary increases in body size from small-bodied mainland ancestors—is a conceptually significant, but poorly studied, evolutionary phenomenon. Gigantism is widespread on Mediterranean islands, particularly among fossil and extant dormice. These include an extant giant population of Eliomys quercinus on Formentera, the giant Balearic genus †Hypnomys and the exceptionally large †Leithia melitensis of Pleistocene Sicily. We quantified patterns of cranial and mandibular shape and their relationships to head size (allometry) among mainland and insular dormouse populations, asking to what extent the morphology of island giants is explained by allometry. We find that gigantism in dormice is not simply an extrapolation of the allometric trajectory of their mainland relatives. Instead, a large portion of their distinctive cranial and mandibular morphology resulted from the population- or species-specific evolutionary shape changes. Our findings suggest that body size increases in insular giant dormice were accompanied by the evolutionary divergence of feeding adaptations. This complements other evidence of ecological divergence in these taxa, which span predominantly faunivorous to herbivorous diets. Our findings suggest that insular gigantism involves context-dependent phenotypic modifications, underscoring the highly distinctive nature of island faunas., JJH is funded by a PhD studentship from the Hull York Medical School. The European Federation of Experimental Morphology provided additional funding enabling the necessary visits to museum collections throughout Europe. Funding was also provided by the European Union’s Horizon 2020 research and innovation program 2014–2018 under grant agreement 677774 (European Research Council [ERC] Starting Grant: TEMPO) to RBJB. The contribution of ET and JAA is a part of the Research Project CGL2016-79795-R funded by the Agencia Estatal de Investigación (Ministerio de Economía, Industria y Competitividad)/Fondo Europeo de Desarrollo Regional (FEDER).

External damages are indicators of the overall quality of fish and fish welfare. Haddock is an important commercial species widespread in the North Atlantic, but few studies related to quality have been carried out on this species. We studied the levels of external damages on haddock captured with a demersal trawl in the Northeast Atlantic. Further, we investigated to what extent the compulsory sorting grid and diamond mesh codend gear configuration employed in this trawl fishery is responsible for the external damages observed during the capture process. We evaluated external damages on 563 haddock captured over 22 hauls. In general, the results showed that catching haddock without any gear inflicted damages using demersal trawls is challenging. However, the results also showed that the severity of most damages is low and the probability to catch haddock with no external damage can be significantly increased removing the grid and changing codend design.

This study investigated the size selectivity and catch efficiency in the North-east Atlantic demersal trawl fishery targeting cod (Gadus morhua) and haddock (Melanogrammus aeglefinus). The use of a sorting grid followed by a size selective codend is compulsory in this fishery. Experimental fishing was conducted with a commercially rigged trawl, flexigrid section, and diamond-mesh codend. The flexigrid section is a dual sorting system and all fish that escaped from the two grids in the flexigrid system and the codend were retained in separate covers. This allowed us to estimate the combined size selectivity of the system, as well as the separate contributions from the first grid, second grid, and codend. The catch efficiencies for cod and haddock below and above the minimum reference length (MRL) were quantified by estimating the values for a set of exploitation pattern indicators. The results showed that most fish escaped from the flexigrid section. Only a few fish below the MRL entered the codend and nearly all of them subsequently escaped through the codend meshes. The probability of retaining undersized cod and haddock was low with the combined system. Furthermore, the results showed that the probability of escape was high through the second grid in the system for fish above the MRL, and this finding was supported by the exploitation pattern indicators. In particular, the estimated exploitation pattern indicators showed that using the current MRL and the fish size distributions encountered during the trials, no haddock and only 2.3 % of cod below the MRL were retained by the gear. However, 77.4 % of the haddock and 16.0 % of the cod above the MRL were found to escape, thereby indicating poor catch efficiency, especially for haddock. These results demonstrate the importance of supplementing size selectivity research with estimates of the actual catch efficiency using the gear employed, which were quantified using exploitation pattern indicators in this study.

Gillnets are among the most widely used fishing gear in global fisheries because of their simplicity, high operability, catch efficiency and low entrance cost for fishermen. In Norway, the Northeast Atlantic (NEA) cod (Gadus morhua) fishing industry represents the most important economic single species fishery and the gillnet fishery accounts for 24% of the national total allowable catch (TAC) of NEA cod. Despite the importance of the gillnet fishery in Norway, significant amounts of gillnets are lost at sea each year. As gillnets are made of synthetic materials (i.e. nylon) with high breaking strength and durability, lost, abandoned and/or discarded fishing gear (LADFG) continues catching target and non-target species for years. This phenomenon, known as "ghost fishing", cause negative impact on the benthic marine environment and to the fisheries management. Over the last years, the development of biodegradable gillnets to replace traditional nylon gillnets has become particularly sought after in fisheries worldwide. However, biodegradable gillnets are less efficient and more expensive than traditional nylon gillnets. As the urgency to eliminate the negative environmental impacts of LADFG increases, a crucial question remains how to successfully implement biodegradable gillnets to replace the more efficient nylon gillnets currently used in commercial fisheries. In this article we investigate how central elements of fisheries management may be used to implement biodegradable gillnets and how this may challenge the current resource allocation policy among different gear- and vessel groups.

Plant species have evolved myriads of solutions, including complex cell type development and regulation, to adapt to dynamic environments. To understand this cellular diversity, we profiled tomato root cell type translatomes. Using xylem differentiation in tomato, examples of functional innovation, repurposing and conservation of transcription factors are described, relative to the model plant Arabidopsis. Repurposing and innovation of genes are further observed within an exodermis regulatory network and illustrate its function. Comparative translatome analyses of rice, tomato and Arabidopsis tissues suggest increased expression conservation of root meristems compared with other homologous tissues. In addition, the functions of constitutively expressed genes are more conserved than those of cell type/tissue-enriched genes. These observations suggest that higher-order properties of cell type and pan-cell type regulation are evolutionarily conserved between plants and animals.

In the North-East Atlantic demersal trawl fishery targeting cod and haddock, the interest on fishing gear designs that preserve fish quality and welfare has grown. However, the gear configurations tested so far imply practical challenges, therefore, more user-friendly designs are still sought by the industry. For a new design to be considered, it needs to have size selective properties that are at least comparable to those obtained with the standard grid and codend gear configuration used in the fishery today. In the present study, we investigated the size selectivity of a new design on three of the most important commercial species in the fishery: cod (Gadus morhua), haddock (Melanogrammus aeglefinnus) and redfish (Sebastes spp.). The new design did not include a sorting grid and was composed of a large mesh segment followed by a quality preserving codend installed in the aft of the gear. The results showed that the experimental gear did not work as intended, catching significantly higher numbers of undersized fish than the standard gear for all three species included in the study. Further, based on hypothesis testing, the null hypothesis of “zero release from the experimental gear” could not be falsified, meaning that it could not be ruled out that there was no escape of fish at all from the experimental gear tested. Despite the negative results obtained, the results from this study enhance the understanding of gear selectivity in towed fishing gears. © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Marsupials show a smaller range of forelimb ecomorphologies than placental mammals, and it is hypothesized that this results from macroevolutionary constraints imposed by the specialized reproductive biology of marsupials. Specifically, the accelerated development of the marsupial forelimb allows neonates to crawl to the mother’s pouch but may constrain adult morphology. This hypothesis makes three main predictions: (i) that marsupial forelimbs should show less interspecific disparity than their hindlimbs, (ii) that morphological integration within the marsupial forelimb is stronger than integration between limbs, and (iii) that these patterns should be strongest in diprotodontians, which undergo the most rigorous crawls as neonates. We use a three-dimensional geometric morphometric data set of limb bones for 51 marsupial species to test these predictions. We find that (i) marsupial forelimbs and hindlimbs show similar disparities, (ii) no clear differences in integration exist either within or between limbs, and (iii) the same patterns occur in diprotodontians as in other marsupials, even correcting for lineage age. Therefore, there is currently little evidence that the developmental biology of marsupials has constrained their macroevolutionary patterns. It is possible that functional selection can overcome the effects of developmental constraint on macroevolutionary timescales. Our findings suggest that the role of developmental constraints in explaining the limited phenotypic variability of marsupials (compared with that of placentals) should be reconsidered.