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Nanobodies are highly valuable tools for numerous bioanalytical and biotechnical applications. Here, we report the characterization of a nanobody that binds a short peptide epitope with extraordinary affinity. Structural analysis reveals an unusual binding mode where the extended peptide becomes part of a β-sheet structure in the nanobody. This interaction relies on sequence-independent backbone interactions augmented by a small number of specificity-determining side chain contacts. Once bound, the peptide is fastened by two nanobody side chains that clamp it in a headlock fashion. Exploiting this unusual binding mode, we generated a novel nanobody-derived capture and detection system. Matrix-coupled nanobody enables the fast and efficient isolation of epitope-tagged proteins from prokaryotic and eukaryotic expression systems. Additionally, the fluorescently labeled nanobody visualizes subcellular structures in different cellular compartments. The high-affinity-binding and modifiable peptide tag of this system renders it a versatile and robust tool to combine biochemical analysis with microscopic studies.

SignificanceOur understanding of the factors that affected the diversification of passerines, the most diverse and widespread bird order (Passeriformes), is limited. Here, we reconstruct passerine evolutionary history and produce the most comprehensive time-calibrated phylogenetic hypothesis of the group using extensive sampling of the genome, complete sampling of all passerine families, and a number of vetted fossil calibration points. Our phylogenetic results refine our knowledge of passerine diversity and yield divergence dates that are consistent with the fossil record, and our macroevolutionary analyses suggest that singular events in Earth history, such as increases in Cenozoic global temperature or the colonization of new continents, were not the primary forces driving passerine diversification. Avian diversification has been influenced by global climate change, plate tectonic movements, and mass extinction events. However, the impact of these factors on the diversification of the hyperdiverse perching birds (passerines) is unclear because family level relationships are unresolved and the timing of splitting events among lineages is uncertain. We analyzed DNA data from 4,060 nuclear loci and 137 passerine families using concatenation and coalescent approaches to infer a comprehensive phylogenetic hypothesis that clarifies relationships among all passerine families. Then, we calibrated this phylogeny using 13 fossils to examine the effects of different events in Earth history on the timing and rate of passerine diversification. Our analyses reconcile passerine diversification with the fossil and geological records; suggest that passerines originated on the Australian landmass ∼47 Ma; and show that subsequent dispersal and diversification of passerines was affected by a number of climatological and geological events, such as Oligocene glaciation and inundation of the New Zealand landmass. Although passerine diversification rates fluctuated throughout the Cenozoic, we find no link between the rate of passerine diversification and Cenozoic global temperature, and our analyses show that the increases in passerine diversification rate we observe are disconnected from the colonization of new continents. Taken together, these results suggest more complex mechanisms than temperature change or ecological opportunity have controlled macroscale patterns of passerine speciation.

A key question for climate change adaptation is whether existing cropping systems can become less sensitive to climate variations. We use a field-level data set on maize and soybean yields in the central United States for 1995 through 2012 to examine changes in drought sensitivity. Although yields have increased in absolute value under all levels of stress for both crops, the sensitivity of maize yields to drought stress associated with high vapor pressure deficits has increased. The greater sensitivity has occurred despite cultivar improvements and increased carbon dioxide and reflects the agronomic trend toward higher sowing densities. The results suggest that agronomic changes tend to translate improved drought tolerance of plants to higher average yields but not to decreasing drought sensitivity of yields at the field scale.

We compare predictions of a simple process-based crop model (Soltani and Sinclair 2012), a simple statistical model (Schlenker and Roberts 2009), and a combination of both models to actual maize yields on a large, representative sample of farmer-managed fields in the Corn Belt region of the United States. After statistical post-model calibration, the process model (Simple Simulation Model, or SSM) predicts actual outcomes slightly better than the statistical model, but the combined model performs significantly better than either model. The SSM, statistical model and combined model all show similar relationships with precipitation, while the SSM better accounts for temporal patterns of precipitation, vapor pressure deficit and solar radiation. The statistical and combined models show a more negative impact associated with extreme heat for which the process model does not account. Due to the extreme heat effect, predicted impacts under uniform climate change scenarios are considerably more severe for the statistical and combined models than for the process-based model.

Abstract Light at night (LAN) has been associated with negative health consequences and metabolic risk factors. Little is known about the prevalence of LAN in older adults in the United States and its association with CVD risk factors. We tested the hypothesis that LAN in older age is associated with higher prevalence of individual CVD risk factors. Five hundred and fifty-two community-dwelling adults aged 63−84 years underwent an examination of CVD risk factor profiles and 7-day actigraphy recording for activity and light measures. Associations between actigraphy-measured LAN, defined as no light vs. light within the 5-hour nadir (L5), and CVD risk factors, including obesity, diabetes, hypertension, and hypercholesterolemia, were examined, after adjusting for age, sex, race, season of recording, and sleep variables. LAN exposure was associated with a higher prevalence of obesity (multivariable-adjusted odds ratio [OR] 1.82 [95% CI 1.26−2.65]), diabetes (OR 2.00 [1.19−3.43]), and hypertension (OR 1.74 [1.21−2.52]) but not with hypercholesterolemia. LAN was also associated with (1) later timing of lowest light exposure (L5-light) and lowest activity (L5-activity), (2) lower inter-daily stability and amplitude of light exposure and activity, and (3) higher wake after sleep onset. Habitual LAN in older age is associated with concurrent obesity, diabetes, and hypertension. Further research is needed to understand long-term effects of LAN on cardiometabolic risks. Graphical Abstract Graphical Abstract

In patients with autosomal dominant polycystic kidney disease, the rate of increase in total kidney volume was not slowed by lisinopril and telmisartan, as compared with lisinopril and placebo, but was slowed with rigorous blood-pressure control. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by gradual cyst enlargement over a period of decades before the loss of kidney function. 1 – 3 Total kidney volume in ADPKD is accurately measured with the use of magnetic resonance imaging (MRI). 4 – 6 Hypertension occurs early 6 , 7 and is associated with progression to end-stage renal disease (ESRD) and death from cardiovascular causes in patients with ADPKD. 8 , 9 Immunohistologic studies 10 , 11 and clinical studies 12 , 13 support a central role of the renin–angiotensin–aldosterone system (RAAS) in the pathogenesis of hypertension in patients with ADPKD. Activation of the RAAS may promote renal-cyst growth by means . . .

Species concepts are well established and apply across diverse groups of organisms; however, there is no consensus on what defines higher taxonomic groups. The genus rank is important to taxonomists because it comprises part of the scientific name of an organism. A consistent and biologically meaningful method for determining generic status is needed for taxonomic stability and utility. Lasiurine bats are a group for which there is disagreement on how many genera to recognize. Some authors argue for splitting this group into three genera based on morphology, genetic divergence, and time of divergence; others argue that a single genus should be maintained. Here, we use lasiurines to explore generic-level taxonomy and how it is applied. Genetic divergence levels are compared among sister genera and within genera of vespertilionine bats using Cytochrome b ( Cytb ) sequences. We used Cytb because it is the most sequenced mitochondrial gene in mammals, but other genes might be more appropriate for a different taxon. Future methods will eventually use complete mitogenomes and genomes. We conclude that lasiurine bats are most appropriately divided into three genera to maintain taxonomic consistency within their subfamily. Since Linnaeus, the quarter millennium of progress in the science of mammalogy has provided a binomial nomenclatural basis from which can be extracted an acceptable range of genetic diversity upon which to establish generic level taxonomy. We offer a biologically meaningful operational definition of the genus, which we call the 2 Sigma Genus Concept, based on genetic divergence between a genus and its sister genus or lineage and compared to the divergence between sister pairs of established genera in the same higher taxonomic category. Our method is phylogenetic; sister genera are based on the best phylogeny for the higher taxonomic category. Genera must be monophyletic and differ from their closest relatives by not more than two standard deviations above or below the mean value of genetic distance for the larger taxonomic group in which they are contained. There should be genetic-based characters (e.g., morphology, protein structure, behavior) that are diagnostic for each genus. Our method is novel in that it uses the statistical distribution of sister divergences within a higher category to guide the allocation of generic status to monophyletic lineages. Within Vespertilioninae, the mean genetic distance between sister genera is 20.68% ± 3.89% (K2P) for the Cytb gene. Therefore, a proposed new genus should have >12.90% genetic distance to its sister genus. Genera that are > 2 standard deviations above the mean (>28.46%) are candidates to be recognized as a higher category such as tribe or subfamily. The sister-genus divergence for the monophyletic lineage that includes all lasiurine bats is 31.14% ± 1.64% which qualifies it as a higher category (i.e., tribe), and the sister-genus divergences of the three monophyletic lineages within Lasiurini (i.e., red, yellow and hoary bats) are 21.77% and 22.91% which qualifies them for genera. We show the applicability of the method beyond Vespertilioninae by providing a case study where we apply it in a distantly related subfamily of bats.

Regular physical activity (PA) is increasingly promoted for people with rheumatic and musculoskeletal diseases as well as the general population. We evaluated if the public health recommendations for PA are applicable for people with inflammatory arthritis (iA; Rheumatoid Arthritis and Spondyloarthritis) and osteoarthritis (hip/knee OA) in order to develop evidence-based recommendations for advice and guidance on PA in clinical practice. The EULAR standardised operating procedures for the development of recommendations were followed. A task force (TF) (including rheumatologists, other medical specialists and physicians, health professionals, patient-representatives, methodologists) from 16 countries met twice. In the first TF meeting, 13 research questions to support a systematic literature review (SLR) were identified and defined. In the second meeting, the SLR evidence was presented and discussed before the recommendations, research agenda and education agenda were formulated. The TF developed and agreed on four overarching principles and 10 recommendations for PA in people with iA and OA. The mean level of agreement between the TF members ranged between 9.8 and 8.8. Given the evidence for its effectiveness, feasibility and safety, PA is advocated as integral part of standard care throughout the course of these diseases. Finally, the TF agreed on related research and education agendas. Evidence and expert opinion inform these recommendations to provide guidance in the development, conduct and evaluation of PA-interventions and promotion in people with iA and OA. It is advised that these recommendations should be implemented considering individual needs and national health systems.

Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy. In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials). HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20–1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05–1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01–1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01–1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16–2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63·8%] of 254 HLA-A*03 non-carriers and 40 [55·6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10−8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0–0·76) HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer. National Institutes of Health, Merck KGaA, and Pfizer.

Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries. Accurate treatment of traumatic brain injuries, a leading cause of neurological disability and death in young people, is hampered by poor accumulation of drugs in the brain. Here, the authors describe a tetrapeptide that can efficiently target brain injuries and deliver therapeutic or diagnostic payload.