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Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies., Competing Interests: NB, JH, MN No competing interests declared, (© 2019, Barton et al.)

Objective: To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants., Study Design: This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 23 0/7  weeks to 27 6/7  weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 29 6/7  weeks) or standard neonatal care, with follow-up to a postmenstrual age of 40 4/7  weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures., Results: Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures., Conclusions: rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage., Trial Registration: ClinicalTrials.gov: NCT01096784., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.

The question of cognitive complexity in early Homo sapiens in North Africa is intimately tied to the emergence of the Aterian culture (~145 ka). One of the diagnostic indicators of cognitive complexity is the presence of specialised bone tools, however significant uncertainty remains over the manufacture and use of these artefacts within the Aterian techno-complex. In this paper we report on a bone artefact from Aterian Middle Stone Age (MSA) deposits in Dar es-Soltan 1 cave on the Atlantic coast of Morocco. It comes from a layer that can be securely dated to ~90 ka. The typological characteristics of this tool, which suggest its manufacture and use as a bone knife, are comparatively similar to other bone artefacts from dated Aterian levels at the nearby site of El Mnasra and significantly different from any other African MSA bone technology. The new find from Dar es-Soltan 1 cave combined with those from El Mnasra suggest the development of a bone technology unique to the Aterian., Competing Interests: The authors have declared that no competing interests exist.

Background: Abdominoplasty is a common operation, used for a range of cosmetic and functional issues, often in the context of divarication of recti, significant weight loss, and after pregnancy. Despite this, patient-surgeon communication gaps can hinder informed decision-making. The integration of large language models (LLMs) in healthcare offers potential for enhancing patient information. This study evaluated the feasibility of using LLMs for answering perioperative queries., Methods: This study assessed the efficacy of four leading LLMs-OpenAI's ChatGPT-3.5, Anthropic's Claude, Google's Gemini, and Bing's CoPilot-using fifteen unique prompts. All outputs were evaluated using the Flesch-Kincaid, Flesch Reading Ease score, and Coleman-Liau index for readability assessment. The DISCERN score and a Likert scale were utilized to evaluate quality. Scores were assigned by two plastic surgical residents and then reviewed and discussed until a consensus was reached by five plastic surgeon specialists., Results: ChatGPT-3.5 required the highest level for comprehension, followed by Gemini, Claude, then CoPilot. Claude provided the most appropriate and actionable advice. In terms of patient-friendliness, CoPilot outperformed the rest, enhancing engagement and information comprehensiveness. ChatGPT-3.5 and Gemini offered adequate, though unremarkable, advice, employing more professional language. CoPilot uniquely included visual aids and was the only model to use hyperlinks, although they were not very helpful and acceptable, and it faced limitations in responding to certain queries., Conclusion: ChatGPT-3.5, Gemini, Claude, and Bing's CoPilot showcased differences in readability and reliability. LLMs offer unique advantages for patient care but require careful selection. Future research should integrate LLM strengths and address weaknesses for optimal patient education., Level of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. The Author(s).)

For at least 150,000 years, the human body has been culturally modified by the wearing of personal ornaments and probably by painting with red pigment. The present study used functional magnetic resonance imaging to explore the brain networks involved in attributing social status from face decorations. Results showed the fusiform gyrus, orbitofrontal cortex, and salience network were involved in social encoding, categorization, and evaluation. The hippocampus and parahippocampus were activated due to the memory and associative skills required for the task, while the inferior frontal gyrus likely interpreted face ornaments as symbols. Resting-state functional connectivity analysis clarified the interaction between these regions. The study highlights the importance of these neural interactions in the symbolic interpretation of social markers on the human face, which were likely active in early Homo species and intensified with Homo sapiens populations as more complex technologies were developed to culturalize the human face., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

When populations colonise new environments, they may be exposed to novel selection pressures but also suffer from extensive genetic drift due to founder effects, small population sizes and limited interpopulation gene flow. Genomic approaches enable us to study how these factors drive divergence, and disentangle neutral effects from differentiation at specific loci due to selection. Here, we investigate patterns of genetic diversity and divergence using whole-genome resequencing (>22× coverage) in Berthelot's pipit (Anthus berthelotii), a passerine endemic to the islands of three north Atlantic archipelagos. Strong environmental gradients, including in pathogen pressure, across populations in the species range, make it an excellent system in which to explore traits important in adaptation and/or incipient speciation. First, we quantify how genomic divergence accumulates across the speciation continuum, that is, among Berthelot's pipit populations, between sub species across archipelagos, and between Berthelot's pipit and its mainland ancestor, the tawny pipit (Anthus campestris). Across these colonisation timeframes (2.1 million-ca. 8000 years ago), we identify highly differentiated loci within genomic islands of divergence and conclude that the observed distributions align with expectations for non-neutral divergence. Characteristic signatures of selection are identified in loci associated with craniofacial/bone and eye development, metabolism and immune response between population comparisons. Interestingly, we find limited evidence for repeated divergence of the same loci across the colonisation range but do identify different loci putatively associated with the same biological traits in different populations, likely due to parallel adaptation. Incipient speciation across these island populations, in which founder effects and selective pressures are strong, may therefore be repeatedly associated with morphology, metabolism and immune defence., (© 2024 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Hybrid zones have been viewed as an opportunity to see speciation in action. When hybrid zones are replicated, it is assumed that if the same genetic incompatibilities are maintaining reproductive isolation across all instances of secondary contact, those incompatibilities should be identifiable by consistent patterns in the genome. In contrast, changes in allele frequencies due to genetic drift should be idiosyncratic for each hybrid zone. To test this assumption, we simulated 20 replicates of each of 12 hybrid zone scenarios with varied genetic incompatibilities, rates of migration, selection and different starting population size ratios of parental species. We found remarkable variability in the outcomes of hybridisation in replicate hybrid zones, particularly with Bateson-Dobzhansky-Muller incompatibilities and strong selection. We found substantial differences among replicates in the overall genomic composition of individuals, including admixture proportions, inter-specific ancestry complement and number of ancestry junctions. Additionally, we found substantial variation in genomic clines among replicates at focal loci, regardless of locus-specific selection. We conclude that processes other than selection are responsible for some consistent outcomes of hybridisation, whereas selection on incompatibilities can lead to genomically widespread and highly variable outcomes. We highlight the challenge of mapping between pattern and process in hybrid zones and call attention to how selection against incompatibilities will commonly lead to variable outcomes. We hope that this study informs future research on replicate hybrid zones and encourages further development of statistical techniques, theoretical models and exploration of additional axes of variation to understand reproductive isolation., (© 2024 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

The present study introduces "rock slope instability score (RSIS)" a novel classification system for assessing rock slope stability. It takes into account geological and geotechnical parameters, as well as the impact of human activities and triggering parameters, which have become more frequent due to climate change and few of them have been ignored in existing classifications. The study focuses on rock slopes of various lithologies from the Indian Himalayas. The development of this new classification system is based on the examination of 81 different rock slopes from various states of the Indian Himalayas. Extensive field surveys, rock sampling, geotechnical laboratory tests, and ground measurements have been conducted at the various slope sites to establish a comprehensive scoring system for the stability assessment. The distributions of weightage to each parameter have been considered, corresponding to its degree of impact in causing slope instability. Sensitivity analysis of all defined parameters of RSIS system has revealed that the majority of the parameters exhibit a strong positive correlation, with Pearson correlation coefficients ranging from 0.74 to 0.61. However, two parameters, namely discontinuity dip and the relationship between slope & discontinuity direction, gives moderate relationship with correlation coefficient values of 0.48 and 0.41, respectively. To avoid any designer biasness in the system, several individuals gathered data set at different times. The proposed classification system has demonstrated a strong correlation with the actual slope condition, and it is quite promising. The outcome of RSIS classification for studied 81 slopes classified 2 slopes under stable condition, 21 slopes as partially stable, 44 as unstable, and 14 as completely unstable., (© 2024. The Author(s).)

Body size variation is central in the evolution of life-history traits in amphibians, but the underlying genetic architecture of this complex trait is still largely unknown. Herein, we studied the genetic basis of body size and fecundity of the alternative morphotypes in a wild population of the Greek smooth newt (Lissotriton graecus). By combining a genome-wide association approach with linkage disequilibrium network analysis, we were able to identify clusters of highly correlated loci thus maximizing sequence data for downstream analysis. The putatively associated variants explained 12.8% to 44.5% of the total phenotypic variation in body size and were mapped to genes with functional roles in the regulation of gene expression and cell cycle processes. Our study is the first to provide insights into the genetic basis of complex traits in newts and provides a useful tool to identify loci potentially involved in fitness-related traits in small data sets from natural populations in non-model species., (© 2024 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

As an alternative to traditional photolithography, printing processes are widely explored for the patterning of customizable devices. However, to date, the majority of high-resolution printing processes for functional nanomaterials are additive in nature. To complement additive printing, there is a need for subtractive processes, where the printed ink results in material removal, rather than addition. In this study, a new subtractive patterning approach that uses electrohydrodynamic-jet (e-jet) printing of acid-based inks to etch nanoscale zinc oxide (ZnO) thin films deposited using atomic layer deposition (ALD) is introduced. By tuning the printing parameters, the depth and linewidth of the subtracted features can be tuned, with a minimum linewidth of 11 µm and a tunable channel depth with ≈5 nm resolution. Furthermore, by tuning the ink composition, the volatility and viscosity of the ink can be adjusted, resulting in variable spreading and dissolution dynamics at the solution/film interface. In the future, acid-based subtractive patterning using e-jet printing can be used for rapid prototyping or customizable manufacturing of functional devices on a range of substrates with nanoscale precision., (© 2023 The Authors. Small Methods published by Wiley‐VCH GmbH.)

The black abalone, Haliotis cracherodii, is a large, long-lived marine mollusc that inhabits rocky intertidal habitats along the coast of California and Mexico. In 1985, populations were impacted by a bacterial disease known as withering syndrome (WS) that wiped out >90% of individuals, leading to the closure of all U.S. black abalone fisheries since 1993. Current conservation strategies include restoring diminished populations by translocating healthy individuals. However, population collapse on this scale may have dramatically lowered genetic diversity and strengthened geographic differentiation, making translocation-based recovery contentious. Additionally, the current prevalence of WS remains unknown. To address these uncertainties, we sequenced and analysed the genomes of 133 black abalone individuals from across their present range. We observed no spatial genetic structure among black abalone, with the exception of a single chromosomal inversion that increases in frequency with latitude. Outside the inversion, genetic differentiation between sites is minimal and does not scale with either geographic distance or environmental dissimilarity. Genetic diversity appears uniformly high across the range. Demographic inference does indicate a severe population bottleneck beginning just 15 generations in the past, but this decline is short lived, with present-day size far exceeding the pre-bottleneck status quo. Finally, we find the bacterial agent of WS is equally present across the sampled range, but only in 10% of individuals. The lack of population genetic structure, uniform diversity and prevalence of WS bacteria indicates that translocation could be a valid and low-risk means of population restoration for black abalone species' recovery., (© 2024 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Genomes are heterogeneous during the early stages of speciation, with small 'islands' of DNA appearing to reflect strong adaptive differences, surrounded by vast seas of relative homogeneity. As species diverge, secondary contact zones between them can act as an interface and selectively filter through advantageous alleles of hybrid origin. Such introgression is another important adaptive process, one that allows beneficial mosaics of recombinant DNA ('rivers') to flow from one species into another. Although genomic islands of divergence appear to be associated with reproductive isolation, and genomic rivers form by adaptive introgression, it is unknown whether islands and rivers tend to be the same or different loci. We examined three replicate secondary contact zones for the Yosemite toad (Anaxyrus canorus) using two genomic data sets and a morphometric data set to answer the questions: (1) How predictably different are islands and rivers, both in terms of genomic location and gene function? (2) Are the adaptive genetic trait loci underlying tadpole growth and development reliably islands, rivers or neither? We found that island and river loci have significant overlap within a contact zone, suggesting that some loci are first islands, and later are predictably converted into rivers. However, gene ontology enrichment analysis showed strong overlap in gene function unique to all island loci, suggesting predictability in overall gene pathways for islands. Genome-wide association study outliers for tadpole development included LPIN3, a lipid metabolism gene potentially involved in climate change adaptation, that is island-like for all three contact zones, but also appears to be introgressing (as a river) across one zone. Taken together, our results suggest that adaptive divergence and introgression may be more complementary forces than currently appreciated., (© 2024 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Evaluating whether hybrid zones are stable or mobile can provide novel insights for evolution and conservation biology. Butterflies exhibit high sensitivity to environmental changes and represent an important model system for the study of hybrid zone origins and maintenance. Here, we review the literature exploring butterfly hybrid zones, with a special focus on their spatiotemporal dynamics and the potential mechanisms that could lead to their movement or stability. We then compare different lines of evidence used to investigate hybrid zone dynamics and discuss the strengths and weaknesses of each approach. Our goal with this review is to reveal general conditions associated with the stability or mobility of butterfly hybrid zones by synthesizing evidence obtained using different types of data sampled across multiple regions and spatial scales. Finally, we discuss spatiotemporal dynamics in the context of a speciation/divergence continuum, the relevance of hybrid zones for conservation biology, and recommend key topics for future investigation., (© 2023 The Authors. Insect Science published by John Wiley & Sons Australia, Ltd on behalf of Institute of Zoology, Chinese Academy of Sciences.)

The far-field high-energy diffraction microscopy technique is presented in the context of high-energy synchrotron x-ray diffraction. For each grain in an illuminated polycrystalline volume, the volume-averaged lattice orientations, lattice strain tensors, and centre-of-mass (COM) coordinates may be determined to a high degree of precision: better than 0.05°, 1 × 10−4, and 0.1 pixel, respectively. Because the full lattice strain tensors are available, corresponding mean stress tensors may be calculated unambiguously using single-crystal elastic moduli. A novel formulation for orientation indexing and cell refinement is introduced and demonstrated using two examples: first, sequential indexing and lattice refinement of a single-crystal ruby standard with known COM coordinates; and second, indexing and refinement of simulated diffraction data from an aggregate of 819 individual grains using several sample rotation ranges and including the influence of experimental uncertainties. The speed of acquisition and penetration depth achievable with high-energy (that is, >50 keV) x-rays make this technique ideal for studies of strain/stress evolution in situ, as well as for residual stress analysis. [ABSTRACT FROM PUBLISHER]

Multiple myeloma has a continued need for more effective and durable therapies. B cell maturation antigen (BCMA), a plasma cell surface antigen and member of the tumor necrosis factor (TNF) receptor superfamily, is an attractive target for immunotherapy of multiple myeloma due to its high prevalence on malignant plasma cells. The current work details the pre-clinical evaluation of BCMA expression and development of a chimeric antigen receptor (CAR) targeting this antigen using a fully human single chain variable fragment (scFv). We demonstrate that BCMA is prevalently, but variably expressed by all MM with expression on 25-100% of malignant plasma cells. Extensive Immunohistochemical analysis of normal tissue expression using commercially available polyclonal antibodies demonstrated expression within B-lineage cells across a number of tissues as expected. Based upon the highly restricted expression of BCMA within normal tissues, we generated a set of novel, fully human scFv binding domains to BCMA by screening a naïve B-cell derived phage display library. Using a series of in vitro and pre-clinical in vivo studies, we identified a scFv with high specificity for BCMA and robust anti-myeloma activity when used as the binding domain of a second-generation CAR bearing a CD137 costimulatory domain. This BCMA-specific CAR is currently being evaluated in a Phase 1b clinical study in relapsed and refractory MM patients (NCT02546167)., Competing Interests: CONFLICTS OF INTEREST E.D.C, R.S., Q. W., J.Z., Y. W., L.W., A.L., S.C., T.E., S. J., K.G. M., K.J.L., W.R.T., H.A.H, DX. B., P.B., N.B., and C.J.R. were paid employees of Novartis at the time this work was performed. The University of Pennsylvania and Novartis hold a patent in the use of CAR T cells in oncology. E.D.C, R.S., M.R., Y. W., Q. W., H.A.H, M.C.M, and C.J.R., are inventors on a patent related to these data.

North Africa is a key region for understanding human history, but the genetic history of its people is largely unknown. We present genomic data from seven 15,000-year-old modern humans, attributed to the Iberomaurusian culture, from Morocco. We find a genetic affinity with early Holocene Near Easterners, best represented by Levantine Natufians, suggesting a pre-agricultural connection between Africa and the Near East. We do not find evidence for gene flow from Paleolithic Europeans to Late Pleistocene North Africans. The Taforalt individuals derive one-third of their ancestry from sub-Saharan Africans, best approximated by a mixture of genetic components preserved in present-day West and East Africans. Thus, we provide direct evidence for genetic interactions between modern humans across Africa and Eurasia in the Pleistocene., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Cis,cis-muconic acid (MA) is a chemical that is recognized for its industrial value and is synthetically accessible from aromatic compounds. This feature provides the attractive possibility of producing MA from mixtures of aromatics found in depolymerized lignin, the most underutilized lignocellulosic biopolymer. Based on the metabolic pathway, the catechol (1,2-dihydroxybenzene) node is the central element of this type of production process: (i) all upper catabolic pathways of aromatics converge at catechol as the central intermediate, (ii) catechol itself is frequently generated during lignin pre-processing, and (iii) catechol is directly converted to the target product MA by catechol 1,2-dioxygenase. However, catechol is highly toxic, which poses a challenge for the bio-production of MA. In this study, the soil bacterium Pseudomonas putida KT2440 was upgraded to a fully genome-based host for the production of MA from catechol and upstream aromatics. At the core of the cell factories created was a designed synthetic pathway module, comprising both native catechol 1,2-dioxygenases, catA and catA2, under the control of the P cat promoter. The pathway module increased catechol tolerance, catechol 1,2-dioxygenase levels, and catechol conversion rates. MA, the formed product, acted as an inducer of the module, triggering continuous expression. Cellular energy level and ATP yield were identified as critical parameters during catechol-based production. The engineered MA-6 strain achieved an MA titer of 64.2 g L -1 from catechol in a fed-batch process, which repeatedly regenerated the energy levels via specific feed pauses. The developed process was successfully transferred to the pilot scale to produce kilograms of MA at 97.9% purity. The MA-9 strain, equipped with a phenol hydroxylase, used phenol to produce MA and additionally converted o-cresol, m-cresol, and p-cresol to specific methylated variants of MA. This strain was used to demonstrate the entire value chain. Following hydrothermal depolymerization of softwood lignin to catechol, phenol and cresols, MA-9 accumulated 13 g L -1 MA and small amounts of 3-methyl MA, which were hydrogenated to adipic acid and its methylated derivative to polymerize nylon from lignin for the first time., (Copyright © 2018. Published by Elsevier Inc.)

Background: Breast implantation is an increasingly common procedure for both cosmesis and reconstruction. Risk of cutaneous reactions to breast implants is low and typically described in postsurgical settings. Adverse skin hypersensitivity-like reactions to implants have also been reported but are not well described., Objective: To review the scientific literature on cutaneous hypersensitivity-like reactions to breast implants., Methods: A systematic literature review was conducted using PubMed. Articles pertaining to breast implants and cutaneous hypersensitivity-like reactions in humans were included., Results: In total, 10 studies on hypersensitivity-like reactions from breast implants were included in the review. Potential allergenic compounds in breast implants include silicone, polyurethane texturing, and acellular dermal matrix. Perivascular lymphocytic infiltrate was a common finding on histopathology. Patch testing and preoperative silicone cube implantation were used to determine sensitivity. Attempted treatments included topical and oral corticosteroids, montelukast and antibiotics. Most cases required implant removal for resolution of symptoms., Conclusion: Cutaneous hypersensitivity-like reactions to breast implants seem to be rare complications, sometimes necessitating implant removal. Future studies are needed to establish their incidence and etiology, and the diagnostic role of patch testing and preoperative screening.

Lignin is nature's second most abundant polymer and displays a largely unexploited renewable resource for value-added bio-production. None of the lignin-based fermentation processes so far managed to use guaiacol (2-methoxy phenol), the predominant aromatic monomer in depolymerized lignin. In this work, we describe metabolic engineering of Amycolatopsis sp. ATCC 39116 to produce cis,cis-muconic acid (MA), a precursor of recognized industrial value for commercial plastics, from guaiacol. The microbe utilized a very broad spectrum of lignin-based aromatics, such as catechol, guaiacol, phenol, toluene, p-coumarate, and benzoate, tolerated them in elevated amounts and even preferred them over sugars. As a next step, we developed a novel approach for genomic engineering of this challenging, GC-rich actinomycete. The successful introduction of conjugation and blue-white screening, using β-glucuronidase, enabled tailored genomic modifications within ten days. Successive deletion of two putative muconate cycloisomerases from the genome provided the mutant Amycolatopsis sp. ATCC 39116 MA-2, which accumulated 3.1gL -1 MA from guaiacol within 24h, achieving a yield of 96%. The mutant was found also capable to produce MA from a guaiacol-rich true lignin hydrolysate, obtained from pine through hydrothermal conversion. This provides an important proof-of-concept to successfully coupling chemical and biochemical process steps into a value chain from the lignin polymer to an industrial chemical. In addition, Amycolatopsis sp. ATCC 39116 MA-2 was able to produce 2-methyl MA from o-cresol (2-methyl phenol), which opens possibilities towards polymers with novel architecture and properties., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)