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Cell identification is an important yet difficult process in data analysis of biological images. Previously, we developed an automated cell identification method called CRF_(I)D and demonstrated its high performance in Caenorhabditis elegans whole-brain images (Chaudhary et al., 2021). However, because the method was optimized for whole-brain imaging, comparable performance could not be guaranteed for application in commonly used C. elegans multi-cell images that display a subpopulation of cells. Here, we present an advancement, CRF_(I)D 2.0, that expands the generalizability of the method to multi-cell imaging beyond whole-brain imaging. To illustrate the application of the advance, we show the characterization of CRF_(I)D 2.0 in multi-cell imaging and cell-specific gene expression analysis in C. elegans. This work demonstrates that high-accuracy automated cell annotation in multi-cell imaging can expedite cell identification and reduce its subjectivity in C. elegans and potentially other biological images of various origins.

Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously, we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al., 2020). Here, we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome). We used data from the Dunedin Study 1972-1973 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets. DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge. DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience. This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.

Background Galliformes are widely distributed throughout the world and economically important to humans as domesticated animals or gamebirds. They are at a unique position for advancing knowledge and techniques of wildlife conservation as the barometer of the status of applied ecology. Populations of many galliform species have declined mainly due to habitat loss and over-hunting. An assessment of knowledge of Galliformes could help to provide guidelines for future research and conservation strategies. Methods Using the Web of Science search engine, we conducted a literature review of galliform-related articles published from 1990 to 2016. We used the “research area” option to filter articles focused on the zoology, environmental sciences ecology, biodiversity conservation, forestry, behavioral sciences, reproductive biology, biochemistry and molecular biology, cell biology, genetics and heredity, evolutionary biology, physiology and developmental biology. We then checked duplication based on the title, abstract and full text. In addition, we examined the reference lists of selected studies to include the publications that were missed by above searching. Results We retained 1874 articles related to the Galliformes from the initial 243,128 publications that were found. About 91.4% focused on one or two species, and 85.0% were conducted within a short duration, typically 1–2 years. The majority of the articles concentrated on macroscopic ecology (55.5%), mainly focusing on habitat selection or habitat use. With recent advances of molecular biology, the studies of taxonomy and phylogenetics rose quickly in last two decades. The study of physiology and biochemistry was no longer limited to simple description but expanded to the mechanisms of phenotype and micro-evolutionary potential. An additional area receiving increasing attention is the conservation of Galliformes, with the assessment of the conservation status and conservation management effectiveness of Galliformes (e.g. species diversity and genetic diversity) becoming the focus. Conclusions The studies on Galliformes have made great achievements since 1990, but there are still gaps, particularly in macroscopic ecology, molecular genetics, and conservation. There is an urgent need to enhance long-term monitoring and analysis of population dynamics, and applying different disciplines to galliform conservation. Moreover, life history information of many galliform species is still lacking, which has hindered conservation efforts and effectiveness. In addition, multidiscipline studies and new technologies are not common for galliform studies, and should be encouraged.

Comparing single-cell transcriptomic atlases from diverse organisms can elucidate the origins of cellular diversity and assist the annotation of new cell atlases. Yet, comparison between distant relatives is hindered by complex gene histories and diversifications in expression programs. Previously, we introduced the self-assembling manifold (SAM) algorithm to robustly reconstruct manifolds from single-cell data (Tarashansky et al., 2019). Here, we build on SAM to map cell atlas manifolds across species. This new method, SAMap, identifies homologous cell types with shared expression programs across distant species within phyla, even in complex examples where homologous tissues emerge from distinct germ layers. SAMap also finds many genes with more similar expression to their paralogs than their orthologs, suggesting paralog substitution may be more common in evolution than previously appreciated. Lastly, comparing species across animal phyla, spanning sponge to mouse, reveals ancient contractile and stem cell families, which may have arisen early in animal evolution.

The idea of reproducing himself with the use of a mechanical robot structure has been in man’s imagination in the last 3000 years. However, the use of robots in medicine has only 30 years of history. The application of robots in surgery originates from the need of modern man to achieve two goals: the telepresence and the performance of repetitive and accurate tasks. The first “robot surgeon” used on a human patient was the PUMA 200 in 1985. In the 1990s, scientists developed the concept of “master–slave” robot, which consisted of a robot with remote manipulators controlled by a surgeon at a surgical workstation. Despite the lack of force and tactile feedback, technical advantages of robotic surgery, such as 3D vision, stable and magnified image, EndoWrist instruments, physiologic tremor filtering, and motion scaling, have been considered fundamental to overcome many of the limitations of the laparoscopic surgery. Since the approval of the da Vinci ® robot by international agencies, American, European, and Asian surgeons have proved its factibility and safety for the performance of many different robot-assisted surgeries. Comparative studies of robotic and laparoscopic surgical procedures in general surgery have shown similar results with regard to perioperative, oncological, and functional outcomes. However, higher costs and lack of haptic feedback represent the major limitations of current robotic technology to become the standard technique of minimally invasive surgery worldwide. Therefore, the future of robotic surgery involves cost reduction, development of new platforms and technologies, creation and validation of curriculum and virtual simulators, and conduction of randomized clinical trials to determine the best applications of robotics.

We recently found that nucleosomes directly block access of CRISPR/Cas9 to DNA (Horlbeck et al., 2016 ). Here, we build on this observation with a comprehensive algorithm that incorporates chromatin, position, and sequence features to accurately predict highly effective single guide RNAs (sgRNAs) for targeting nuclease-dead Cas9-mediated transcriptional repression (CRISPRi) and activation (CRISPRa). We use this algorithm to design next-generation genome-scale CRISPRi and CRISPRa libraries targeting human and mouse genomes. A CRISPRi screen for essential genes in K562 cells demonstrates that the large majority of sgRNAs are highly active. We also find CRISPRi does not exhibit any detectable non-specific toxicity recently observed with CRISPR nuclease approaches. Precision-recall analysis shows that we detect over 90% of essential genes with minimal false positives using a compact 5 sgRNA/gene library. Our results establish CRISPRi and CRISPRa as premier tools for loss- or gain-of-function studies and provide a general strategy for identifying Cas9 target sites.

In this work, we expand the normative model repository introduced in Rutherford et al., 2022a to include normative models charting lifespan trajectories of structural surface area and brain functional connectivity, measured using two unique resting-state network atlases (Yeo-17 and Smith-10), and an updated online platform for transferring these models to new data sources. We showcase the value of these models with a head-to-head comparison between the features output by normative modeling and raw data features in several benchmarking tasks: mass univariate group difference testing (schizophrenia versus control), classification (schizophrenia versus control), and regression (predicting general cognitive ability). Across all benchmarks, we show the advantage of using normative modeling features, with the strongest statistically significant results demonstrated in the group difference testing and classification tasks. We intend for these accessible resources to facilitate the wider adoption of normative modeling across the neuroimaging community.

Stress signaling is important for determining the fates of neurons following axonal insults. Previously, we showed that the stress-responsive kinase PERK contributes to injury-induced neurodegeneration (Larhammar et al., 2017). Here, we show that PERK acts primarily through activating transcription factor-4 (ATF4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve damage. Using conditional knockout mice, we find an extensive PERK/ATF4-dependent transcriptional response that includes canonical ATF4 target genes and modest contributions by C/EBP Homologous Protein (CHOP). Overlap with c-Jun-dependent transcription suggests interplay with a parallel stress pathway that orchestrates regenerative and apoptotic responses. Accordingly, neuronal knockout of ATF4 recapitulates the neuroprotection afforded by PERK deficiency, and PERK or ATF4 knockout impairs optic axon regeneration enabled by disrupting the tumor suppressor PTEN. These findings reveal an integral role for PERK/ATF4 in coordinating neurodegenerative and regenerative responses to CNS axon injury.

Previously, we described a novel alternative to chromatin immunoprecipitation, CUT&RUN, in which unfixed permeabilized cells are incubated with antibody, followed by binding of a protein A-Micrococcal Nuclease (pA/MNase) fusion protein (Skene and Henikoff, 2017). Here we introduce three enhancements to CUT&RUN: A hybrid protein A-Protein G-MNase construct that expands antibody compatibility and simplifies purification, a modified digestion protocol that inhibits premature release of the nuclease-bound complex, and a calibration strategy based on carry-over of E. coli DNA introduced with the fusion protein. These new features, coupled with the previously described low-cost, high efficiency, high reproducibility and high-throughput capability of CUT&RUN make it the method of choice for routine epigenomic profiling.

Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson’s disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1–121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50–57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.