Next-generation characterization of the Cancer Cell Line Encyclopedia.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.

Dose length product to effective dose coefficients in adults.

OBJECTIVES: The most accurate method for estimating patient effective dose (a principal metric for tracking patient radiation exposure) from computed tomography (CT) requires time-intensive Monte Carlo simulation. A simpler method multiplies a scalar coefficient by the widely available scanner-reported dose length product (DLP) to estimate effective dose. We developed new adult effective dose coefficients using actual patient scans and assessed their agreement with Monte Carlo simulation. METHODS: A multicenter sample of 216,906 adult CT scans was prospectively assembled in 2015-2020 from the University of California San Francisco International CT Dose Registry and the University of Florida library of computational phantoms. We generated effective dose coefficients for eight body regions, stratified by patient sex, diameter, and scanner manufacturer. We applied the new coefficients to DLPs to calculate effective doses and assess their correlations with Monte Carlo radiation transport-generated effective dose. RESULTS: Effective dose coefficients varied by body region and decreased in magnitude with increasing patient diameter. Coefficients were approximately twofold higher for torso scans in smallest compared with largest diameter categories. For example, abdomen and pelvis coefficients decreased from 0.027 to 0.013 mSv/mGy-cm between the 16-20 cm and 41+ cm categories. There were modest but consistent differences by sex and manufacturer. Diameter-based coefficients used to estimate effective dose produced strong correlations with the reference standard (Pearson correlations 0.77-0.86). The reported conversion coefficients differ from previous studies, particularly in neck CT. CONCLUSIONS: New effective dose coefficients derived from empirical clinical scans can be used to easily estimate effective dose using scanner-reported DLP. CLINICAL RELEVANCE STATEMENT: Scalar coefficients multiplied by DLP offer a simple approximation to effective dose, a key radiation dose metric. New effective dose coefficients from this study strongly correlate with gold standard, Monte Carlo-generated effective dose, and differ somewhat from previous studies. KEY POINTS: • Previous effective dose coefficients were derived from theoretical models rather than real patient data. • The new coefficients (from a large registry/phantom library) differ from previous studies. • The new coefficients offer reasonably reliable values for estimating effective dose.

More than just changeability: Specific factors are used to explain the changeability of personality traits.

Implicit theories and psychological essentialism are valuable frameworks used to model how changeable many traits are perceived to be. These frameworks, however, characterise changeability as a broad and generalised construct and do not fully capture the nuance and specificity involved in personality changeability. We therefore sought to deconstruct implicit theories about changeability into underlying more specific aspects of changeability. We measured how changeable people theorise personality traits to be according to three underlying specific factors: volitional control, context and age. We investigated how specific implicit theories about changeability vary across different personality traits. We show that two personality traits (agreeableness and conscientiousness) are linked to dissociable patterns of specific factors used to explain how changeable they are. These findings yield new insight into the way people explain why personality traits are changeable and demonstrate that different types of reasons are used to explain the changeability of agreeableness and conscientiousness.

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation.

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.

Erratum: The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation.

This corrects the article DOI: 10.1038/nature24029.

A Regression-Based Analysis of Ribosome-Profiling Data Reveals a Conserved Complexity to Mammalian Translation.

A fundamental goal of genomics is to identify the complete set of expressed proteins. Automated annotation strategies rely on assumptions about protein-coding sequences (CDSs), e.g., they are conserved, do not overlap, and exceed a minimum length. However, an increasing number of newly discovered proteins violate these rules. Here we present an experimental and analytical framework, based on ribosome profiling and linear regression, for systematic identification and quantification of translation. Application of this approach to lipopolysaccharide-stimulated mouse dendritic cells and HCMV-infected human fibroblasts identifies thousands of novel CDSs, including micropeptides and variants of known proteins, that bear the hallmarks of canonical translation and exhibit translation levels and dynamics comparable to that of annotated CDSs. Remarkably, many translation events are identified in both mouse and human cells even when the peptide sequence is not conserved. Our work thus reveals an unexpected complexity to mammalian translation suited to provide both conserved regulatory or protein-based functions.

Dose length product to effective dose coefficients in children.

BACKGROUND: The most accurate method for estimating effective dose (the most widely understood metric for tracking patient radiation exposure) from computed tomography (CT) requires time-intensive Monte Carlo simulation. A simpler method multiplies a scalar coefficient by the widely available scanner-reported dose length product (DLP) to estimate effective dose. OBJECTIVE: Develop pediatric effective dose coefficients and assess their agreement with Monte Carlo simulation. MATERIALS AND METHODS: Multicenter, population-based sample of 128,397 pediatric diagnostic CT scans prospectively assembled in 2015-2020 from the University of California San Francisco International CT Dose Registry and the University of Florida library of highly realistic hybrid computational phantoms. We generated effective dose coefficients for seven body regions, stratified by patient age, diameter, and scanner manufacturer. We applied the new coefficients to DLPs to calculate effective doses and assessed their correlations with Monte Carlo radiation transport-generated effective doses. RESULTS: The reported effective dose coefficients, generally higher than previous studies, varied by body region and decreased in magnitude with increasing age. Coefficients were approximately 4 to 13-fold higher (across body regions) for patients <1 year old compared with patients 15-21 years old. For example, head CT (54% of scans) dose coefficients decreased from 0.039 to 0.003 mSv/mGy-cm in patients <1 year old vs. 15-21 years old. There were minimal differences by manufacturer. Using age-based conversion coefficients to estimate effective dose produced moderate to strong correlations with Monte Carlo results (Pearson correlations 0.52-0.80 across body regions). CONCLUSIONS: New pediatric effective dose coefficients update existing literature and can be used to easily estimate effective dose using scanner-reported DLP.

The role of culture on the link between worldviews on nature and psychological health during the COVID-19 pandemic.

Worldviews about human's relationship with the natural world play an important role in psychological health. However, very little is currently known regarding the way worldviews about nature are linked with psychological health during a severe natural disaster and how this link may differ according to cultural context. In this study, we measured individual differences in worldviews about nature and psychological health during the 2020 COVID-19 pandemic within two different cultural contexts (Japan and United States). We found that across Japanese and American cultural contexts, holding a harmony-with-nature worldview was positively associated with improved psychological health during the COVID-19 pandemic. We also found that culture moderated the link between mastery-over-nature worldviews and negative affect. Americans showed a stronger link between mastery-over-nature worldviews and negative affect than Japanese. These findings support the biophilia hypothesis and contribute to theories differentiating Japanese and American cultural contexts based on naïve dialecticism and susceptibility to cognitive dissonance.

Psychopathy is associated with fear-specific reductions in neural activity during affective perspective-taking.

Psychopathic individuals are notorious for their callous disregard for others' emotions. Prior research has linked psychopathy to deficits in affective mechanisms underlying empathy (e.g., affective sharing), yet research relating psychopathy to cognitive mechanisms underlying empathy (e.g., affective perspective-taking and Theory of Mind) requires further clarification. To elucidate the neurobiology of cognitive mechanisms of empathy in psychopathy, we administered an fMRI task and tested for global as well as emotion-specific deficits in affective perspective-taking. Adult male incarcerated offenders (N = 94) viewed images of two people interacting, with one individual's face obscured by a shape. Participants were cued to either identify the emotion of the obscured individual or identify the shape from one of two emotion or shape choices presented on each trial. Target emotions included anger, fear, happiness, sadness, and neutral. Contrary to predictions, psychopathy was unrelated to neural activity in the Affective Perspective-taking > Shape contrast. In line with predictions, psychopathy was negatively related to task accuracy during affective perspective-taking for fear, happiness, and sadness. Psychopathy was related to reduced hemodynamic activity exclusively during fear perspective-taking in several areas: left anterior insula extending into posterior orbitofrontal cortex, right precuneus, left superior parietal lobule, and left superior occipital cortex. Although much prior research has emphasized psychopathy-related abnormalities in affective mechanisms mediating empathy, current results add to growing evidence of psychopathy-related abnormalities in a cognitive mechanism related to empathy. These findings highlight brain regions that are hypoactive in psychopathy when explicitly processing another's fear.

von Willebrand factor D and EGF domains is an evolutionarily conserved and required feature of blastemas capable of multitissue appendage regeneration.

Regenerative ability varies tremendously across species. A common feature of regeneration of appendages such as limbs, fins, antlers, and tails is the formation of a blastema-a transient structure that houses a pool of progenitor cells that can regenerate the missing tissue. We have identified the expression of von Willebrand factor D and EGF domains (vwde) as a common feature of blastemas capable of regenerating limbs and fins in a variety of highly regenerative species, including axolotl (Ambystoma mexicanum), lungfish (Lepidosiren paradoxa), and Polpyterus (Polypterus senegalus). Further, vwde expression is tightly linked to the ability to regenerate appendages in Xenopus laevis. Functional experiments demonstrate a requirement for vwde in regeneration and indicate that Vwde is a potent growth factor in the blastema. These data identify a key role for vwde in regenerating blastemas and underscore the power of an evolutionarily informed approach for identifying conserved genetic components of regeneration.

Advances in Decoding Axolotl Limb Regeneration.

Humans and other mammals are limited in their natural abilities to regenerate lost body parts. By contrast, many salamanders are highly regenerative and can spontaneously replace lost limbs even as adults. Because salamander limbs are anatomically similar to human limbs, knowing how they regenerate should provide important clues for regenerative medicine. Although interest in understanding the mechanics of this process has never wavered, until recently researchers have been vexed by seemingly impenetrable logistics of working with these creatures at a molecular level. Chief among the problems has been the very large size of salamander genomes, and not a single salamander genome has been fully sequenced to date. Recently the enormous gap in sequence information has been bridged by approaches that leverage mRNA as the starting point. Together with functional experimentation, these data are rapidly enabling researchers to finally uncover the molecular mechanisms underpinning the astonishing biological process of limb regeneration.

Epigenetic modification of OXT and human sociability.

Across many mammalian species there exist genetic and biological systems that facilitate the tendency to be social. Oxytocin is a neuropeptide involved in social-approach behaviors in humans and others mammals. Although there exists a large, mounting body of evidence showing that oxytocin signaling genes are associated with human sociability, very little is currently known regarding the way the structural gene for oxytocin (OXT) confers individual differences in human sociability. In this study, we undertook a comprehensive approach to investigate the association between epigenetic modification of OXT via DNA methylation, and overt measures of social processing, including self-report, behavior, and brain function and structure. Genetic data were collected via saliva samples and analyzed to target and quantify DNA methylation across the promoter region of OXT We observed a consistent pattern of results across sociability measures. People that exhibit lower OXT DNA methylation (presumably linked to higher OXT expression) display more secure attachment styles, improved ability to recognize emotional facial expressions, greater superior temporal sulcus activity during two social-cognitive functional MRI tasks, and larger fusiform gyrus gray matter volume than people that exhibit higher OXT DNA methylation. These findings provide empirical evidence that epigenetic modification of OXT is linked to several overt measures of sociability in humans and serve to advance progress in translational social neuroscience research toward a better understanding of the evolutionary and genetic basis of normal and abnormal human sociability.

Influence of Component Geometry on Patellar Mechanics in Posterior-Stabilized Rotating Platform Total Knee Arthroplasty.

BACKGROUND: Patellofemoral complications may cause pain and discomfort, sometimes leading to revision surgery for total knee arthroplasty patients, and patellar implant design has an impact on function of the reconstructed knee. The purpose of this in vivo biomechanics study was to understand the kinematic, functional, strength, and patient-reported outcome data of patients with anatomic and dome patellar implants. METHODS: Satisfactory age-matched, gender-matched, and body mass index-matched patients who underwent rotating-platform total knee arthroplasty from one joint replacement system with either dome (n = 16) or anatomic (n = 16) patellar components were tested in a human motion laboratory using high-speed stereoradiography during an unweighted seated knee extension and a weight-bearing lunge activity. Patellar kinematics, range of motion, strength, and patient-reported outcomes were compared between subjects with anatomic or dome component geometry. RESULTS: Both groups of patients achieved similar functional knee range of motion and reported similar outcomes and satisfaction. On average, patients with the anatomic component had 36% greater extensor strength compared with dome subjects. Patients with anatomic patellar components demonstrated significantly greater flexion of the patella relative to the femur and lower external rotation during the weighted lunge activity. CONCLUSIONS: Relative to the modified dome geometry, patients with anatomic patellar geometry achieved greater patellar flexion which may better replicate normal patellar motion. Patients with anatomic implants may regain more extensor strength compared to patients with dome implants due to geometric differences in the patellar component designs.

What is the added sensitivity of non-lateral cervical spine radiographs in the evaluation of acute cervical spine trauma?

PURPOSE: Plain radiography of the cervical spine is used as a screening test for trauma patients. We evaluated the diagnostic yield of performing anteroposterior (AP), odontoid, and oblique views in addition to the lateral view in the current era when radiographs are performed only on low-risk patients. METHODS: All imaging reports from cervical spine radiography studies on patients aged 18 years and older in the emergency room of a major academic medical center between November 22, 2003, and January 17, 2012, were retrospectively reviewed. For the clinical workflow employed at the time of study acquisition, radiologists prospectively reviewed the lateral projection and subsequently reviewed the entirety of the images obtained. Exam reports and, when necessary, images were reviewed to determine which patients had fractures and on which projection the fractures were identified. RESULTS: Six fractures were detected in 7218 exams. Three of these fractures were identified on the lateral radiograph, and three of these fractures were visualized on the additional projections (two on oblique and one on odontoid views). The yield of the additional projections is one fracture per 9713 radiographic projections (90% confidence interval of one fracture per 1245-47,946 examinations). For two of the patients with fractures identified on the lateral projection, an additional fracture was seen when CT was then performed. CONCLUSIONS: Performing additional radiographs of the cervical spine including AP, odontoid, and bilateral oblique projections in trauma patients with low pretest probability of fracture augments the diagnostic yield of lateral radiographs. Considering the potential for devastating neurological outcomes from missed cervical fractures, addition of AP, odontoid, and oblique projections continues to detect fractures at a low rate.

Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells.

Both intrinsic cell state changes and variations in the composition of stem cell populations have been implicated as contributors to aging. We used single-cell RNA-seq to dissect variability in hematopoietic stem cell (HSC) and hematopoietic progenitor cell populations from young and old mice from two strains. We found that cell cycle dominates the variability within each population and that there is a lower frequency of cells in the G1 phase among old compared with young long-term HSCs, suggesting that they traverse through G1 faster. Moreover, transcriptional changes in HSCs during aging are inversely related to those upon HSC differentiation, such that old short-term (ST) HSCs resemble young long-term (LT-HSCs), suggesting that they exist in a less differentiated state. Our results indicate both compositional changes and intrinsic, population-wide changes with age and are consistent with a model where a relationship between cell cycle progression and self-renewal versus differentiation of HSCs is affected by aging and may contribute to the functional decline of old HSCs.

Use of the MS2 aptamer and coat protein for RNA localization in yeast: A response to "MS2 coat proteins bound to yeast mRNAs block 5' to 3' degradation and trap mRNA decay products: implications for the localization of mRNAs by MS2-MCP system".

The MS2 system has been extensively used to visualize single mRNA molecules in live cells and follow their localization and behavior. In their Letter to the Editor recently published, Garcia and Parker suggest that use of the MS2 system may yield erroneous mRNA localization results due to the accumulation of 3' decay products. Here we cite published works and provide new data which demonstrate that this is not a phenomenon general to endogenously expressed MS2-tagged transcripts, and that some of the results obtained in their study could have arisen from artifacts of gene expression.

Loggerhead sea turtle embryos (Caretta caretta) regulate expression of stress response and developmental genes when exposed to a biologically realistic heat stress.

Oviparous reptile embryos are expected to breach their critical thermal maxima if temperatures reach those predicted under current climate change models due to the lack of the maternal buffering processes and parental care. Heat-shock proteins (HSPs) are integral in the molecular response to thermal stress, and their expression is heritable, but the roles of other candidate families such as the heat-shock factors (HSFs) have not been determined in reptiles. Here, we subject embryonic sea turtles (Caretta caretta) to a biologically realistic thermal stress and employ de novo transcriptomic profiling of brain tissue to investigate the underlying molecular response. From a reference transcriptome of 302 293 transcripts, 179 were identified as differentially expressed between treatments. As anticipated, genes enriched in the heat-shock treatment were primarily associated with the Hsp families, or were genes whose products play similar protein editing and chaperone functions (e.g. bag3, MYOC and serpinh1). Unexpectedly, genes encoding the HSFs were not significantly upregulated under thermal stress, indicating their presence in unstressed cells in an inactive state. Genes that were downregulated under thermal stress were less well functionally defined but were associated with stress response, development and cellular organization, suggesting that developmental processes may be compromised at realistically high temperatures. These results confirm that genes from the Hsp families play vital roles in the thermal tolerance of developing reptile embryos and, in addition with a number of other genes, should be targets for evaluating the capacity of oviparous reptiles to respond adaptively to the effects of climate change.

CT-Guided Percutaneous Lung Biopsies in Patients With Suspicion for Infection May Yield Clinically Useful Information.

OBJECTIVE: The objective of our study was to assess the frequency and time frame with which CT-guided lung biopsies for suspected infection yield information that can affect patient management. MATERIALS AND METHODS: All CT-guided lung biopsies over a 68-month period performed for the purpose of diagnosing a suspected infection were reviewed to determine the proportion that yielded information affecting patient management. Patients were included if infection was the only consideration causing the pulmonary lesion in question. RESULTS: Twenty-one biopsies were performed to identify a specific organism causing infection in patients with suspected infection; all patients were receiving antibiotics, 20 (95%) were immunocompromised, and 15 (71%) had undergone a prior bronchoscopy. Material collected from the biopsy provided a diagnosis in nine (43%) patients, whereas the biopsy results were nondiagnostic in the remaining 12 (57%). Of the nine patients for whom the biopsy yielded a diagnosis, eight biopsies revealed the species causing an infection (38%) and one biopsy (5%) detected posttransplant lymphoproliferative disease. Of the nine diagnoses, management was changed as a result of the biopsy in six patients (29% of all patients). The organisms identified by CT-guided lung biopsy in eight patients were fungi of the order Mucorales (i.e., mucormycosis) (n = 3), Aspergillus (n = 3), Pseudomonas (n = 1), and Nocardia (n = 1). The mean elapsed time between biopsy and pathologic diagnosis was 4 days (median, 3 days). There was no association between prior bronchoscopy and nondiagnostic biopsy results. CONCLUSION: CT-guided lung biopsies in patients with a high pretest suspicion for infection result in information sufficient to change patient management in 29% of patients. Organisms identified in these patients were most frequently fungi.

Trying to trust: Brain activity during interpersonal social attitude change.

Interpersonal trust and distrust are important components of human social interaction. Although several studies have shown that brain function is associated with either trusting or distrusting others, very little is known regarding brain function during the control of social attitudes, including trust and distrust. This study was designed to investigate the neural mechanisms involved when people attempt to control their attitudes of trust or distrust toward another person. We used a novel control-of-attitudes fMRI task, which involved explicit instructions to control attitudes of interpersonal trust and distrust. Control of trust or distrust was operationally defined as changes in trustworthiness evaluations of neutral faces before and after the control-of-attitudes fMRI task. Overall, participants (n = 60) evaluated faces paired with the distrust instruction as being less trustworthy than faces paired with the trust instruction following the control-of-distrust task. Within the brain, both the control-of-trust and control-of-distrust conditions were associated with increased temporoparietal junction, precuneus (PrC), inferior frontal gyrus (IFG), and medial prefrontal cortex activity. Individual differences in the control of trust were associated with PrC activity, and individual differences in the control of distrust were associated with IFG activity. Together, these findings identify a brain network involved in the explicit control of distrust and trust and indicate that the PrC and IFG may serve to consolidate interpersonal social attitudes.