Cambridge School

UCSF ChimeraX is the next-generation interactive visualization program from the Resource for Biocomputing, Visualization, and Informatics (RBVI), following UCSF Chimera. ChimeraX brings (a) significant performance and graphics enhancements; (b) new implementations of Chimera's most highly used tools, many with further improvements; (c) several entirely new analysis features; (d) support for new areas such as virtual reality, light-sheet microscopy, and medical imaging data; (e) major ease-of-use advances, including toolbars with icons to perform actions with a single click, basic "undo" capabilities, and more logical and consistent commands; and (f) an app store for researchers to contribute new tools. ChimeraX includes full user documentation and is free for noncommercial use, with downloads available for Windows, Linux, and macOS from https://www.rbvi.ucsf.edu/chimerax.

SUMMARY According to ‘Gause's hypothesis’ a corollary of the process of evolution by natural selection is that in a community at equilibrium every species must occupy a different niche. Many botanists have found this idea improbable because they have ignored the processes of regeneration in plant communities. Most plant communities are longer‐lived than their constituent individual plants. When an individual dies, it may or may not be replaced by an individual of the same species. It is this replacement stage which is all‐important to the argument presented. Several mechanisms not involving regeneration also contribute to the maintenance of species‐richness: differences in life‐form coupled with the inability of larger plants to exhaust or cut off all resources, also the development of dependence‐relationships, differences in phenology coupled with tolerance of suppression, fluctuations in the environment coupled with relatively small differences in competitive ability between many species, the ability of certain species‐pairs to form stable mixtures because of a balance of intraspecific competition against interspecific competition, the production of substances more toxic to the producer‐species than to the other species, differences in the primary limiting mineral nutrients or pore‐sizes in the soil for neighbouring plants of different soecies, and differences in the competitive abilities of species dependent on their physiological age coupled with the uneven‐age structure of many populations. The mechanisms listed above do not go far to explain the indefinite persistence in mixture of the many species in the most species‐rich communities known. In contrast there seem to be almost limitless possibilities for differences between species in their requirements for regeneration, i.e. the replacement of the individual plants of one generation by those of the next. This idea is illustrated for tree species and it is emphasized that foresters were the first by a wide margin to appreciate its importance. The processes involved in the successful invasion of a gap by a given plant species and some characters of the gap that may be important are summarized in Table 2. The definition of a plant's niche requires recognition of four components: the habitat niche, the life‐form niche, the phenological niche, and the regeneration niche. A brief account is given of the patterns of regeneration in different kinds of plant community to provide a background for studies of differentiation in the regeneration niche. All stages in the regeneration‐cycle are potentially important and examples of differentiation between species are given for each of the following stages: Production of viable seed (including the sub‐stages of flowering, pollination and seed‐set), dispersal, in space and time, germination, establishment, and further development of the immature plant. In the concluding discussion emphasis is placed on the following themes: the kinds of work needed in future to prove or disprove that differentiation in the regeneration niche is the major explanation of the maintenance of species‐richness in plant communities, the relation of the present thesis to published ideas on the origin of phenological spread, the relevance of the present thesis to the discussion on the presence of continua in vegetation, the co‐incidence of the present thesis and the emerging ideas of evolutionists about differentiation of angiosperm taxa, and the importance of regeneration‐studies for conservation.

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

The concept of a general two-person cooperative game is defined and a concept of a solution for such games is developed.

A new interview schedule for the diagnosis and measurement of dementia in the elderly is described. The schedule named the Cambridge Mental Disorders of the Elderly Examination (CAMDEX), consists of three main sections: A structured clinical interview with the patient to obtain systematic information about the present state, past history and family history; a range of objective cognitive tests which constitute a mini-neuropsychological battery; a structured interview with a relative or other informant to obtain independent information about the respondent's present state, past history and family history. The CAMDEX is acceptable to patients, has a high inter-rater reliability and the cognitive section has been shown to have high sensitivity and specificity.

BACKGROUND: Droplet-based single-cell RNA sequence analyses assume that all acquired RNAs are endogenous to cells. However, any cell-free RNAs contained within the input solution are also captured by these assays. This sequencing of cell-free RNA constitutes a background contamination that confounds the biological interpretation of single-cell transcriptomic data. RESULTS: We demonstrate that contamination from this "soup" of cell-free RNAs is ubiquitous, with experiment-specific variations in composition and magnitude. We present a method, SoupX, for quantifying the extent of the contamination and estimating "background-corrected" cell expression profiles that seamlessly integrate with existing downstream analysis tools. Applying this method to several datasets using multiple droplet sequencing technologies, we demonstrate that its application improves biological interpretation of otherwise misleading data, as well as improving quality control metrics. CONCLUSIONS: We present SoupX, a tool for removing ambient RNA contamination from droplet-based single-cell RNA sequencing experiments. This tool has broad applicability, and its application can improve the biological utility of existing and future datasets.

Innate immunity has been considered only to provide rapid, incomplete antimicrobial host defense until the slower, more definitive acquired immune response develops. However, innate immunity may have an additional role in determining which antigens the acquired immune system responds to and the nature of that response. Knowledge of the molecules and pathways involved may create new therapeutic options for infectious and autoimmune diseases.

Importance: Depression is the leading cause of mental health-related disease burden and may be reduced by physical activity, but the dose-response relationship between activity and depression is uncertain. Objective: To systematically review and meta-analyze the dose-response association between physical activity and incident depression from published prospective studies of adults. Data Sources: PubMed, SCOPUS, Web of Science, PsycINFO, and the reference lists of systematic reviews retrieved by a systematic search up to December 11, 2020, with no language limits. The date of the search was November 12, 2020. Study Selection: We included prospective cohort studies reporting physical activity at 3 or more exposure levels and risk estimates for depression with 3000 or more adults and 3 years or longer of follow-up. Data Extraction and Synthesis: Data extraction was completed independently by 2 extractors and cross-checked for errors. A 2-stage random-effects dose-response meta-analysis was used to synthesize data. Study-specific associations were estimated using generalized least-squares regression and the pooled association was estimated by combining the study-specific coefficients using restricted maximum likelihood. Main Outcomes and Measures: The outcome of interest was depression, including (1) presence of major depressive disorder indicated by self-report of physician diagnosis, registry data, or diagnostic interviews and (2) elevated depressive symptoms established using validated cutoffs for a depressive screening instrument. Results: Fifteen studies comprising 191 130 participants and 2 110 588 person-years were included. An inverse curvilinear dose-response association between physical activity and depression was observed, with steeper association gradients at lower activity volumes; heterogeneity was large and significant (I2 = 74%; P < .001). Relative to adults not reporting any activity, those accumulating half the recommended volume of physical activity (4.4 marginal metabolic equivalent task hours per week [mMET-h/wk]) had 18% (95% CI, 13%-23%) lower risk of depression. Adults accumulating the recommended volume of 8.8 mMET hours per week had 25% (95% CI, 18%-32%) lower risk with diminishing potential benefits and higher uncertainty observed beyond that exposure level. There were diminishing additional potential benefits and greater uncertainty at higher volumes of physical activity. Based on an estimate of exposure prevalences among included cohorts, if less active adults had achieved the current physical activity recommendations, 11.5% (95% CI, 7.7%-15.4%) of depression cases could have been prevented. Conclusions and Relevance: This systematic review and meta-analysis of associations between physical activity and depression suggests significant mental health benefits from being physically active, even at levels below the public health recommendations. Health practitioners should therefore encourage any increase in physical activity to improve mental health.

Abstract Objective: To determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community. Design: Randomised double blind controlled trial of 100 000 IU oral vitamin D 3 (cholecalciferol) supplementation or matching placebo every four months over five years. Setting and participants: 2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk. Main outcome measures: Fracture incidence and total mortality by cause. Results: After five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population. Conclusion: Four monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community. What is already known in this topic Vitamin D and calcium supplements are effective in preventing fractures in elderly women Whether isolated vitamin D supplementation prevents fractures is not clear What this paper adds Four monthly oral supplementation with 100 000 IU vitamin D reduces fractures in men and women aged over 65 living in the general community Total fracture incidence was reduced by 22% and fractures in major osteoporotic sites by 33%

In 2014, two groups of scientists published open letters on the efficacy of brain-training interventions, or "brain games," for improving cognition. The first letter, a consensus statement from an international group of more than 70 scientists, claimed that brain games do not provide a scientifically grounded way to improve cognitive functioning or to stave off cognitive decline. Several months later, an international group of 133 scientists and practitioners countered that the literature is replete with demonstrations of the benefits of brain training for a wide variety of cognitive and everyday activities. How could two teams of scientists examine the same literature and come to conflicting "consensus" views about the effectiveness of brain training?In part, the disagreement might result from different standards used when evaluating the evidence. To date, the field has lacked a comprehensive review of the brain-training literature, one that examines both the quantity and the quality of the evidence according to a well-defined set of best practices. This article provides such a review, focusing exclusively on the use of cognitive tasks or games as a means to enhance performance on other tasks. We specify and justify a set of best practices for such brain-training interventions and then use those standards to evaluate all of the published peer-reviewed intervention studies cited on the websites of leading brain-training companies listed on Cognitive Training Data (www.cognitivetrainingdata.org), the site hosting the open letter from brain-training proponents. These citations presumably represent the evidence that best supports the claims of effectiveness.Based on this examination, we find extensive evidence that brain-training interventions improve performance on the trained tasks, less evidence that such interventions improve performance on closely related tasks, and little evidence that training enhances performance on distantly related tasks or that training improves everyday cognitive performance. We also find that many of the published intervention studies had major shortcomings in design or analysis that preclude definitive conclusions about the efficacy of training, and that none of the cited studies conformed to all of the best practices we identify as essential to drawing clear conclusions about the benefits of brain training for everyday activities. We conclude with detailed recommendations for scientists, funding agencies, and policymakers that, if adopted, would lead to better evidence regarding the efficacy of brain-training interventions.

Abstract Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

C. C. D. SHUTE, P. R. LEWIS; THE ASCENDING CHOLINERGIC RETICULAR SYSTEM: NEOCORTICAL, OLFACTORY AND SUBCORTICAL PROJECTIONS, Brain, Volume 90, Issue 3, 1 S

OBJECTIVE: To examine the value of glycated haemoglobin (HbA(1c)) concentration, a marker of blood glucose concentration, as a predictor of death from cardiovascular and all causes in men. DESIGN: Prospective population study. SETTING: Norfolk cohort of European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). SUBJECTS: 4662 men aged 45-79 years who had had glycated haemoglobin measured at the baseline survey in 1995-7 who were followed up to December 1999. MAIN OUTCOME MEASURES: Mortality from all causes, cardiovascular disease, ischaemic heart disease, and other causes. RESULTS: Men with known diabetes had increased mortality from all causes, cardiovascular disease, and ischaemic disease (relative risks 2.2, 3.3, and 4.2, respectively, P <0.001 independent of age and other risk factors) compared with men without known diabetes. The increased risk of death among men with diabetes was largely explained by HbA(1c) concentration. HbA(1c) was continuously related to subsequent all cause, cardiovascular, and ischaemic heart disease mortality through the whole population distribution, with lowest rates in those with HbA(1c) concentrations below 5%. An increase of 1% in HbA(1c) was associated with a 28% (P<0.002) increase in risk of death independent of age, blood pressure, serum cholesterol, body mass index, and cigarette smoking habit; this effect remained (relative risk 1.46, P=0.05 adjusted for age and risk factors) after men with known diabetes, a HbA(1c) concentration >/=7%, or history of myocardial infarction or stroke were excluded. 18% of the population excess mortality risk associated with a HbA(1c) concentration >/=5% occurred in men with diabetes, but 82% occurred in men with concentrations of 5%-6.9% (the majority of the population). CONCLUSIONS: Glycated haemoglobin concentration seems to explain most of the excess mortality risk of diabetes in men and to be a continuous risk factor through the whole population distribution. Preventive efforts need to consider not just those with established diabetes but whether it is possible to reduce the population distribution of HbA(1c) through behavioural means.

Abstract A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

Policies to promote public health and welfare often fail or worsen the problems they are intended to solve. Evidence-based learning should prevent such policy resistance, but learning in complex systems is often weak and slow. Complexity hinders our ability to discover the delayed and distal impacts of interventions, generating unintended "side effects." Yet learning often fails even when strong evidence is available: common mental models lead to erroneous but self-confirming inferences, allowing harmful beliefs and behaviors to persist and undermining implementation of beneficial policies. Here I show how systems thinking and simulation modeling can help expand the boundaries of our mental models, enhance our ability to generate and learn from evidence, and catalyze effective change in public health and beyond.

P. R. LEWIS, C. C. D. SHUTE; THE CHOLINERGIC LIMBIC SYSTEM: PROJECTIONS TO HIPPOCAMPAL FORMATION, MEDIAL CORTEX, NUCLEI OF THE ASCENDING CHOLINERGIC RETICU

The clinical features, age at onset and survival of 152 patients with von Hippel-Lindau disease were studied. Mean age at onset was 26.3 years and 97 per cent of patients had presented by aged 60 years. Retinal angioma was the first manifestation in 65 patients (43 per cent), followed by cerebellar haemangioblastoma (n = 60, 39 per cent) and renal cell carcinoma (n = 15, 10 per cent). Overall, 89 patients (59 per cent) developed a cerebellar haemangioblastoma, 89 (59 per cent) a retinal angioma, 43 (28 per cent) renal cell carcinoma, 20 (13 per cent) spinal haemangioblastoma and 11 (7 per cent) a phaeochromocytoma. Renal, pancreatic and epididymal cysts were frequent findings but their exact incidence was not accurately assessed. Mean age at diagnosis of renal cell carcinoma (44.0 +/- 10.9 years) was significantly older than that for cerebellar haemangioblastoma (29.0 +/- 10.0 years) and retinal angioma (25.4 +/- 12.7 years). The probability of a patient with von Hippel-Lindan disease developing a cerebellar haemangioblastoma, retinal angioma or renal cell carcinoma by age 60 years was 0.84, 0.7 and 0.69, respectively. A comprehensive screening protocol for affected patients and at-risk relatives is presented, based on detailed analysis of age at onset data for each of the major complications. Median actuarial survival was 49 years, with renal cell carcinoma the leading cause of death.

Over the last decade, there has been an increasing focus on service across socioeconomic sectors coupled with transformational developments in information and communication technologies (ICTs). Together these developments are engendering dramatic new opportunities for service innovation, the study of which is both timely and important. Fully understanding these opportunities challenges us to question conventional approaches that construe service as a distinctive form of socioeconomic exchange (i.e., as services) and to reconsider what service means and thus how service innovation may develop. The aim of this special issue, therefore, is to bring together some of the latest scholarship from the Marketing and Information Systems disciplines to advance theoretical developments on service innovation in a digital age.

Abstract The permeability of a porous material to water is a function of the geometry of the boundary between the solid component and the pore space. Expressions of the Kozeny type purporting to represent this function are based upon the particle size or specific surface of the solids, and whilst, for engineering practice, they have given satisfaction for saturated sands, they may fail badly in other cases. By developing a Kozeny type of expression for the particular structure of a bundle of capillary tubes of assorted radii, we demonstrate the cause of the failure. Such failure may be avoided by relating permeability to pore-size distribution, which is the factor of prime concern and which may be measured directly by even simpler means than are used to determine particle-size distribution. The pore-size distribution is arrived at by an interpretation of the moisture characteristic of the material, i.e. of the curve of moisture content plotted against pressure deficiency. A simple statistical theory, based upon the calculation of the probability of occurrence of sequences of pairs of pores of all the possible sizes, and of the contribution to the permeability made by each such pair, leads to an expression of the permeability as the sum of a series of terms. By stopping the summation at a selected upper limit of pore size one may calculate the permeability at any chosen moisture content and plot it as a function of that content. An example is presented, using a coarse graded sand specified by its moisture characteristic. To check these calculations, experimental determinations of the permeabilities of unsaturated materials are presented, using two different grades of sand and a sample of slate dust, the results being compared with computed values. The agreement seems good, and is certainly better than that provided by the Kozeny formula as developed, with difficulty, for the purpose. The limitations and possible improvements of our concept are very briefly discussed, and finally it is shown how a combined use of the moisture characteristic and the permeability (which is itself derivable from the moisture characteristic) leads to an expression for the coefficient of diffusion of water in the material as a function of moisture content. From this it should be possible, in principle, to calculate in suitable cases the course of water movement down a gradient of moisture content. Such a calculation awaits a satisfactory solution of the problem of non-linear diffusion.