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Determining the structure and mechanisms of all individual functional modules of cells at high molecular detail has often been seen as equal to understanding how cells work. Recent technical advances have led to a flush of high-resolution structures of various macromolecular machines, but despite this wealth of detailed information, our understanding of cellular function remains incomplete. Here, we discuss present-day limitations of structural biology and highlight novel technologies that may enable us to analyze molecular functions directly inside cells. We predict that the progression toward structural cell biology will involve a shift toward conceptualizing a 4D virtual reality of cells using digital twins. These will capture cellular segments in a highly enriched molecular detail, include dynamic changes, and facilitate simulations of molecular processes, leading to novel and experimentally testable predictions. Transferring biological questions into algorithms that learn from the existing wealth of data and explore novel solutions may ultimately unveil how cells work.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
From hunting and foraging to clearing land for agriculture, humans modify forest biodiversity, landscapes, and climate. Forests constantly undergo disturbance–recovery dynamics and understanding them is a major objective of ecologists and conservationists. Chronosequences are a useful tool for understanding global restoration efforts. They represent a space-for-time substitution approach suited for the quantification of the resistance of ecosystem properties to withstand disturbance and the resilience of these properties until reaching pre-disturbance levels. Here we introduce a newly established chronosequence with 62 plots (50 ⍰ 50 m) in active cacao plantations and pastures, early and late regeneration, and mature old-growth forests, across a 200 km2 area in the extremely wet Chocó rainforest. Our chronosequence covers by far the largest total area of plots compared to others in the Neotropics. Plots ranged from 159–615 masl in a forested landscape with 74 ± 2.8 % forest cover within a 1-km radius including substantial old-growth forest cover. Land-use legacy and regeneration time were not confounded by elevation. We tested how six forest structure variables (maximum tree height and DBH, basal area, number of stems, vertical vegetation heterogeneity, and light availability), aboveground biomass (AGB), and rarefied tree species richness change along our chronosequence. Forest structure variables, AGB, and tree species richness increased with regeneration time and are predicted to reach similar levels to those in old-growth forests after ca. 30–116, 202, and 108 yrs, respectively. Compared to previous work in the Neotropics, old-growth forests in Canandé accumulate high AGB that takes one of the largest time spans reported until total recovery. Our chronosequence comprises one of the largest tree species pools, covers the largest total area of regenerating and old-growth forests, and has higher forest cover than other Neotropical chronosequences. Hence, our chronosequence can be used to determine the time for recovery and stability (resistance and resilience) of different taxa and ecosystem functions, including species interaction networks. This integrative effort will ultimately help to understand how one of the most diverse forests on the planet recovers from large-scale disturbances.
Detailed information on species temperature preferences are needed to measure the effects of global warming on species and communities in European rivers. However, information currently available in the literature on taxon-specific temperature preferences or temperature tolerances is very heterogeneous and therefore not well suited for forecasting purposes. To close this gap, we derived so-called ’central temperature tendencies’ (CTTt values) for benthic invertebrate species. For this end, 547 species and temperature data from regional monitoring programmes in Germany collected at 4249 sites were analysed. Due to the vulnerability of species to high
temperatures, CTTt values were calculated for mean summer temperatures, following a robust approach of calculating a weighted average based on temperature classes. Derived CTTt values correspond well to species temperature preferences as reported in literature as long as the latter were homogeneous in terms of how they were derived and which temperature reference was at focus. Based on taxon-specific CTTt values, a community value, CTTCom, was calculated for each benthic invertebrate sample. CTTCom values were validated by correlation with mean summer water temperatures. As the slope a of the linear regression model between CTTCom values and measured summer temperatures was comparatively low (a = 0.49), a correction function was derived in order to optimise the relation between both. This was crucial, because it is assumed that although CTTt was derived solely from taxa abundances within summer temperature classes, CTTCom not only reflects the effect of (summer) water temperature itself, but also corresponds to a temperature equivalent value, which describes the overall quality of all respiration-relevant aquatic summer habitat conditions that determine the metabolism of respective benthic invertebrates. By comparing this equivalent value with water temperatures measured in the year previous of sampling, statements can be made about the influence of flow conditions and other factors determining oxygen availability.
Thus, CTTCom reflects the mean aerobic scope of the overall benthic invertebrate fauna: the better the respiration conditions for rheophilic species with high oxygen demand, the larger the aerobic scope and the lower CTTCom.
The approach taken in our study is promising and provides a tool to track and even project past, present, and future impacts of global warming on benthic invertebrates in rivers based on measured values of respiratory relevant environmental variables. We encourage all stakeholders in the field of freshwater ecology to test this
Nowadays, several options are available to treat patients with conductive or mixed hearing loss. Whenever surgical intervention is not possible or contra-indicated, and amplification by a conventional hearing device (e.g., behind-the-ear device) is not feasible, then implantable hearing devices are an indispensable next option. Implantable bone-conduction devices and middle-ear implants have advantages but also limitations concerning complexity/invasiveness of the surgery, medical complications, and effectiveness. To counsel the patient, the clinician should have a good overview of the options with regard to safety and reliability as well as unequivocal technical performance data. The present consensus document is the outcome of an extensive iterative process including ENT specialists, audiologists, health-policy scientists, and representatives/technicians of the main companies in this field. This document should provide a first framework for procedures and technical characterization to enhance effective communication between these stakeholders, improving health care.
Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.
(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.
Background: To study neoadjuvant chemoradiotherapy (nCRT) and potential predictive factors for response in locally advanced oral cavity cancer (LA-OCC).
Methods: The INVERT trial is an ongoing single-center, prospective phase 2, proof-of-principle trial. Operable patients with stage III-IVA squamous cell carcinomas of the oral cavity were eligible and received nCRT consisting of 60 Gy with concomitant cisplatin and 5-fluorouracil. Surgery was scheduled 6-8 weeks after completion of nCRT. Explorative, multiplex immunohistochemistry (IHC) was performed on pretreatment tumor specimen, and diffusion-weighted magnetic resonance imaging (DW-MRI) was conducted prior to, during nCRT (day 15), and before surgery to identify potential predictive biomarkers and imaging features. Primary endpoint was the pathological complete response (pCR) rate.
Results: Seventeen patients with stage IVA OCC were included in this interim analysis. All patients completed nCRT. One patient died from pneumonia 10 weeks after nCRT before surgery. Complete tumor resection (R0) was achieved in 16/17 patients, of whom 7 (41%, 95% CI: 18-67%) showed pCR. According to the Clavien-Dindo classification, grade 3a and 3b complications were found in 4 (25%) and 5 (31%) patients, respectively; grade 4-5 complications did not occur. Increased changes in the apparent diffusion coefficient signal intensities between MRI at day 15 of nCRT and before surgery were associated with better response (p=0.022). Higher abundances of programmed cell death protein 1 (PD1) positive cytotoxic T-cells (p=0.012), PD1+ macrophages (p=0.046), and cancer-associated fibroblasts (CAFs, p=0.036) were associated with incomplete response to nCRT.
Conclusion: nCRT for LA-OCC followed by radical surgery is feasible and shows high response rates. Larger patient cohorts from randomized trials are needed to further investigate nCRT and predictive biomarkers such as changes in DW-MRI signal intensities, tumor infiltrating immune cells, and CAFs.
New particle formation in the upper free troposphere is a major global source of cloud condensation nuclei (CCN)1,2,3,4. However, the precursor vapours that drive the process are not well understood. With experiments performed under upper tropospheric conditions in the CERN CLOUD chamber, we show that nitric acid, sulfuric acid and ammonia form particles synergistically, at rates that are orders of magnitude faster than those from any two of the three components. The importance of this mechanism depends on the availability of ammonia, which was previously thought to be efficiently scavenged by cloud droplets during convection. However, surprisingly high concentrations of ammonia and ammonium nitrate have recently been observed in the upper troposphere over the Asian monsoon region5,6. Once particles have formed, co-condensation of ammonia and abundant nitric acid alone is sufficient to drive rapid growth to CCN sizes with only trace sulfate. Moreover, our measurements show that these CCN are also highly efficient ice nucleating particles—comparable to desert dust. Our model simulations confirm that ammonia is efficiently convected aloft during the Asian monsoon, driving rapid, multi-acid HNO3–H2SO4–NH3 nucleation in the upper troposphere and producing ice nucleating particles that spread across the mid-latitude Northern Hemisphere.
Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation of identified hits often poses a challenge. The development of small molecules with narrow or exclusive target selectivity such as chemical probes and chemogenomic (CG) libraries, greatly diminishes this challenge, but non-specific effects caused by compound toxicity or interference with basic cellular functions still pose a problem to associate phenotypic readouts with molecular targets. Hence, each compound should ideally be comprehensively characterized regarding its effects on general cell functions. Here, we report an optimized live-cell multiplexed assay that classifies cells based on nuclear morphology, presenting an excellent indicator for cellular responses such as early apoptosis and necrosis. This basic readout in combination with the detection of other general cell damaging activities of small molecules such as changes in cytoskeletal morphology, cell cycle and mitochondrial health provides a comprehensive time-dependent characterization of the effect of small molecules on cellular health in a single experiment. The developed high-content assay offers multi-dimensional comprehensive characterization that can be used to delineate generic effects regarding cell functions and cell viability, allowing an assessment of compound suitability for subsequent detailed phenotypic and mechanistic studies.