Refine
Year of publication
- 2021 (2514)
- 2020 (2165)
- 2019 (1828)
- 2022 (1821)
- 2018 (1774)
- 2017 (1688)
- 2016 (1440)
- 2015 (1260)
- 2014 (1213)
- 2023 (1195)
- 2012 (1193)
- 2013 (1120)
- 2011 (939)
- 2009 (859)
- 2010 (856)
- 2008 (768)
- 2007 (587)
- 2006 (584)
- 2005 (568)
- 2004 (483)
- 2024 (456)
- 2003 (450)
- 2001 (380)
- 2002 (364)
- 2000 (315)
- 1999 (259)
- 1998 (203)
- 1997 (143)
- 1996 (133)
- 1995 (126)
- 1993 (107)
- 1994 (99)
- 1992 (89)
- 1990 (76)
- 1991 (60)
- 1989 (57)
- 1986 (48)
- 1988 (44)
- 1985 (43)
- 1981 (38)
- 1983 (36)
- 1982 (32)
- 1984 (32)
- 1976 (30)
- 1987 (29)
- 1980 (28)
- 1977 (22)
- 1971 (21)
- 1974 (21)
- 1975 (21)
- 1978 (18)
- 1979 (18)
- 1972 (17)
- 1969 (16)
- 1966 (14)
- 1973 (12)
- 1964 (11)
- 1967 (11)
- 1970 (11)
- 1908 (10)
- 1915 (10)
- 1923 (10)
- 1926 (10)
- 1937 (10)
- 1938 (10)
- 1893 (9)
- 1909 (9)
- 1965 (9)
- 1913 (8)
- 1936 (8)
- 1897 (7)
- 1898 (7)
- 1920 (7)
- 1935 (7)
- 1940 (7)
- 1961 (7)
- 1894 (6)
- 1896 (6)
- 1901 (6)
- 1903 (6)
- 1904 (6)
- 1910 (6)
- 1911 (6)
- 1912 (6)
- 1918 (6)
- 1922 (6)
- 1924 (6)
- 1927 (6)
- 1930 (6)
- 1933 (6)
- 1958 (6)
- 1881 (5)
- 1887 (5)
- 1900 (5)
- 1917 (5)
- 1919 (5)
- 1931 (5)
- 1957 (5)
- 1968 (5)
- 1842 (4)
- 1859 (4)
- 1862 (4)
- 1868 (4)
- 1890 (4)
- 1891 (4)
- 1899 (4)
- 1906 (4)
- 1914 (4)
- 1916 (4)
- 1928 (4)
- 1929 (4)
- 1942 (4)
- 1959 (4)
- 1962 (4)
- 1843 (3)
- 1846 (3)
- 1854 (3)
- 1857 (3)
- 1860 (3)
- 1870 (3)
- 1871 (3)
- 1875 (3)
- 1876 (3)
- 1880 (3)
- 1882 (3)
- 1885 (3)
- 1888 (3)
- 1892 (3)
- 1905 (3)
- 1921 (3)
- 1925 (3)
- 1934 (3)
- 1939 (3)
- 1943 (3)
- 1946 (3)
- 1947 (3)
- 1948 (3)
- 1952 (3)
- 1953 (3)
- 1960 (3)
- 1963 (3)
- 1743 (2)
- 1825 (2)
- 1835 (2)
- 1836 (2)
- 1838 (2)
- 1855 (2)
- 1856 (2)
- 1858 (2)
- 1869 (2)
- 1874 (2)
- 1879 (2)
- 1883 (2)
- 1884 (2)
- 1886 (2)
- 1902 (2)
- 1907 (2)
- 1932 (2)
- 1597 (1)
- 1757 (1)
- 1762 (1)
- 1770 (1)
- 1798 (1)
- 1800 (1)
- 1812 (1)
- 1816 (1)
- 1818 (1)
- 1820 (1)
- 1822 (1)
- 1830 (1)
- 1837 (1)
- 1840 (1)
- 1844 (1)
- 1845 (1)
- 1848 (1)
- 1850 (1)
- 1853 (1)
- 1861 (1)
- 1863 (1)
- 1865 (1)
- 1866 (1)
- 1872 (1)
- 1873 (1)
- 1878 (1)
- 1895 (1)
- 1941 (1)
- 1944 (1)
- 1945 (1)
- 1949 (1)
- 1950 (1)
- 1951 (1)
- 1954 (1)
- 1956 (1)
Document Type
- Article (15684)
- Part of Periodical (2814)
- Working Paper (2350)
- Doctoral Thesis (2053)
- Preprint (1957)
- Book (1736)
- Part of a Book (1071)
- Conference Proceeding (750)
- Report (471)
- Review (165)
Language
- English (29242) (remove)
Keywords
- taxonomy (738)
- new species (441)
- morphology (173)
- Deutschland (142)
- Syntax (125)
- Englisch (120)
- distribution (116)
- biodiversity (100)
- Deutsch (98)
- inflammation (97)
Institute
- Medizin (5323)
- Physik (3721)
- Wirtschaftswissenschaften (1906)
- Frankfurt Institute for Advanced Studies (FIAS) (1660)
- Biowissenschaften (1543)
- Center for Financial Studies (CFS) (1485)
- Informatik (1391)
- Biochemie und Chemie (1085)
- Sustainable Architecture for Finance in Europe (SAFE) (1065)
- House of Finance (HoF) (708)
The STAR Collaboration presents measurements of the semi-inclusive distribution of charged-particle jets recoiling from energetic direct-photon γdir and neutral-pion (π0) triggers in p+p and central Au+Au collisions at sNN−−−√=200 GeV over a broad kinematic range, for jet resolution parameters R=0.2 and 0.5. Medium-induced jet yield suppression is observed to be larger for R=0.2 than for 0.5, reflecting the angular range of jet energy redistribution due to quenching. The magnitude of suppression is similar for γdir- and π0-triggered data, which constrains the color-charge and path-length dependence of jet quenching. Theoretical model calculations incorporating jet quenching do not fully describe the measurements.
Using an 𝑒+𝑒− collision data sample with a total integrated luminosity of 3.19 fb−1 collected with the BESIII detector at a center-of-mass energy of 4.178 GeV, the branching fraction of the inclusive decay of the 𝐷+𝑠 meson to final states including at least three charged pions is measured for the first time to be ℬ(𝐷+𝑠→𝜋+𝜋+𝜋−𝑋)=(32.81±0.35stat±0.63syst)%. In this measurement the charged pions from 𝐾0𝑆 meson decays are excluded. The partial branching fractions of 𝐷+𝑠→𝜋+𝜋+𝜋−𝑋 are also measured as a function of the 𝜋+𝜋+𝜋− invariant mass.
The process e+e−→Σ+Σ¯− is studied from threshold up to 3.04 GeV/c2 via the initial-state radiation technique using data with an integrated luminosity of 12.0 fb−1, collected at center-of-mass energies between 3.773 and 4.258 GeV with the BESIII detector at the BEPCII collider. The pair production cross sections and the effective form factors of Σ are measured in eleven Σ+Σ¯− invariant mass intervals from threshold to 3.04 GeV/c2. The results are consistent with the previous results from Belle and BESIII. Furthermore, the branching fractions of the decays J/ψ→Σ+Σ¯− and ψ(3686)→Σ+Σ¯− are determined and the obtained results are consistent with the previous results of BESIII.
The process 𝑒+𝑒−→Σ+¯Σ− is studied from threshold up to 3.04 GeV/𝑐2 via the initial-state radiation technique using data with an integrated luminosity of 12.0 fb−1, collected at center-of-mass energies between 3.773 and 4.258 GeV with the BESIII detector at the BEPCII collider. The pair production cross sections and the effective form factors of Σ are measured in eleven Σ+¯Σ− invariant mass intervals from threshold to 3.04 GeV/𝑐2. The results are consistent with the previous results from Belle and BESIII. Furthermore, the branching fractions of the decays 𝐽/𝜓→Σ+¯Σ− and 𝜓(3686)→Σ+¯Σ− are determined and the obtained results are consistent with the previous results of BESIII.
Natural Language Processing (NLP) for big data requires an efficient and sophisticated infrastructure to complete tasks both fast and correctly. Providing an intuitive and lightweight interaction with a framework that abstracts and simplifies complex tasks assists in reaching this goal. This bachelor thesis extends the NLP framework Docker Unified UIMA Interface (DUUI) by an API and a web-based graphical user interface to control and manage pipelines for automated analysis of large quantities of natural language. The extension aims to reduce the entry barrier into the field as well as to accelerate the creation and management of pipelines according to UIMA standards. Pipelines can be executed in the browser or using the web API directly and then monitored on a document level. The evaluation in usability and user experience indicates that the implementation benefits the framework by making its usage more user friendly, lightweight, and intuitive while also making the management of pipelines more efficient.
Graph4Med: a web application and a graph database for visualizing and analyzing medical databases
(2022)
Background
Medical databases normally contain large amounts of data in a variety of forms. Although they grant significant insights into diagnosis and treatment, implementing data exploration into current medical databases is challenging since these are often based on a relational schema and cannot be used to easily extract information for cohort analysis and visualization. As a consequence, valuable information regarding cohort distribution or patient similarity may be missed. With the rapid advancement of biomedical technologies, new forms of data from methods such as Next Generation Sequencing (NGS) or chromosome microarray (array CGH) are constantly being generated; hence it can be expected that the amount and complexity of medical data will rise and bring relational database systems to a limit.
Description
We present Graph4Med, a web application that relies on a graph database obtained by transforming a relational database. Graph4Med provides a straightforward visualization and analysis of a selected patient cohort. Our use case is a database of pediatric Acute Lymphoblastic Leukemia (ALL). Along routine patients’ health records it also contains results of latest technologies such as NGS data. We developed a suitable graph data schema to convert the relational data into a graph data structure and store it in Neo4j. We used NeoDash to build a dashboard for querying and displaying patients’ cohort analysis. This way our tool (1) quickly displays the overview of patients’ cohort information such as distributions of gender, age, mutations (fusions), diagnosis; (2) provides mutation (fusion) based similarity search and display in a maneuverable graph; (3) generates an interactive graph of any selected patient and facilitates the identification of interesting patterns among patients.
Conclusion
We demonstrate the feasibility and advantages of a graph database for storing and querying medical databases. Our dashboard allows a fast and interactive analysis and visualization of complex medical data. It is especially useful for patients similarity search based on mutations (fusions), of which vast amounts of data have been generated by NGS in recent years. It can discover relationships and patterns in patients cohorts that are normally hard to grasp. Expanding Graph4Med to more medical databases will bring novel insights into diagnostic and research.
Monitoring woody cover by remote sensing is considered a key methodology towards sustainable management of trees in dryland forests. However, while modern very high resolution satellite (VHRS) sensors allow woodland mapping at the individual tree level, the historical perspective is often hindered by lack of appropriate image data. In this first study employing the newly accessible historical HEXAGON KH-9 stereo-panoramic camera images for environmental research, we propose their use for mapping trees in open-canopy conditions. The 2–4 feet resolution panchromatic HEXAGON satellite photographs were taken 1971–1986 within the American reconnaissance programs that are better known to the scientific community for their lower-resolution CORONA images. Our aim is to evaluate the potential of combining historical CORONA and HEXAGON with recent WorldView VHRS imagery for retrospective woodland change mapping on the tree level. We mapped all trees on 30 1-ha test sites in open-canopy argan woodlands in Morocco in the field and from the VHRS imagery for estimating changes of tree density and size between 1967/1972 and 2018. Prior to image interpretation, we used simulations based on unmanned aerial system (UAS) imagery for exemplarily examining the role of illumination, viewing geometry and image resolution on the appearance of trees and their shadows in the historical panchromatic images. We show that understanding these parameters is imperative for correct detection and size-estimation of tree crowns. Our results confirm that tree maps derived solely from VHRS image analysis generally underestimate the number of small trees and trees in clumped-canopy groups. Nevertheless, HEXAGON images compare remarkably well with WorldView images and have much higher tree-mapping potential than CORONA. By classifying the trees in three sizes, we were able to measure tree-cover changes on an ordinal scale. Although we found no clear trend of forest degradation or recovery, our argan forest sites show varying patterns of change, which are further analysed in Part B of our study. We conclude that the HEXAGON stereo-panoramic camera images, of which 670,000 worldwide will soon be available, open exciting opportunities for retrospective monitoring of trees in open-canopy conditions and other woody vegetation patterns back into the 1980s and 1970s.
Climate forecasts show that in many regions the temporal distribution of precipitation events will become less predictable. Root traits may play key roles in dealing with changes in precipitation predictability, but their functional plastic responses, including transgenerational processes, are scarcely known. We investigated root trait plasticity of Papaver rhoeas with respect to higher versus lower intra-seasonal and inter-seasonal precipitation predictability (i.e., the degree of temporal autocorrelation among precipitation events) during a four-year outdoor multi-generation experiment. We first tested how the simulated predictability regimes affected intra-generational plasticity of root traits and allocation strategies of the ancestors, and investigated the selective forces acting on them. Second, we exposed three descendant generations to the same predictability regime experienced by their mothers or to a different one. We then investigated whether high inter-generational predictability causes root trait differentiation, whether transgenerational root plasticity existed and whether it was affected by the different predictability treatments. We found that the number of secondary roots, root biomass and root allocation strategies of ancestors were affected by changes in precipitation predictability, in line with intra-generational plasticity. Lower predictability induced a root response, possibly reflecting a fast-acquisitive strategy that increases water absorbance from shallow soil layers. Ancestors’ root traits were generally under selection, and the predictability treatments did neither affect the strength nor the direction of selection. Transgenerational effects were detected in root biomass and root weight ratio (RWR). In presence of lower predictability, descendants significantly reduced RWR compared to ancestors, leading to an increase in performance. This points to a change in root allocation in order to maintain or increase the descendants’ fitness. Moreover, transgenerational plasticity existed in maximum rooting depth and root biomass, and the less predictable treatment promoted the lowest coefficient of variation among descendants’ treatments in five out of six root traits. This shows that the level of maternal predictability determines the variation in the descendants’ responses, and suggests that lower phenotypic plasticity evolves in less predictable environments. Overall, our findings show that roots are functional plastic traits that rapidly respond to differences in precipitation predictability, and that the plasticity and adaptation of root traits may crucially determine how climate change will affect plants.
Background
The assessment of therapeutic adherence and competence is essential to understand mechanisms that contribute to treatment outcome. Nevertheless, their assessment is often neglected in psychotherapy research.
Aims/Objective
To develop an adherence and a treatment-specific competence rating scale for Dialectical Behaviour Therapy for Posttraumatic Stress Disorder (DBT-PTSD), and to examine their psychometric properties. Global cognitive behavioural therapeutic competence and disorder-specific therapeutic competence were assessed using already existing scales to confirm their psychometric properties in our sample of patients with PTSD and emotion regulation difficulties.
Method
Two rating scales were developed using an inductive procedure. 155 videotaped therapy sessions from a multicenter randomised controlled trial were rated by trained raters using these scales, 40 randomly chosen videotapes involving eleven therapists and fourteen patients were doubly rated by two raters.
Results
Both the adherence scale (Patient-level ICC = .98; αs = .65; αp = .75) and the treatment-specific competence scale (Patient-level ICC = .98; αs = .78; αp = .82) for DBT-PTSD showed excellent interrater – and good reliability on the patient level. Content validity, including relevance and appropriateness of all items, was confirmed by experts in DBT-PTSD for the new treatment-specific competence scale.
Conclusion
Our results indicate that both scales are reliable instruments. They will be useful to examine possible effects of adherence and treatment-specific competence on DBT-PTSD treatment outcome.
Measurement of inclusive charged-particle jet production in Au+Au collisions at √sNN = 200 GeV
(2021)
The STAR Collaboration at the Relativistic Heavy Ion Collider reports the first measurement of inclusive jet production in peripheral and central Au+Au collisions at sNN−−−−√=200 GeV. Jets are reconstructed with the anti-kT algorithm using charged tracks with pseudorapidity |η|<1.0 and transverse momentum 0.2<pchT,jet<30 GeV/c, with jet resolution parameter R=0.2, 0.3, and 0.4. The large background yield uncorrelated with the jet signal is observed to be dominated by statistical phase space, consistent with a previous coincidence measurement. This background is suppressed by requiring a high-transverse-momentum (high-pT) leading hadron in accepted jet candidates. The bias imposed by this requirement is assessed, and the pT region in which the bias is small is identified. Inclusive charged-particle jet distributions are reported in peripheral and central Au+Au collisions for 5<pchT,jet<25 GeV/c and 5<pchT,jet<30 GeV/c, respectively. The charged-particle jet inclusive yield is suppressed for central Au+Au collisions, compared to both the peripheral Au+Au yield from this measurement and to the pp yield calculated using the PYTHIA event generator. The magnitude of the suppression is consistent with that of inclusive hadron production at high pT, and that of semi-inclusive recoil jet yield when expressed in terms of energy loss due to medium-induced energy transport. Comparison of inclusive charged-particle jet yields for different values of R exhibits no significant evidence for medium-induced broadening of the transverse jet profile for R<0.4 in central Au+Au collisions. The measured distributions are consistent with theoretical model calculations that incorporate jet quenching.
Measurement of inclusive charged-particle jet production in Au + Au collisions at √sNN=200 GeV
(2020)
The STAR Collaboration at the Relativistic Heavy Ion Collider reports the first measurement of inclusive jet production in peripheral and central Au+Au collisions at √𝑠𝑁𝑁=200 GeV. Jets are reconstructed with the anti-𝑘𝑇 algorithm using charged tracks with pseudorapidity |𝜂|<1.0 and transverse momentum 0.2<𝑝ch
𝑇,jet<30 GeV/𝑐, with jet resolution parameter 𝑅=0.2, 0.3, and 0.4. The large background yield uncorrelated with the jet signal is observed to be dominated by statistical phase space, consistent with a previous coincidence measurement. This background is suppressed by requiring a high-transverse-momentum (high-𝑝𝑇) leading hadron in accepted jet candidates. The bias imposed by this requirement is assessed, and the 𝑝𝑇 region in which the bias is small is identified. Inclusive charged-particle jet distributions are reported in peripheral and central Au+Au collisions for 5<𝑝ch
𝑇,jet<25 GeV/𝑐 and 5<𝑝ch
𝑇,jet<30 GeV/𝑐, respectively. The charged-particle jet inclusive yield is suppressed for central Au+Au collisions, compared to both the peripheral Au+Au yield from this measurement and to the 𝑝𝑝 yield calculated using the PYTHIA event generator. The magnitude of the suppression is consistent with that of inclusive hadron production at high 𝑝𝑇 and that of semi-inclusive recoil jet yield when expressed in terms of energy loss due to medium-induced energy transport. Comparison of inclusive charged-particle jet yields for different values of 𝑅 exhibits no significant evidence for medium-induced broadening of the transverse jet profile for 𝑅 <0.4 in central Au+Au collisions. The measured distributions are consistent with theoretical model calculations that incorporate jet quenching.
The main focus of this thesis is the application of the nonperturbative Functional Renormalization Group (FRG) to the study of low-energies effective models for Quantum Chromodynamics (QCD). The study of effective field theories and models is crucial for our understanding of physics, especially when we deal with fundamental interaction theories like QCD. In particular, the ultimate goal is the understanding of the critical properties of these models in such a way that we can have an insight on the actual critical phenomena of QCD, with a special focus on its chiral phase transition. The choice of the FRG method derives from the fact that it belongs to the class of functional non-perturbative methods and has also the advantage of linking physics at different energy scales. These features make FRG perfectly compatible with the task of studying non-perturbative phenomena and in particular phase transitions, like the ones expected for strongly interacting matter. However, the functional nature of the FRG approach and of the Wetterich equation has a consequence that its exact resolution is hardly possible, and an ansatz for the effective action is generally needed. In this work we choose to adopt the local-potential approximation (LPA), which prescribes to stop at zeroth order in the expansion in derivative operators of the quantum effective action, including only the quantum effective potential. In this work we exploited the key observation that the FRG flow equation can be cast, for specific models and truncation schemes, in the form of an advection-diffusion, possibly with a source term. This type of equation belongs to the class of problems faced in the context of viscous hydrodynamics. Therefore, an innovative approach to the solution of the FRG flow equation consists in the choice of a method developed specifically for the resolution of this class of hydrodynamic equations. In particular, the Kurganov-Tadmor finite-volume scheme is adopted. Throughout this work we apply this scheme to the study of different physical systems, showing the reliability and the flexibility of this approach.
In the first part of the thesis, we discuss the well-known O(N) model, using the hydrodynamic formulation to solve the FRG flow equation in the LPA truncation. We focus on the study of the critical behaviour of the system and calculate the corresponding critical exponents. Particular attention is given to the error estimation in the extraction of critical exponents, which is a needed and not widely explored aspect. The results are well compatible with others in the literature, obtained with different perturbative and nonperturbative methods, which validates the procedure. In the second part of the thesis, we introduce the quark-meson model as a low-energy effective model for QCD, with a specific focus on its chiral symmetry-breaking pattern and the subsequent dynamical quark-mass generation. The LPA flow equation is of the advection-diffusion type, with an extra source contribution which is due to the inclusion of fermionic degrees of freedom. We thus adopt the developed numerical techniques to derive the phase diagram of the model, which is in agreement with the one obtained with other techniques in the literature.
We also follow another possible way for the study of the critical properties of the quark-meson model: the so-called thermodynamic geometry. This approach is based on the interpretation of the parameter space of the system as a differential manifold. One can then obtain relevant information about the phase transitions from the Ricci scalar. We studied the chiral crossover investigating the behavior of the Ricci scalar up to the critical point, featuring a peaking behavior in the presence of the crossover. We then repeated this analysis in the chiral limit, where the phase transition is expected to be of second order. Via this geometric technique it is possible to have a different view on the chiral phase transition of QCD. This is the case since this approach is based on the calculation of quantities which are influenced by higher-order momenta of the thermodynamic potential, thus allowing for a more comprehensive analysis of the phase transition.
Finally, we exploit the numerical advancement to face the issue of the regulator choice in the FRG calculations. This is one of the most delicate issues which arise when using approximations to solve the FRG flow equation and deserves extensive investigation. In particular, we performed a vacuum parameter study and used the RG consistency requirement to determine the impact of the choice of the regulator on the physical observables and on the phase diagram of the model. Via this study we develop a systematic method to comparison the results obtained via different regulators. We show the importance of the choice of an appropriate UV cutoff in the determination of UV-independent IR observables and, consequently, the impact on the latter that the truncation of the effective average action and the choice of the regulator have.
The STAR Collaboration reports measurements of the transverse single-spin asymmetry (TSSA) of inclusive 𝜋0 at center-of-mass energies (√𝑠) of 200 GeV and 500 GeV in transversely polarized proton-proton collisions in the pseudo-rapidity region 2.7 to 4.0. The results at the two different energies show a continuous increase of the TSSA with Feynman-𝑥, and, when compared to previous measurements, no dependence on √𝑠 from 19.4 GeV to 500 GeV is found. To investigate the underlying physics leading to this large TSSA, different topologies have been studied. 𝜋0 with no nearby particles tend to have a higher TSSA than inclusive 𝜋0. The TSSA for inclusive electromagnetic jets, sensitive to the Sivers effect in the initial state, is substantially smaller, but shows the same behavior as the inclusive 𝜋0 asymmetry as a function of Feynman-𝑥. To investigate final-state effects, the Collins asymmetry of 𝜋0 inside electromagnetic jets has been measured. The Collins asymmetry is analyzed for its dependence on the 𝜋0 momentum transverse to the jet thrust axis and its dependence on the fraction of jet energy carried by the 𝜋0. The asymmetry was found to be small in each case for both center-of-mass energies. All the measurements are compared to QCD-based theoretical calculations for transverse-momentum-dependent parton distribution functions and fragmentation functions. Some discrepancies are found, which indicates new mechanisms might be involved.
We report a new measurement of transverse single-spin asymmetries for dijet production in collisions of polarized protons at s√ = 200 GeV. Correlations between the proton spin and the transverse momenta of its partons, each perpendicular to the proton momentum direction, are probed at high Q2 ≈160 GeV2. The associated Sivers observable ⟨kT⟩, the average parton transverse momentum, is extracted using simple kinematics. Nonzero Sivers effects are observed for the first time in dijets from proton-proton collisions, but only when the jets are sorted by their net charge, which enhances the u- or d-quark contributions to separate data samples. This also enables a simple kinematic approach for determination of the individual partonic contributions to the observed asymmetries.
In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis1–3. Studies of human and mouse GSDM pores reveal the functions and architectures of 24–33 protomers assemblies4–9, but the mechanism and evolutionary origin of membrane targeting and GSDM pore formation remain unknown. Here we determine a structure of a bacterial GSDM (bGSDM) pore and define a conserved mechanism of pore assembly. Engineering a panel of bGSDMs for site-specific proteolytic activation, we demonstrate that diverse bGSDMs form distinct pore sizes that range from smaller mammalian-like assemblies to exceptionally large pores containing >50 protomers. We determine a 3.3 Å cryo-EM structure of a Vitiosangium bGSDM in an active slinky-like oligomeric conformation and analyze bGSDM pores in a native lipid environment to create an atomic-level model of a full 52-mer bGSDM pore. Combining our structural analysis with molecular dynamics simulations and cellular assays, we define a stepwise model of GSDM pore assembly and demonstrate that pore formation is driven by local unfolding of membrane-spanning β-strand regions and pre-insertion of a covalently bound palmitoyl into the target membrane. These results yield insights into the diversity of GSDM pores found in nature and the function of an ancient post-translational modification in enabling a programmed host cell death process.
In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis1–3. Studies of human and mouse GSDM pores reveal the functions and architectures of 24–33 protomers assemblies4–9, but the mechanism and evolutionary origin of membrane targeting and GSDM pore formation remain unknown. Here we determine a structure of a bacterial GSDM (bGSDM) pore and define a conserved mechanism of pore assembly. Engineering a panel of bGSDMs for site-specific proteolytic activation, we demonstrate that diverse bGSDMs form distinct pore sizes that range from smaller mammalian-like assemblies to exceptionally large pores containing >50 protomers. We determine a 3.3 Å cryo-EM structure of a Vitiosangium bGSDM in an active slinky-like oligomeric conformation and analyze bGSDM pores in a native lipid environment to create an atomic-level model of a full 52-mer bGSDM pore. Combining our structural analysis with molecular dynamics simulations and cellular assays, our results support a stepwise model of GSDM pore assembly and suggest that a covalently bound palmitoyl can leave a hydrophobic sheath and insert into the membrane before formation of the membrane-spanning β-strand regions. These results reveal the diversity of GSDM pores found in nature and explain the function of an ancient post-translational modification in enabling programmed host cell death.
Background: Alternative splicing is a key mechanism in eukaryotic cells to increase the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied both across human tissues and in genetically diverse individuals. This has identified disease-relevant splicing events, as well as associations between splicing and genomic variations, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue and its determinants remain poorly understood.
Results: We applied parallel DNA methylation and transcriptome sequencing to differentiating human induced pluripotent stem cells to characterize splicing variation (exon skipping) and its determinants. Our results shows that splicing rates in single cells can be accurately predicted based on sequence composition and other genomic features. We also identified a moderate but significant contribution from DNA methylation to splicing variation across cells. By combining sequence information and DNA methylation, we derived an accurate model (AUC=0.85) for predicting different splicing modes of individual cassette exons. These explain conventional inclusion and exclusion patterns, but also more subtle modes of cell-to-cell variation in splicing. Finally, we identified and characterized associations between DNA methylation and splicing changes during cell differentiation.
Conclusions: Our study yields new insights into alternative splicing at the single-cell level and reveals a previously underappreciated component of DNA methylation variation on splicing.
Background: Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic variations, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue or cell type and its determinants remain poorly understood.
Results: We applied parallel DNA methylation and transcriptome sequencing to differentiating human induced pluripotent stem cells to characterize splicing variation (exon skipping) and its determinants. Our results shows that variation in single-cell splicing can be accurately predicted based on local sequence composition and genomic features. We observe moderate but consistent contributions from local DNA methylation profiles to splicing variation across cells. A combined model that is built based on sequence as well as DNA methylation information accurately predicts different splicing modes of individual cassette exons (AUC=0.85). These categories include the conventional inclusion and exclusion patterns, but also more subtle modes of cell-to-cell variation in splicing. Finally, we identified and characterized associations between DNA methylation and splicing changes during cell differentiation.
Conclusions: Our study yields new insights into alternative splicing at the single-cell level and reveals a previously underappreciated link between DNA methylation variation and splicing.
Background: Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic features, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue or cell type and its determinants remains poorly understood.
Results: We applied parallel DNA methylation and transcriptome sequencing to differentiating human induced pluripotent stem cells to characterize splicing variation (exon skipping) and its determinants. Our results show that variation in single-cell splicing can be accurately predicted based on local sequence composition and genomic features. We observe moderate but consistent contributions from local DNA methylation profiles to splicing variation across cells. A combined model that is built based on genomic features as well as DNA methylation information accurately predicts different splicing modes of individual cassette exons. These categories include the conventional inclusion and exclusion patterns, but also more subtle modes of cell-to-cell variation in splicing. Finally, we identified and characterized associations between DNA methylation and splicing changes during cell differentiation.
Conclusions: Our study yields new insights into alternative splicing at the single-cell level and reveals a previously underappreciated link between DNA methylation variation and splicing.
Predator-prey interactions are vital for organismal survival. They shape anti-predator mechanisms and often depend on sensory abilities. Tadpoles use chemical cues, such as injury cues (alarm cues), to assess predation risks and modify their life-history, morphology, and behaviours accordingly. However, the prevalence of chemically mediated anti-predator responses in species with distinct ecological niches (e.g. within phytotelmata) remains unknown, hindering our understanding of the ecological significance and evolution of alarm substances. Therefore, our study aimed to investigate chemically mediated anti-predator responses in tadpoles of two Neotropical poison dart frogs, Ranitomeya sirensis and Epipedobates anthonyi (and compare their responses to two Palearctic model organisms, Rana temporaria and Bufo bufo, which are known to utilise alarm substances). Through behavioural bioassays, we exposed predator-naïve tadpoles to extracts of each species (i.e. con- and heterospecific cues), including water as a control (i.e. five treatments per species). We assessed changes in their activity before and after stimulus introduction. Our results show that E. anthonyi did not respond to any of the stimuli, whereas R. sirensis displayed increased activity levels exclusively in response to conspecific cues, but not to heterospecific cues. With this, our findings suggest a specialized recognition system in R. sirensis, potentially directed at conspecific competitors but likely unrelated to anti-predator mechanisms. In contrast, E. anthonyi may be insensitive to injury cues or utilize alternative sensory modalities to respond to acute predation events. This study sheds light on the chemical alarm response system of Neotropical poison dart frog tadpoles, providing foundational understanding of how dendrobatids react to injury cues. It prompts questions about the ecological significance and evolutionary implications of chemical communication in species facing extreme resource limitation during development and underscores the importance of comparative research for understanding chemical communication in diverse aquatic ecosystems.
Interacting with the environment to process sensory information, generate perceptions, and shape behavior engages neural networks in brain areas with highly varied representations, ranging from unimodal sensory cortices to higher-order association areas. Recent work suggests a much greater degree of commonality across areas, with distributed and modular networks present in both sensory and non-sensory areas during early development. However, it is currently unknown whether this initially common modular structure undergoes an equally common developmental trajectory, or whether such a modular functional organization persists in some areas—such as primary visual cortex—but not others. Here we examine the development of network organization across diverse cortical regions in ferrets of both sexes using in vivo widefield calcium imaging of spontaneous activity. We find that all regions examined, including both primary sensory cortices (visual, auditory, and somatosensory—V1, A1, and S1, respectively) and higher order association areas (prefrontal and posterior parietal cortices) exhibit a largely similar pattern of changes over an approximately 3 week developmental period spanning eye opening and the transition to predominantly externally-driven sensory activity. We find that both a modular functional organization and millimeter-scale correlated networks remain present across all cortical areas examined. These networks weakened over development in most cortical areas, but strengthened in V1. Overall, the conserved maintenance of modular organization across different cortical areas suggests a common pathway of network refinement, and suggests that a modular organization—known to encode functional representations in visual areas—may be similarly engaged in highly diverse brain areas.
Significance Different areas of the mature brain encode vastly different representations of the world. This study shows that a modular functional organization where nearby neurons participate in similar functional networks is shared across different brain areas not only during early development, but also as the brain matures where it remains a shared feature that shapes neural activity. The largely conserved trajectory of developmental changes across brain areas suggests that similar circuit mechanisms may drive this maturation. This implies that the large literature on developing cortical circuits, which is largely focused on sensory areas, may also apply more broadly, and that perturbations during development that impinge on any such shared mechanisms may produce deficits that extend across multiple brain systems.
A broad range of neuropsychiatric disorders are associated with alterations in macroscale brain circuitry and connectivity. Identifying consistent brain patterns underlying these disorders by means of structural and functional MRI has proven challenging, partly due to the vast number of tests required to examine the entire brain, which can lead to an increase in missed findings. In this study, we propose polyconnectomic score (PCS) as a metric designed to quantify the presence of disease-related brain connectivity signatures in connectomes. PCS summarizes evidence of brain patterns related to a phenotype across the entire landscape of brain connectivity into a subject-level score. We evaluated PCS across four brain disorders (autism spectrum disorder, schizophrenia, attention deficit hyperactivity disorder, and Alzheimer’s disease) and 14 studies encompassing ∼35,000 individuals. Our findings consistently show that patients exhibit significantly higher PCS compared to controls, with effect sizes that go beyond other single MRI metrics ([min, max]: Cohen’s d = [0.30, 0.87], AUC = [0.58, 0.73]). We further demonstrate that PCS serves as a valuable tool for stratifying individuals, for example within the psychosis continuum, distinguishing patients with schizophrenia from their first-degree relatives (d = 0.42, p = 4 x 10−3, FDR-corrected), and first-degree relatives from healthy controls (d = 0.34, p = 0.034, FDR-corrected). We also show that PCS is useful to uncover associations between brain connectivity patterns related to neuropsychiatric disorders and mental health, psychosocial factors, and body measurements.
Purpose: To evaluate intermediate and long-term visual outcomes and safety of a phakic intraocular posterior chamber lens with a central hole (ICL V4c) for myopic eyes.
Methods: Retrospective, consecutive case study of patients that uneventfully received a ICL V4c for myopia correction, with a 5-year postoperative follow-up. Department of Ophthalmology, Goethe University Frankfurt, Germany.
Results: From 241 eyes that underwent ICL implantation, we included 45 eyes with a mean age at surgery of 33 years ± 6 (18–48 years), with a 5 years follow-up. CDVA improved from 0.05logMAR ± 0.15 CDVA preoperatively to − 0.00 ± 0,07 at 5 years and did not change significantly from 3 to 5 years’ time (p = 0.266). The mean spherical equivalent (SE) improved from -10.13D ± 3.39 to − 0.45D ± 0.69. The change in endothelial cell count showed a mean decrease of 1.9% per year throughout the follow-up. Safety and efficacy index were 1.16 and 0.78, respectively. Cataract formation was seen in 2 of 241 eyes (0.8%), but in none of the 45 eyes that finished the 5-year follow-up.
Conclusions: Our data show a good intermediate and long-term stability, efficiency, and safety of ICL V4c phakic lenses in myopic eyes comparable to other known literature.
The category of abelian varieties over Fq is shown to be anti-equivalent to a category of Z-lattices that are modules for a non-commutative pro-ring of endomorphisms of a suitably chosen direct system of abelian varieties over Fq. On full subcategories cut out by a finite set w of conjugacy classes of Weil q-numbers, the anti-equivalence is represented by what we call w-locally projective abelian varieties.
We consider ground state solutions u ∈ H2(RN) of biharmonic (fourth-order) nonlinear Schrodinger equations of the form ¨2u + 2au + bu − |u| p−2u = 0 in RN with positive constants a, b > 0 and exponents 2 < p < 2∗, where 2∗ = 2N N−4 if N > 4 and 2∗ = ∞ if N ≤ 4. By exploiting a connection to the adjoint Stein–Tomas inequality on the unit sphere and by using trial functions due to Knapp, we prove a general symmetry breaking result by showing that all ground states u ∈ H2(RN) in dimension N ≥ 2 fail to be radially symmetric for all exponents 2 < p < 2N+2 N−1 in a suitable regime of a, b > 0. As applications of our main result, we also prove symmetry breaking for a minimization problem with constrained L2-mass and for a related problem on the unit ball in RN subject to Dirichlet boundary conditions.
ABC transporters are found in all organisms and almost every cellular compartment. They mediate the transport of various solutes across membranes, energized by ATP binding and hydrolysis. Dysfunctions can result in severe diseases, such as cystic fibrosis or antibiotic resistance. In type IV ABC transporters, each of the two nucleotide-binding domains is connected to a transmembrane domain by two coupling helices, which are part of cytosolic loops. Although there are many structural snapshots of different conformations, the interdomain communication is still enigmatic. Therefore, we analyzed the function of three conserved, charged residues in the intra-cytosolic loop 1 of the human homodimeric, lysosomal peptide transporter TAPL. Substitution of D278 in coupling helix 1 by alanine interrupted peptide transport by impeding ATP hydrolysis. Alanine substitution of R288 and D292, both localized next to the coupling helix 1 extending to transmembrane helix 3, reduced peptide transport but increased basal ATPase activity. Surprisingly, the ATPase activity of the R288A variant dropped in a peptide-dependent manner while ATPase activity of wildtype and D292A was unaffected. Interestingly, R288A and D292A mutants did not differentiate between ATP and GTP in respect of hydrolysis. However, in contrast to wildtype TAPL, only ATP energized peptide transport. In sum, D278 seems to be involved in bidirectional interdomain communication mediated by network of polar interactions while the two residues in the cytosolic extension of TMH3 are involved in regulation of ATP hydrolysis, most likely by stabilization of the outward facing conformation.
The article discusses the University Library Frankfurt am Main’s current exhibition focusing on the background of and the systematic search for looted assets in the library holdings as part of a wider provenance research project. It offers an overview of various topical areas reaching from initial changes in 1933 to raids throughout Europe by Nazi organisations and restitution procedures during the post-war period. The scope and first findings of the provenance research project will also be addressed.
By analyzing 𝑒+𝑒− annihilation data with an integrated luminosity of 2.93 fb−1 collected at the center-of-mass energy √𝑠=3.773 GeV with the BESIII detector, we present the first absolute measurements of the branching fractions of twenty Cabibbo-suppressed hadronic 𝐷0(+) decays involving multiple pions. The highest four branching fractions obtained are ℬ(𝐷0→𝜋+𝜋−𝜋0) = (1.343±0.013stat±0.016syst)%, ℬ(𝐷0→𝜋+𝜋−2𝜋0) = (1.002±0.019stat±0.024syst)%, ℬ(𝐷+→2𝜋+𝜋−𝜋0) = (1.165±0.021stat±0.021syst)%, and ℬ(𝐷+→2𝜋+𝜋−2𝜋0) = (1.074±0.040stat±0.030syst)%. The 𝐶𝑃 asymmetries for the six decays with highest signal yields are also determined and found to be compatible with zero.
By analyzing e+e− annihilation data with an integrated luminosity of 2.93 fb−1 collected at the center-of-mass energy s√= 3.773 GeV with the BESIII detector, we present the first absolute measurements of the branching fractions of twenty Cabibbo-suppressed hadronic D0(+) decays involving multiple pions. The largest four branching fractions obtained are B(D0→π+π−π0) = >(1.343±0.013stat±0.016syst)%, B(D0→π+π−2π0) = (0.998±0.019stat±0.024syst)%, B(D+→2π+π−π0)
(1.174±0.021stat±0.021syst)%, and B(D+→2π+π−2π0) = (1.074±0.040stat±0.030syst)%. The CP asymmetries for the six decays with highest event yields are also determined.
Using a sample of (448.1±2.9)×106 𝜓(3686) decays collected with the BESIII detector at BEPCII, we report an observation of Ξ− transverse polarization with a significance of 7.3𝜎 in the decay 𝜓(3686)→Ξ− ¯Ξ+ (Ξ−→Λ𝜋−, ¯Ξ+→¯Λ𝜋+, Λ→𝑝𝜋−, ¯Λ→¯𝑝𝜋+). The relative phase of the electric and magnetic form factors is determined to be ΔΦ=(0.667±0.111±0.058) rad. This is the first measurement of the relative phase for a 𝜓(3686) decay into a pair of Ξ−¯Ξ+ hyperons. The Ξ− decay parameters (𝛼Ξ−, 𝜙Ξ−) and their conjugates (𝛼¯Ξ+, 𝜙¯Ξ+), the angular-distribution parameter 𝛼𝜓, and the strong-phase difference 𝛿𝑝−𝛿𝑠 for Λ𝜋− scattering are measured to be consistent with previous BESIII results.
Luminosities and energies of e⁺e⁻ collision data taken between √s=4.61 GeV and 4.95 GeV at BESIII
(2022)
From December 2019 to June 2021, the BESIII experiment collected about 5.85 fb−1 of data at center-of-mass energies between 4.61 GeV and 4.95 GeV. This is the highest collision energy BEPCII has reached so far. The accumulated e+e− annihilation data samples are useful for studying charmonium(-like) states and charmed-hadron decays. By adopting a novel method of analyzing the production of Λ+cΛ¯−c pairs in e+e− annihilation, the center-of-mass energies are measured with a precision of ∼0.6 MeV. Integrated luminosities are measured with a precision of better than 1\% by analyzing the events of large-angle Bhabha scattering. These measurements provide important inputs to the analyses based on these data samples.
The production cross section of inclusive isolated photons has been measured by the ALICE experiment at the CERN LHC in pp collisions at centre-of-momentum energy of s√=13 TeV collected during the LHC Run 2 data-taking period. The measurement is performed by combining the measurements of the electromagnetic calorimeter EMCal and the central tracking detectors ITS and TPC, covering a pseudorapidity range of |ηγ|<0.67 and a transverse momentum range of 7<pγT<200 GeV/c. The result extends to lower pγT and xγT=2pγT/s√ ranges, the lowest xγT of any isolated photon measurements to date, extending significantly those measured by the ATLAS and CMS experiments towards lower pγT at the same collision energy with a small overlap between the measurements. The measurement is compared with next-to-leading order perturbative QCD calculations and the results from the ATLAS and CMS experiments as well as with measurements at other collision energies. The measurement and theory prediction are in agreement with each other within the experimental and theoretical uncertainties.
A common element of market structure analysis is the spatial representation of firms’ competitive positions on maps. Such maps typically capture static snapshots in time. Yet, competitive positions tend to change. Embedded in such changes are firms’ trajectories, that is, the series of changes in firms’ positions over time relative to all other firms in a market. Identifying these trajectories contributes to market structure analysis by providing a forward-looking perspective on competition, revealing firms’ (re)positioning strategies and indicating strategy effectiveness. To unlock these insights, we propose EvoMap, a novel dynamic mapping framework that identifies firms’ trajectories from high-frequency and potentially noisy data. We validate EvoMap via extensive simulations and apply it empirically to study the trajectories of more than 1,000 publicly listed firms over 20 years. We find substantial changes in several firms’ positioning strategies, including Apple, Walmart, and Capital One. Because EvoMap accommodates a wide range of mapping methods, analysts can easily apply it in other empirical settings and to data from various sources.
Regulators worldwide have been implementing different privacy laws. They vary in their impact on the value for advertisers, publishers and users, but not much is known about these differences. This article focuses on three important privacy laws (i.e., General Data Protection Regulation [GDPR], California Consumer Privacy Act [CCPA] and Personal Information Protection Law [PIPL]) and compares their impact on the value for the three primary actors of the online advertising market, namely, advertisers, publishers and users. This article first compares these three privacy laws by developing a legal strictness score. It then uses the existing literature to derive the effects of the legal strictness of each privacy law on each actor’s value. Finally, it quantifies the three privacy laws’ impact on each actor’s value. The results show that GDPR and PIPL are similar and stricter than CCPA. Stricter privacy laws bring larger negative changes to the value for actors. As a result, both GDPR and PIPL decrease the actors’ value more substantially than CCPA. These value declines are the largest for publishers and are rather similar for users and advertisers. Scholars and practitioners can use our findings to explore ways to create value for multiple actors under various privacy laws.
For many services, consumers can choose among a range of optional tariffs that differ in their access and usage prices. Recent studies indicate that tariff-specific preferences may lead consumers to choose a tariff that does not minimize their expected billing rate. This study analyzes how tariff-specific preferences influence the responsiveness of consumers’ usage and tariff choice to changes in price. We show that consumer heterogeneity in tariff-specific preferences leads to heterogeneity in their sensitivity to price changes. Specifically, consumers with tariff-specific preferences are less sensitive to price increases of their preferred tariff than other consumers. Our results provide an additional reason why firms should offer multiple tariffs rather than a uniform nonlinear pricing plan to extract maximum consumer surplus.
Thought to be monotypic for decades, the only species in the goosefish genus Lophiomus Gill, Lm. setigerus (Vahl), shows a wide range of morphological variation and is distributed widely in the Indo-West Pacific (IWP). In this study, datasets for two mitochondrial and two nuclear genes sequences obtained from samples of Lophiomus collected in different localities across the IWP were constructed and analyzed to explore the phylogeny and species diversity within the genus. Our integrated approach with multiline evidence unveiled an unanticipated richness of at least six delimited species of Lophiomus. Herein, based on materials already available from museums and new specimens obtained primarily through the Tropical Deep-Sea Benthos program surveying IWP benthic fauna, we formally describe three new species: Lm. immaculioralis sp. nov., Lm. nigriventris sp. nov., and Lm. carusoi sp. nov. Also, we resurrect Lm. laticeps stat. rev. from synonyms of Lm. setigerus. These species can be diagnosed by genetics, body coloration, patterns on the floor of the mouth, peritoneum pigmentation, morphometric measurements, and meristic counts of cranial spines, dorsal-fin spines, and pectoral-fin and pelvic-fin rays from each other and from Lm. setigerus. The species Lm. setigerus, as well as the genus Lophiomus, are re-described accordingly based on the new results. Amended identification keys to the four extant lophiid genera and to species of Lophiomus are also provided.
Exploring strategies to improve the reverse beta-oxidation pathway in Saccharomyces cerevisiae
(2024)
Microbes are the most diverse living organisms on Earth, with various metabolic adaptations that allow them to live in different conditions and produce compounds with different chemical complexity. Microbial biotechnology exploits the metabolic diversity of microorganisms to manufacture products for different industries. Today, the chemical industry is a significant energy consumer and carbon dioxide emitter, with processes that harm natural ecosystems, like the extraction of medium-chain fatty acids (MCFAs). MCFAs are used as precursors for biofuels, volatile esters, surfactants, or polymers in materials with enhanced properties.
However, their current extraction process uses large, non-sustainable monocultures of coconut and palm trees. Therefore, the microbial production of MCFAs can help reduce the current environmental impact of obtaining these products and their derivatives.
In nature, fatty acids are mostly produced via fatty acid biosynthesis (FAB). However, the reverse β-oxidation (rBOX) is a more energy-efficient pathway compared to FAB. The rBOX pathway consists of four reactions, which result in the elongation of an acyl-CoA molecule by two carbon units from acetyl-CoA in each cycle. In this work we used Saccharomyces cerevisiae, an organism with a high tolerance towards toxic compounds, as the expression host of the rBOX pathway to produce MCFAs and medium-chain fatty alcohols (MCFOHs).
In the first part of this work, we expanded the length of the products from expressing the rBOX in the cytosol and increased the MCFAs titres. First, we deleted the major glycerol-3-phosphate dehydrogenase (GPD2). This resulted in a platform strain with significantly reduced glycerol fermentation and increased rBOX pathway activity, probably due to an increased availability of NADH. Then, we tested different combinations of rBOX enzymes to increase the length and titres of MCFA. Expressing the thiolase CnbktB and β-hydroxyacyl-CoA dehydrogenase CnpaaH1 from Cupriavidus necator, Cacrt from Clostridium acetobutylicum and the trans-enoyl-CoA reductase Tdter (Treponema denticola) resulted in hexanoic acid as the main product.
Expressing Cncrt2 (C. necator) or YlECH (Y. lipolytica) as enoyl-CoA hydratases resulted in octanoic acid as the main product. Then, we integrated the octanoic (Cncrt2 or YlECH) and the hexanoic acid (Cacrt)-producing variants in the genome of the platform strain and we achieved titers of ≈75 mg/L (hexanoic acid) and ≈ 60 mg/L (octanoic acid) when growing these strains in a complex, highly buffered medium. These are the highest titers of octanoic and hexanoic acid obtained in S. cerevisiae with the rBOX. Additionally, we deleted TES1 and FAA2 to prevent competition for butyryl-CoA and degradation of the produced fatty acids, respectively.
However, these deletions did not improve MCFA titers. In addition, we tested two dual acyl-CoA reductase/alcohol dehydrogenases (ACR/ADH), CaadhE2 from C. acetobutylicum and the putative ACR/ADH EceutE from Escherichia coli, in an octanoyl-CoA-producing strain to produce MCFOH. As a result, we produced 1-hexanol and 1-octanol for the first time in S. cerevisiae with these two enzymes. Nonetheless, the titres were low (<10 mg/L and <2 mg/L, respectively), and four-carbon 1-butanol was the main product in both cases (>80 mg/L). This showed the preference of these two enzymes for butyryl-CoA.
In the second part of this work, we expressed the rBOX in the mitochondria of S. cerevisiae to benefit from the high levels of acetyl-CoA and the reducing environment in that organelle. First, in an adh-deficient strain, we mutated MTH1, a transcription factor regulating the expression of hexose transporters, and deleted GPD2. This resulted in a strain with a reduced Crabtree effect and, therefore, an increased carbon flux to the mitochondria. We partially validated the increased flux to the mitochondria by expressing the ethanol-acetyltransferase EAT1 from Kluyveromyces marxianus in this organelle. This resulted in a higher isoamyl acetate production in the MTH1-mutant strain. Isoamyl acetate is synthesised by Eat1 from acetyl-CoA and isoamyl alcohol, a product of the metabolism of amino acids in the mitochondria. Then, we targeted different butyryl-CoA-producing rBOX variants to the mitochondria, and we used the production of 1-butanol and butyric acid as a proof-of-concept. The strong expression of all the enzymes was toxic for the cell, and the highest butyric acid titres (≈ 50 mg/L) in the mitochondria from the rBOX were obtained from the weak expression of the pathway. The highest 1-butanol titers (≈ 5 mg/L) were obtained with the downregulation of the mitochondrial NADH-oxidase NDI1. However, this downregulation led to a non-desirable petite phenotype.
In summary, we produced hexanoic and octanoic acid for the first time in S. cerevisiae using the rBOX and achieved the highest reported titers of hexanoic and octanoic acid so far using this pathway in S. cerevisiae. In addition, we successfully compartmentalised the rBOX in the mitochondria. However, competing reactions, some of them essential for the viability of the cell, limit the use of this organelle for the rBOX.
Background: Prostate cancer is a major health concern in aging men. Paralleling an aging society, prostate cancer prevalence increases emphasizing the need for efcient diagnostic algorithms.
Methods: Retrospectively, 106 prostate tissue samples from 48 patients (mean age,
66 ± 6.6 years) were included in the study. Patients sufered from prostate cancer (n = 38) or benign prostatic hyperplasia (n = 10) and were treated with radical prostatectomy or Holmium laser enucleation of the prostate, respectively. We constructed tissue microarrays (TMAs) comprising representative malignant (n = 38) and benign (n = 68) tissue cores. TMAs were processed to histological slides, stained, digitized and assessed for the applicability of machine learning strategies and open–source tools in diagnosis of prostate cancer. We applied the software QuPath to extract features for shape, stain intensity, and texture of TMA cores for three stainings, H&E, ERG, and PIN-4. Three machine learning algorithms, neural network (NN), support vector machines (SVM), and random forest (RF), were trained and cross-validated with 100 Monte Carlo random splits into 70% training set and 30% test set. We determined AUC values for single color channels, with and without optimization of hyperparameters by exhaustive grid search. We applied recursive feature elimination to feature sets of multiple color transforms.
Results: Mean AUC was above 0.80. PIN-4 stainings yielded higher AUC than H&E and
ERG. For PIN-4 with the color transform saturation, NN, RF, and SVM revealed AUC of 0.93 ± 0.04, 0.91 ± 0.06, and 0.92 ± 0.05, respectively. Optimization of hyperparameters improved the AUC only slightly by 0.01. For H&E, feature selection resulted in no increase of AUC but to an increase of 0.02–0.06 for ERG and PIN-4.
Conclusions: Automated pipelines may be able to discriminate with high accuracy between malignant and benign tissue. We found PIN-4 staining best suited for classifcation. Further bioinformatic analysis of larger data sets would be crucial to evaluate the reliability of automated classifcation methods for clinical practice and to evaluate potential discrimination of aggressiveness of cancer to pave the way to automatic precision medicine.
Climate change affects ecosystems worldwide and is threatening biodiversity. Insects, as ectotherm organisms, are strongly dependent on the thermal environment. Yet, little is known about the effects of summer heat and drought on insect diversity. In the Mediterranean climate zone, a region strongly affected by climate change, hot summers might have severe effects on insect communities. Especially the larval stage might be sensitive to thermal variation, as larvae—compared to other life stages—cannot avoid hot temperatures and drought by dormancy. Here we ask, whether inter-annual fluctuations in Mediterranean moth diversity can be explained by temperature (TLarv) and precipitation during larval development (HLarv). To address our question, we analyzed moth communities of a Mediterranean coastal forest during the last 20 years. For species with summer-developing larvae, species richness was significantly negatively correlated with TLarv, while the community composition was affected by both, TLarv and HLarv. Therefore, summer-developing larvae seem particularly sensitive to climate change, as hot summers might exceed the larval temperature optima and drought reduces food plant quality. Increasing frequency and severity of temperature and drought extremes due to climate change, therefore, might amplify insect decline in the future.
This prospective study sought to evaluate potential savings of radiation dose to medical staff using real-time dosimetry coupled with visual radiation dose feedback during angiographic interventions. For this purpose, we analyzed a total of 214 angiographic examinations that consisted of chemoembolizations and several other types of therapeutic interventions. The Unfors RaySafe i2 dosimeter was worn by the interventionalist at chest height over the lead protection. A total of 110 interventions were performed with real-time radiation dosimetry allowing the interventionalist to react upon higher x-ray exposure and 104 examinations served as the comparative group without real-time radiation monitoring. By using the real-time display during interventions, the overall mean operator radiation dose decreased from 3.67 (IQR, 0.95–23.01) to 2.36 μSv (IQR, 0.52–12.66) (−36%; p = 0.032) at simultaneously reduced operator exposure time by 4.5 min (p = 0.071). Dividing interventions into chemoembolizations and other types of therapeutic interventions, radiation dose decreased from 1.31 (IQR, 0.46-3.62) to 0.95 μSv (IQR, 0.53-3.11) and from 24.39 (IQR, 12.14-63.0) to 10.37 μSv (IQR, 0.85-36.84), respectively, using live-screen dosimetry (p ≤ 0.005). Radiation dose reductions were also observed for the participating assistants, indicating that they could also benefit from real-time visual feedback dosimetry during interventions (−30%; p = 0.039). Integration of real-time dosimetry into clinical processes might be useful in reducing occupational radiation exposure time during angiographic interventions. The real-time visual feedback raised the awareness of interventionalists and their assistants to the potential danger of prolonged radiation exposure leading to the adoption of radiation-sparing practices. Therefore, it might create a safer environment for the medical staff by keeping the applied radiation exposure as low as possible.
Biodiversity patterns of marine crustaceans are still unknown in many locations or might have been overlooked due to our knowledge gaps, despite increasing sampling and data sharing efforts during the last decades. By analysing big data extracted from open portals such as Ocean Biodiversity Information System (OBIS) and Global Biodiversity Information System (GBIF), we aim to revisit the distribution and biodiversity patterns of the highly speciose and abundant Crustacea in the Northwest Pacific (NWP) from shallowest depths to the deep sea. This study focussed on selected benthic and pelagic crustacean (sub) classes and their species richness, sampling effort, and expected species richness (ES50) using equal/sized hexagonal cells, 5° latitudinal bands, 500 m depth intervals were analyzed. Crustacean species richness was highest in the tropical Philippines as well as around the Japanese islands. Pelagic crustacean species richness peaked at 30° latitude and declined beyond that. Benthic taxa; however, depicted high levels of species richness across most of the latitudinal gradient, reaching its highest point at 45° latitude. Due to the prevalence of certain crustacean orders in the deep sea, benthic species richness showed a distribution pattern with two distinct peaks across bathymetric gradients; with highest species richness recorded at shallow-water depths and also at abyssal depths. The most important environmental drivers of benthic and pelagic crustacean species richness were primary productivity (positive correlation) and salinity (negative correlation). Our study provides first insights into biodiversity patterns of the highly diverse Crustacea in the NWP and highlights strong differences between benthic and pelagic taxa. The results presented here could help us to better understand whether benthic or pelagic taxa might respond differently to climate changes in the NWP based on their distinct physiological and biological characteristics. This information is crucial in establishing species management strategies and ecosystem restorations in both shallow water and deep-sea environments.
The combination of histological and biomolecular analyses provides deep understanding of different biological processes and is of high interest for basic and applied research. However, the available analytical methods are still limited, especially when considering bone samples. This study compared different fixation media to identify a sufficient analytical method for the combination of histological, immuno-histological and biomolecular analyses of the same fixed, processed and paraffin embedded bone sample. Bone core biopsies of rats’ femurs were fixed in different media (RNAlater + formaldehyde (R + FFPE), methacarn (MFPE) or formaldehyde (FFPE)) for 1 week prior to decalcification by EDTA and further histological processing and paraffin embedding. Snap freezing (unfixed frozen tissue, UFT) and incubation in RNAlater were used as additional controls. After gaining the paraffin sections for histological and immunohistological analysis, the samples were deparaffined and RNA was isolated by a modified TRIZOL protocol. Subsequently, gene expression was evaluated using RT-qPCR. Comparable histo-morphological and immuno-histological results were evident in all paraffin embedded samples of MFPE, FFPE and R + FFPE. The isolated RNA in the group of MFPE showed a high concentration and high purity, which was comparable to the UFT and RNAlater groups. However, in the groups of FFPE and R + FFPE, the RNA quality and quantity were statistically significantly lower when compared to MFPE, UFT and RNAlater. RT-qPCR results showed a comparable outcome in the group of MFPE and UFT, whereas the groups of FFPE and R + FFPE did not result in a correctly amplified gene product. Sample fixation by means of methacarn is of high interest for clinical samples to allow a combination of histological, immunohistological and biomolecular analysis. The implementation of such evaluation method in clinical research may allow a deeper understanding of the processes of bone formation and regeneration.
Alternating acquisition of background and sample spectra is often employed in conventional Fourier-transform infrared spectroscopy or ultraviolet–visible spectroscopy for accurate background subtraction. For example, for solvent background correction, typically a spectrum of a cuvette with solvent is measured and subtracted from a spectrum of a cuvette with solvent and solute. Ultrafast spectroscopies, though, come with many peculiarities that make the collection of well-matched, subtractable background and sample spectra challenging. Here, we present a demountable split-sample cell in combination with a modified Lissajous scanner to overcome these challenges. It allows for quasi-simultaneous measurements of background and sample spectra, mitigating the effects of drifts of the setup and maintaining the beam and sample geometry when swapping between background and sample measurements. The cell is moving between subsequent laser shots to refresh the excited sample volume. With less than 45 μl of solution for 150 μm optical thickness, sample usage is economical. Cell assembly is a key step and covered in an illustrated protocol.
Hepatic cells are sensitive to internal and external signals. Ethanol is one of the oldest and most widely used drugs in the world. The focus on the mechanistic engine of the alcohol-induced injury has been in the liver, which is responsible for the pathways of alcohol metabolism. Ethanol undergoes a phase I type of reaction, mainly catalyzed by the cytoplasmic enzyme, alcohol dehydrogenase (ADH), and by the microsomal ethanol-oxidizing system (MEOS). Reactive oxygen species (ROS) generated by cytochrome (CYP) 2E1 activity and MEOS contribute to ethanol-induced toxicity. We aimed to: (1) Describe the cellular, pathophysiological and clinical effects of alcohol misuse on the liver; (2) Select the biomarkers and analytical methods utilized by the clinical laboratory to assess alcohol exposure; (3) Provide therapeutic ideas to prevent/reduce alcohol-induced liver injury; (4) Provide up-to-date knowledge regarding the Corona virus and its affect on the liver; (5) Link rare diseases with alcohol consumption. The current review contributes to risk identification of patients with alcoholic, as well as non-alcoholic, liver disease and metabolic syndrome. Additional prevalence of ethnic, genetic, and viral vulnerabilities are presented.
Mitochondrial RNA granules (MRGs) are membraneless, highly specialized compartments that play an essential role in the post-transcriptional regulation of mitochondrial gene expression. This regulation is crucial for maintaining energy production, controlling metabolic functions and ensuring homeostasis in cells. Dysregulation of mitochondrial genes has been linked to various human diseases, including neurodegenerative and metabolic disorders as well as certain types of cancer.
MRGs are composed of different RNA species, including mitochondrial precursor RNA (pre-RNA), mature tRNAs, rRNAs and mRNAs complexed with multiple proteins involved in RNA processing and mitoribosome assembly. However, despite the significance of MRGs, their protein composition, structural organization, stability and dynamics during stress conditions remain elusive. In the study reported here, I adopted a three-step approach to address the aforementioned fundamental issues.
First and foremost, I identified the protein composition of MRGs and unveiled their architectural complexity. To characterize the MRG proteome, I applied the cutting-edge TurboID-based proximity labeling approach combined with quantitative mass spectrometry. Proximity labeling was conducted on 20 distinct MRG-associated human proteins, resulting in the identification of more than 1,700 protein-protein interactions. This expansive dataset enabled me to create a comprehensive network, providing valuable insights into both the (sub)architecture as well as the core structure of MRGs in-depth.
Secondly, I investigated the spatio-temporal dynamics of MRGs under various mitochondrial stress conditions. To monitor the morphological alterations and compositional changes of MRGs, I utilized time-resolved confocal fluorescence microscopy and proteomics, respectively. In this analysis, I applied IMT1, the first specific inhibitor that selectively targets mitochondrial transcription. Using this methodology, I pinpointed precise conditions that triggered MRGs’ disassembly during stress, followed by their reassembly when nascent RNA production was restored. The results of this examination elucidate that MRGs are highly dynamic and stress adaptive structures, capable of rapid dissolution and reassembly, a process closely connected to mitochondrial transcription.
Thirdly, I aimed to explore the impact of RNA turnover on MRGs’ integrity during stress, employing confocal fluorescence microscopy and quantitative real-time PCR. I observed that depletion of MRG proteins associated with RNA degradation counteracts MRGs’ disassembly under stress conditions, a phenomenon attributed to the accumulation of double-stranded RNA (dsRNA). These results emphasize the critical role of pre-RNA turnover in maintaining MRG integrity and reveal that MRGs can be stabilized by dsRNA.
Taken together, the comprehensive investigation reported in this thesis has substantially broadened and deepened our understanding of MRGs’ complexity. By identifying their molecular structure and dynamics, I have gained significant insights into the fundamental characteristics and biological functions of MRGs in cellular processes. This knowledge contributes to the identification of disease-related pathways linked to mitochondrial gene expression and may inspire future studies to develop novel therapeutic approaches.
Temperate forests are increasingly subject to natural disturbance by stand replacing windthrows or bark-beetle attacks. Forests are commonly salvage logged after disturbance, whereby substantial parts of biological legacies, such as surviving trees and deadwood, are removed. Despite increasing concerns about the ecological consequences of salvage logging operations, our knowledge on the effects on the soil microbiome and associated functioning remains limited.
Here, we studied soil fungal communities, decomposition processes, and soil organic matter dynamics in 21 intact or disturbed, temperate Norway spruce stands about one decade after they were damaged by windthrow or bark-beetle attacks. Disturbed stands comprised different post-disturbance management, i.e. deadwood retention and salvage logged plots. We used high-throughput sequencing and ergosterol measurements to explore fungal communities and biomass, and enzyme assays to study decomposition processes.
Disturbance shifted soil fungal communities from ectomycorrhizal to saprotrophic dominated assemblages. Fungal biomass declined with decreasing tree abundance after disturbance. Activities of organic matter degrading enzymes declined by ca. 30–80% after disturbance. The relative abundance of ectomycorrhizal fungi was positively related to enzymatic activities. Tree biomass parameters and amounts of deadwood retained were positively related to fungal biomass, certain ectomycorrhizal taxa, and relative ectomycorrhizal fungal abundance among disturbed stands, which, in turn, was associated with higher enzymatic activities.
Our findings demonstrate a significant response of soil fungal communities to natural forest disturbance and salvage logging, with consequences for decomposition and soil organic matter dynamics. We conclude that the retention of surviving trees and deadwood as biological legacies attenuated associated changes to a significant extent, highlighting their importance for the preservation of ectomycorrhizal fungi and the maintenance of decomposition processes after disturbance.
Growing up in cities is associated with increased risk for developing mental health problems. Stress exposure and altered stress regulation have been proposed as mechanisms linking urbanicity and psychopathology, with most research conducted in adult populations. Here, we focus on early childhood, and investigate urbanicity, behavior problems and the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, a central circuit of the stress system, in a sample of N = 399 preschoolers aged 45 months. Urbanicity was coded dichotomously distinguishing between residences with more or less than 100,000 inhabitants. Behavior problems were measured using the Child Behavior Checklist (CBCL) 1½ - 5. Cortisol stress reactivity was assessed using an age-appropriated game-like stress task, and cortisol in the first morning urine was measured to assess nocturnal HPA axis activity. Urbanicity was not associated with behavior problems, urinary cortisol or the cortisol stress response. Neither urinary cortisol nor salivary cortisol response after stress exposure were identified as mediators of the relationship between urbanicity and behavior problems. The findings suggest no strong association of urbanicity with behavior problems and HPA axis regulation in preschool age. To our knowledge, this is the youngest sample to date studying the relationship between urbanicity and behavior problems as well as HPA axis regulation. Future research should examine at which age associations can first be identified and which mechanisms contribute to these relationships.
Aim
To compare overall mortality (OM), cancer-specific mortality (CSM), and other cause mortality (OCM) rates between radical prostatectomy (RP) versus radiotherapy (RT) in clinical node-positive (cN1) prostate cancer (PCa).
Materials and Methods
Within Surveillance, Epidemiology, End Results (SEER) (2004–2016), we identified 4685 cN1 PCa patients, of whom 3589 (76.6%) versus 1096 (24.4%) were treated with RP versus RT. After 1:1 propensity score matching (PSM), Kaplan–Meier plots and Cox regression models tested the effect of RP versus RT on OM, while cumulative incidence plots and competing-risks regression (CRR) models addressed CSM and OCM between RP and RT patients. All analyses were repeated after the inverse probability of treatment weighting (IPTW). For CSM and OCM analyses, the propensity score was used as a covariate in the regression model.
Results
Overall, RT patients were older, harbored higher prostate-specific antigen values, higher clinical T and higher Gleason grade groups. PSM resulted in two equally sized groups of 894 RP versus 894 RT patients. After PSM, 5-year OM, CSM, and OCM rates were, respectively, 15.4% versus 25%, 9.3% versus 17%, and 6.1% versus 8% for RP versus RT (all p < 0.001) and yielded respective multivariate hazard ratios (HRs) of 0.63 (0.52–0.78, p < 0.001), 0.66 (0.52–0.86, p < 0.001), 0.71 (0.5–1.0, p = 0.05), all favoring RP. After IPTW, Cox regression models yielded HR of 0.55 (95% confidence interval [CI] = 0.46–0.66) for OM, and CRR yielded HRs of 0.49 (0.34–0.70) and 0.54 (0.36–0.79) for, respectively, CSM and OCM, all favoring RP (all p < 0.001).
Conclusions
RP may hold a CSM advantage over RT in cN1 PCa patients.
The intensity and the features of sensory stimuli are encoded in the activity of neurons in the cortex. In the visual and piriform cortices, the stimulus intensity rescales the activity of the population without changing its selectivity for the stimulus features. The cortical representation of the stimulus is therefore intensity invariant. This emergence of network-invariant representations appears robust to local changes in synaptic strength induced by synaptic plasticity, even though (i) synaptic plasticity can potentiate or depress connections between neurons in a feature-dependent manner, and (ii) in networks with balanced excitation and inhibition, synaptic plasticity determines the nonlinear network behavior. In this study we investigate the consistency of invariant representations with a variety of synaptic states in balanced networks. By using mean-field models and spiking network simulations, we show how the synaptic state controls the emergence of intensity-invariant or intensity-dependent selectivity. In particular, we demonstrate that an effective power-law synaptic transformation at the population level is necessary for invariance. In a range of firing rates, purely depressing short-term synapses fulfills this condition, and in this case, the network is contrast-invariant. Instead, facilitating short-term plasticity generally narrows the network selectivity. We found that facilitating and depressing short-term plasticity can be combined to approximate a power-law that leads to contrast invariance. These results explain how the physiology of individual synapses is linked to the emergence of invariant representations of sensory stimuli at the network level.