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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.
Using data samples collected with the BESIII detector operating at the BEPCII storage ring, the cross section of the inclusive process e+e−→η+X, normalized by the total cross section of e+e−→hadrons, is measured at eight center-of-mass energy points from 2.0000 GeV to 3.6710 GeV. These are the first measurements with momentum dependence in this energy region. Our measurement shows a significant discrepancy from calculations with the existing fragmentation functions. To address this discrepancy, a new QCD analysis is performed at the next-to-next-to-leading order with hadron mass corrections and higher twist effects, which can explain both the established high-energy data and our measurements reasonably well.
We report the first measurements of the absolute branching fractions of D0 → K0 Lϕ, D0 → K0Lη, D0 → K0Lω, and D0 → K0Lη0, by analyzing 2.93 fb−1 of eþe− collision data taken at a center-of-mass energy of 3.773 GeV with the BESIII detector. Taking the world averages of the branching fractions of D0 → K0Sϕ, D0 → K0Sη, D0 → K0Sω, and D0 → K0Sη0, the K0S − K0L asymmetries RðD0; XÞ in these decay modes are obtained. The CP asymmetries in these decays are also determined. No significant CP violation is observed
The cross sections of e+e−→K+K−J/ψ at center-of-mass energies from 4.127 to 4.600~GeV are measured based on 15.6 fb−1 data collected with the BESIII detector operating at the BEPCII storage ring. Two resonant structures are observed in the line shape of the cross sections. The mass and width of the first structure are measured to be (4225.3±2.3±21.5) MeV and (72.9±6.1±30.8)~MeV, respectively. They are consistent with those of the established Y(4230). The second structure is observed for the first time with a statistical significance greater than 8σ, denoted as Y(4500). Its mass and width are determined to be (4484.7±13.3±24.1) MeV and (111.1±30.1±15.2) MeV, respectively. The first presented uncertainties are statistical and the second ones are systematic. The product of the electronic partial width with the decay branching fraction Γ(Y(4230)→e+e−)B(Y(4230)→K+K−J/ψ) is reported.
We report a search for a heavier partner of the recently observed Zcs(3985)− state, denoted as Z′−cs, in the process e+e−→K+D∗−sD∗0+c.c., based on e+e− collision data collected at the center-of-mass energies of s√=4.661, 4.682 and 4.699 GeV with the BESIII detector. The Z′−cs is of interest as it is expected to be a candidate for a hidden-charm and open-strange tetraquark. A partial-reconstruction technique is used to isolate K+ recoil-mass spectra, which are probed for a potential contribution from Z′−cs→D∗−sD∗0 (c.c.). We find an excess of Z′−cs→D∗−sD∗0 (c.c.) candidates with a significance of 2.9σ, after considering systematic uncertainties, at a mass of (4123.5±0.7stat.±1.1syst.)MeV/c2. As the data set is limited in size, the upper limits are evaluated at the 90% confidence level on the product of the Born cross section and the branching fraction of Z′−cs→D∗−sD∗0, σBorn⋅B at the three energy points, under different assumptions of the Z′−cs mass from 4.120 to 4.140 MeV and of the width from 10 to 50 MeV. Under various mass and width assumptions, the upper limits of σBorn⋅B are found to lie in the range of 2∼6, 3∼7 and 3∼6 pb at s√=4.661, 4.682 and 4.699 GeV, respectively. The larger data samples that will be collected in the coming years will allow a clearer picture to emerge concerning the existence and nature of the Z′−cs state.
The cross sections of e+e−→K+K−J/ψ at center-of-mass energies from 4.127 to 4.600~GeV are measured based on 15.6 fb−1 data collected with the BESIII detector operating at the BEPCII storage ring. Two resonant structures are observed in the line shape of the cross sections. The mass and width of the first structure are measured to be (4225.3±2.3±21.5) MeV and (72.9±6.1±30.8)~MeV, respectively. They are consistent with those of the established Y(4230). The second structure is observed for the first time with a statistical significance greater than 8σ, denoted as Y(4500). Its mass and width are determined to be (4484.7±13.3±24.1) MeV and (111.1±30.1±15.2) MeV, respectively. The first presented uncertainties are statistical and the second ones are systematic. The product of the electronic partial width with the decay branching fraction Γ(Y(4230)→e+e−)B(Y(4230)→K+K−J/ψ) is reported.
The cross sections of e+e−→K+K−J/ψ at center-of-mass energies from 4.127 to 4.600 GeV are measured based on 15.6 fb−1 data collected with the BESIII detector operating at the BEPCII storage ring. Two resonant structures are observed in the line shape of the cross sections. The mass and width of the first structure are measured to be (4225.3 ± 2.3 ± 21.5) MeV and (72.9±6.1±30.8) MeV, respectively. They are consistent with those of the established Y(4230). The second structure is observed for the first time with a statistical significance greater than 8σ, denoted as Y(4500). Its mass and width are determined to be (4484.7 ± 13.3 ± 24.1) MeV and (111.1 ± 30.1 ± 15.2) MeV, respectively. The first presented uncertainties are statistical and the second ones are systematic. The product of the electronic partial width with the decay branching fraction Γ(Y(4230)→e+e−)B(Y(4230) → K+K−J/ψ) is reported.
Using about 23 fb−1 of data collected with the BESIII detector operating at the BEPCII storage ring, a precise measurement of the e+e−→π+π−J/ψ Born cross section is performed at center-of-mass energies from 3.7730 to 4.7008 GeV. Two structures, identified as the Y(4220) and the Y(4320) states, are observed in the energy-dependent cross section with a significance larger than 10σ. The masses and widths of the two structures are determined to be (M,Γ) = (4221.4±1.5±2.0 MeV/c2, 41.8±2.9±2.7 MeV) and (M,Γ) = (4298±12±26 MeV/c2, 127±17±10 MeV), respectively. A small enhancement around 4.5 GeV with a significance about 3σ, compatible with the ψ(4415), might also indicate the presence of an additional resonance in the spectrum. The inclusion of this additional contribution in the fit to the cross section affects the resonance parameters of the Y(4320) state.
Using about 23 fb−1 of data collected with the BESIII detector operating at the BEPCII storage ring, a precise measurement of the e+e−→π+π−J/ψ Born cross section is performed at center-of-mass energies from 3.7730 to 4.7008 GeV. Two structures, identified as the Y(4220) and the Y(4320) states, are observed in the energy-dependent cross section with a significance larger than 10σ. The masses and widths of the two structures are determined to be (M,Γ) = (4221.4±1.5±2.0 MeV/c2, 41.8±2.9±2.7 MeV) and (M,Γ) = (4298±12±26 MeV/c2, 127±17±10 MeV), respectively. A small enhancement around 4.5 GeV with a significance about 3σ, compatible with the ψ(4415), might also indicate the presence of an additional resonance in the spectrum. The inclusion of this additional contribution in the fit to the cross section affects the resonance parameters of the Y(4320) state.
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 cross sections of e+e−→K+K−J/ψ at center-of-mass energies from 4.127 to 4.600~GeV are measured based on 15.6 fb−1 data collected with the BESIII detector operating at the BEPCII storage ring. Two resonant structures are observed in the line shape of the cross sections. The mass and width of the first structure are measured to be (4225.3±2.3±21.5) MeV and (72.9±6.1±30.8)~MeV, respectively. They are consistent with those of the established Y(4230). The second structure is observed for the first time with a statistical significance greater than 8σ, denoted as Y(4500). Its mass and width are determined to be (4484.7±13.3±24.1) MeV and (111.1±30.1±15.2) MeV, respectively. The first presented uncertainties are statistical and the second ones are systematic. The product of the electronic partial width with the decay branching fraction Γ(Y(4230)→e+e−)B(Y(4230)→K+K−J/ψ) is reported.
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 data samples with an integrated luminosity of 6.4~fb−1 collected by the BESIII detector operating at the BEPCII storage ring, the process of e+e−→γϕJ/ψ is studied. The processes of e+e−→ϕχc1,c2, χc1,c2→γJ/ψ are observed with a significance of more than 10σ. The s√-dependent cross section of e+e−→ϕχc1,c2 is measured between 4.600 and 4.951~GeV, and evidence of a resonance structure is found for the first time in the ϕχc2 process. We also search for the processes of e+e−→γX(4140), γX(4274) and γX(4500) via the γϕJ/ψ final state, but no obvious structures are found. The upper limits on the production cross section times the branching fraction for these processes at the 90% confidence level are reported.
Improved measurement of the branching fractions of the inclusive decays D⁺ → Kₛ⁰X and D⁰ → Kₛ⁰X
(2023)
By analyzing 2.93 fb−1 of e+e− collision data taken at the center-of-mass energy of 3.773 GeV with the BESIII detector, the branching fractions of the inclusive decays D+→K0SX and D0→K0SX are measured to be (32.78±0.13±0.27)% and (20.54±0.12±0.18)%, respectively, where the first uncertainties are statistical and the second are systematic. These results are consistent with the world averages of previous measurements, but with improved precision.
We report a search for a heavier partner of the recently observed Zcs(3985)− state, denoted as Z′−cs, in the process e+e−→K+D∗−sD∗0+c.c., based on e+e− collision data collected at the center-of-mass energies of s√=4.661, 4.682 and 4.699 GeV with the BESIII detector. The Z′−cs is of interest as it is expected to be a candidate for a hidden-charm and open-strange tetraquark. A partial-reconstruction technique is used to isolate K+ recoil-mass spectra, which are probed for a potential contribution from Z′−cs→D∗−sD∗0 (c.c.). We find an excess of Z′−cs→D∗−sD∗0 (c.c.) candidates with a significance of 2.1σ, after considering systematic uncertainties, at a mass of (4123.5±0.7stat.±4.7syst.) MeV/c2. As the data set is limited in size, the upper limits are evaluated at the 90\% confidence level on the product of the Born cross sections (σBorn) and the branching fraction (B) of Z′−cs→D∗−sD∗0, under different assumptions of the Z′−cs mass from 4.120 to 4.140 MeV and of the width from 10 to 50 MeV at the three center-of-mass energies. The upper limits of σBorn⋅B are found to be at the level of O(1) pb at each energy. Larger data samples are needed to confirm the Z′−cs state and clarify its nature in the coming years.
We report a search for a heavier partner of the recently observed Zcs(3985)− state, denoted as Z′−cs, in the process e+e−→K+D∗−sD∗0+c.c., based on e+e− collision data collected at the center-of-mass energies of s√=4.661, 4.682 and 4.699 GeV with the BESIII detector. The Z′−cs is of interest as it is expected to be a candidate for a hidden-charm and open-strange tetraquark. A partial-reconstruction technique is used to isolate K+ recoil-mass spectra, which are probed for a potential contribution from Z′−cs→D∗−sD∗0 (c.c.). We find an excess of Z′−cs→D∗−sD∗0 (c.c.) candidates with a significance of 2.1σ, after considering systematic uncertainties, at a mass of (4123.5±0.7stat.±4.7syst.) MeV/c2. As the data set is limited in size, the upper limits are evaluated at the 90\% confidence level on the product of the Born cross sections (σBorn) and the branching fraction (B) of Z′−cs→D∗−sD∗0, under different assumptions of the Z′−cs mass from 4.120 to 4.140 MeV and of the width from 10 to 50 MeV at the three center-of-mass energies. The upper limits of σBorn⋅B are found to be at the level of O(1) pb at each energy. Larger data samples are needed to confirm the Z′−cs state and clarify its nature in the coming years.
The Born cross section of the process e+e−→ηJ/ψ at a center-of-mass energy s√=3.773 GeV is measured to be (8.89±0.88±0.42) pb, using a data sample collected with the BESIII detector operating at the BEPCII storage ring. The decay ψ(3770)→ηJ/ψ is observed for the first time with a statistical significance of 7.4σ. From a fit to the dressed cross-section line-shape of e+e−→ηJ/ψ from s√=3.773 to 4.600 GeV we obtain the branching fraction of the decay ψ(3770)→ηJ/ψ to be (11.6±6.1±1.0)×10−4 when the ψ(3770) decay amplitude is added coherently to the other contributions, and (7.9±1.0±0.7)×10−4 when it is added incoherently. Here the first uncertainties are statistical and the second are systematic.
Using a data sample collected with the BESIII detector operating at the BEPCII storage ring, the Born cross section of the process 𝑒+𝑒−→𝜂𝐽/𝜓 at a center-of-mass energy √𝑠=3.773 GeV is measured to be (8.88±0.87±0.42) pb. We fit the cross section line shape before correcting for the initial state radiation from √𝑠=3.773 to 4.600 GeV to obtain the branching fraction ℬ(𝜓(3770)→𝜂𝐽/𝜓). We obtain ℬ(𝜓(3770)→𝜂𝐽/𝜓)=(11.3±5.9±1.1)×10−4 when the 𝜓(3770) decay amplitude is added coherently to the other contributions, and (8.7±1.0±0.8)×10−4 when it is added incoherently. Here the quoted uncertainties are statistical and systematic, respectively. In both cases, the statistical significance of 𝜓(3770) resonance is above 7𝜎. This is the first time the decay 𝜓(3770)→𝜂𝐽/𝜓 is observed with a statistical significance greater than 5𝜎.
We search for the semi-leptonic decays Λ + c → Λπ+π−e+νe and Λ + c → pK0 Sπ−e+νe in a sample of 4.5 fb−1 of e+e− annihilation data collected in the center-of-mass energy region between 4.600 GeV and 4.699 GeV by the BESIII detector at the BEPCII. No significant signals are observed, and the upper limits on the decay branching fractions are set to be B(Λ+c → Λπ+π−e+νe ) < 3.9 × 10−4 and B(Λ + c → pK0Sπ−e+νe ) < 3.3 × 10−4 at the 90% confidence level, respectively.
We search for an axion-like particle (ALP) a through the process ψ(3686)→π+π−J/ψ, J/ψ→γa, a→γγ in a data sample of (2.71±0.01)×109 ψ(3686) events collected by the BESIII detector. No significant ALP signal is observed over the expected background, and the upper limits on the branching fraction of the decay J/ψ→γa and the ALP-photon coupling constant gaγγ are set at 95% confidence level in the mass range of 0.165≤ma≤2.84GeV/c2. The limits on B(J/ψ→γa) range from 8.3×10−8 to 1.8×10−6 over the search region, and the constraints on the ALP-photon coupling are the most stringent to date for 0.165≤ma≤1.468GeV/c2.
We report a search for a dark photon using 14.9~fb−1 of e+e− annihilation data taken at center-of-mass energies from 4.13 to 4.60~GeV with the BESIII detector operated at the BEPCII storage ring. The dark photon is assumed to be produced in the radiative annihilation process of e+e− and to predominantly decay into light dark matter particles, which escape from the detector undetected. The mass range from 1.5 to 2.9~GeV is scanned for the dark photon candidate, and no significant signal is observed. The mass dependent upper limits at the 90% confidence level on the coupling strength parameter ϵ for a dark photon coupling with an ordinary photon vary between 1.6×10−3 and 5.7×10−3.
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
The transition from local to global patterns governs the differentiation of mouse blastocysts
(2020)
During mammalian blastocyst development, inner cell mass (ICM) cells differentiate into epiblast (Epi) or primitive endoderm (PrE). These two fates are characterized by the expression of the transcription factors NANOG and GATA6, respectively. Here, we investigate the spatio-temporal distribution of NANOG and GATA6 expressing cells in the ICM of the mouse blastocysts with quantitative three-dimensional single cell-based neighbourhood analyses. We define the cell neighbourhood by local features, which include the expression levels of both fate markers expressed in each cell and its neighbours, and the number of neighbouring cells. We further include the position of a cell relative to the centre of the ICM as a global positional feature. Our analyses reveal a local three-dimensional pattern that is already present in early blastocysts: 1) Cells expressing the highest NANOG levels are surrounded by approximately nine neighbours, while 2) cells expressing GATA6 cluster according to their GATA6 levels. This local pattern evolves into a global pattern in the ICM that starts to emerge in mid blastocysts. We show that FGF/MAPK signalling is involved in the three-dimensional distribution of the cells and, using a mutant background, we further show that the GATA6 neighbourhood is regulated by NANOG. Our quantitative study suggests that the three-dimensional cell neighbourhood plays a role in Epi and PrE precursor specification. Our results highlight the importance of analysing the three-dimensional cell neighbourhood while investigating cell fate decisions during early mouse embryonic development.
Three-dimensional multicellular aggregates such as spheroids provide reliable in vitro substitutes for tissues. Quantitative characterization of spheroids at the cellular level is fundamental. We present the first pipeline that provides three-dimensional, high-quality images of intact spheroids at cellular resolution and a comprehensive image analysis that completes traditional image segmentation by algorithms from other fields. The pipeline combines light sheet-based fluorescence microscopy of optically cleared spheroids with automated nuclei segmentation (F score: 0.88) and concepts from graph analysis and computational topology. Incorporating cell graphs and alpha shapes provided more than 30 features of individual nuclei, the cellular neighborhood and the spheroid morphology. The application of our pipeline to a set of breast carcinoma spheroids revealed two concentric layers of different cell density for more than 30,000 cells. The thickness of the outer cell layer depends on a spheroid’s size and varies between 50% and 75% of its radius. In differently-sized spheroids, we detected patches of different cell densities ranging from 5 × 105 to 1 × 106 cells/mm3. Since cell density affects cell behavior in tissues, structural heterogeneities need to be incorporated into existing models. Our image analysis pipeline provides a multiscale approach to obtain the relevant data for a system-level understanding of tissue architecture.
Background: Due to the large amount of data produced by advanced microscopy, automated image analysis is crucial in modern biology. Most applications require reliable cell nuclei segmentation. However, in many biological specimens cell nuclei are densely packed and appear to touch one another in the images. Therefore, a major difficulty of three-dimensional cell nuclei segmentation is the decomposition of cell nuclei that apparently touch each other. Current methods are highly adapted to a certain biological specimen or a specific microscope. They do not ensure similarly accurate segmentation performance, i.e. their robustness for different datasets is not guaranteed. Hence, these methods require elaborate adjustments to each dataset.
Results: We present an advanced three-dimensional cell nuclei segmentation algorithm that is accurate and robust. Our approach combines local adaptive pre-processing with decomposition based on Lines-of-Sight (LoS) to separate apparently touching cell nuclei into approximately convex parts. We demonstrate the superior performance of our algorithm using data from different specimens recorded with different microscopes. The three-dimensional images were recorded with confocal and light sheet-based fluorescence microscopes. The specimens are an early mouse embryo and two different cellular spheroids. We compared the segmentation accuracy of our algorithm with ground truth data for the test images and results from state-of-the-art methods. The analysis shows that our method is accurate throughout all test datasets (mean F-measure: 91%) whereas the other methods each failed for at least one dataset (F-measure≤69%). Furthermore, nuclei volume measurements are improved for LoS decomposition. The state-of-the-art methods required laborious adjustments of parameter values to achieve these results. Our LoS algorithm did not require parameter value adjustments. The accurate performance was achieved with one fixed set of parameter values.
Conclusion: We developed a novel and fully automated three-dimensional cell nuclei segmentation method incorporating LoS decomposition. LoS are easily accessible features that ensure correct splitting of apparently touching cell nuclei independent of their shape, size or intensity. Our method showed superior performance compared to state-of-the-art methods, performing accurately for a variety of test images. Hence, our LoS approach can be readily applied to quantitative evaluation in drug testing, developmental and cell biology.
Intensive land use is a driving force for biodiversity decline in many ecosystems. In semi-natural grasslands, land-use activities such as mowing, grazing and fertilization affect the diversity of plants and arthropods, but the combined effects of different drivers and the chain of effects are largely unknown. In this study we used structural equation modelling to analyse how the arthropod communities in managed grasslands respond to land use and whether these responses are mediated through changes in resource diversity or resource quantity (biomass). Plants were considered resources for herbivores which themselves were considered resources for predators. Plant and arthropod (herbivores and predators) communities were sampled on 141 meadows, pastures and mown pastures within three regions in Germany in 2008 and 2009. Increasing land-use intensity generally increased plant biomass and decreased plant diversity, mainly through increasing fertilization. Herbivore diversity decreased together with plant diversity but showed no response to changes in plant biomass. Hence, land-use effects on herbivore diversity were mediated through resource diversity rather than quantity. Land-use effects on predator diversity were mediated by both herbivore diversity (resource diversity) and herbivore quantity (herbivore biomass), but indirect effects through resource quantity were stronger. Our findings highlight the importance of assessing both direct and indirect effects of land-use intensity and mode on different trophic levels. In addition to the overall effects, there were subtle differences between the different regions, pointing to the importance of regional land-use specificities. Our study underlines the commonly observed strong effect of grassland land use on biodiversity. It also highlights that mechanistic approaches help us to understand how different land-use modes affect biodiversity.
Spheroids resemble features of tissues and serve as model systems to study cell–cell and cell–ECM interactions in non-adhesive three-dimensional environments. Although it is generally accepted that mature spheroids resemble tissue properties very well, no studies relate different phases in the spheroid formation processes that contribute to tissue integrity. Tissue integrity involves the cellular processes adhesion formation, adhesion reinforcement, rearrangement as well as proliferation. They maintain the structure and function of tissues and, upon dysregulation, contribute to malignancy. We investigated spheroid formation dynamics in cell lines of different metastatic potential. We dissected spheroid formation into phases of aggregation, compaction and growth to identify the respective contributions of E-cadherin, actin, microtubules and FAK. E-cadherin, actin and microtubules drive the first two phases. Microtubules and FAK are involved in the proliferation phase. FAK activity correlates with the metastatic potential of the cells. A robust computational model based on a very large number of experiments reveals the temporal resolution of cell adhesion. Our results provide novel hypotheses to unveil the general mechanisms that contribute to tissue integrity.
Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach
(2020)
During the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.
Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important intermediate at the branch point of these pathways and is continuously monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. In this study, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for selective binding of PA over phosphatidylserine (PS). The insertion of the AH into the membrane core renders Opi1 sensitive to the lipid acyl chain composition and provides a means to adjust membrane biogenesis. By rational design of the AH, we tune the membrane-binding properties of Opi1 and control its responsiveness in vivo. Using extensive molecular dynamics simulations, we identify two PA-selective three-finger grips that tightly bind the PA phosphate headgroup while interacting less intimately with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.
Apheresis therapies for NMOSD attacks : a retrospective study of 207 therapeutic interventions
(2018)
Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).
Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.
Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).
Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.
Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important lipid intermediate and signaling lipid at the branch point of these pathways and constantly monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. Here, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for the selective binding to membranes containing PA over phosphatidylserine (PS). The insertion of the AH into the hydrophobic core of the membrane renders Opi1 sensitive to the lipid acyl chain composition as an important factor contributing to the regulation of membrane biogenesis. Based on these findings, we rationally designed the membrane binding properties of Opi1 to control its responsiveness in the physiological context. Using extensive molecular dynamics (MD) simulations, we identified two PA-selective three-finger grips that tightly bind the phosphate headgroup, while interacting less intimately and more transiently with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.
Species’ functional traits set the blueprint for pair-wise interactions in ecological networks. Yet, it is unknown to what extent the functional diversity of plant and animal communities controls network assembly along environmental gradients in real-world ecosystems. Here we address this question with a unique dataset of mutualistic bird–fruit, bird–flower and insect–flower interaction networks and associated functional traits of 200 plant and 282 animal species sampled along broad climate and land-use gradients on Mt. Kilimanjaro. We show that plant functional diversity is mainly limited by precipitation, while animal functional diversity is primarily limited by temperature. Furthermore, shifts in plant and animal functional diversity along the elevational gradient control the niche breadth and partitioning of the respective other trophic level. These findings reveal that climatic constraints on the functional diversity of either plants or animals determine the relative importance of bottom-up and top-down control in plant–animal interaction networks.
A non-monotonic energy dependence of the K + / pi + ratio with a sharp maximum close to 30 A GeV is observed in central Pb+Pb collisions. Within a statistical model of the early stage, this is interpreted as a sign of the phase transition to a QGP, which causes a sharp change in the energy dependence of the strangeness to entropy ratio. This observation naturally motivates us to study the production of multistrange hyperons (Xi, Omega) as a function of the beam energy. Furthermore it was suggested that the kinematic freeze-out of Omega takes place directly at QGP hadronization. If this is indeed the case, the transverse momentum spectra of the Omega directly reflect the transverse expansion velocity of a hadronizing QGP. In this report we show preliminary NA49 results on Omega - and Omega + production in central Pb+Pb collisions at 40 and 158 A GeV and compare them to measurements of Xi - and Xi + production in central Pb+Pb collisions at 30, 40, 80 and 158 A GeV.
The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification
(2019)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Forest fragmentation and selective logging are two main drivers of global environmental change and modify biodiversity and environmental conditions in many tropical forests. The consequences of these changes for the functioning of tropical forest ecosystems have rarely been explored in a comprehensive approach. In a Kenyan rainforest, we studied six animal-mediated ecosystem processes and recorded species richness and community composition of all animal taxa involved in these processes. We used linear models and a formal meta-analysis to test whether forest fragmentation and selective logging affected ecosystem processes and biodiversity and used structural equation models to disentangle direct from biodiversity-related indirect effects of human disturbance on multiple ecosystem processes. Fragmentation increased decomposition and reduced antbird predation, while selective logging consistently increased pollination, seed dispersal and army-ant raiding. Fragmentation modified species richness or community composition of five taxa, whereas selective logging did not affect any component of biodiversity. Changes in the abundance of functionally important species were related to lower predation by antbirds and higher decomposition rates in small forest fragments. The positive effects of selective logging on bee pollination, bird seed dispersal and army-ant raiding were direct, i.e. not related to changes in biodiversity, and were probably due to behavioural changes of these highly mobile animal taxa. We conclude that animal-mediated ecosystem processes respond in distinct ways to different types of human disturbance in Kakamega Forest. Our findings suggest that forest fragmentation affects ecosystem processes indirectly by changes in biodiversity, whereas selective logging influences processes directly by modifying local environmental conditions and resource distributions. The positive to neutral effects of selective logging on ecosystem processes show that the functionality of tropical forests can be maintained in moderately disturbed forest fragments. Conservation concepts for tropical forests should thus include not only remaining pristine forests but also functionally viable forest remnants.
In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axiorecombination, the "BCA processes." Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling gae and axion-photon interaction strength ga using the CAST phase-I data (vacuum phase). For ma <~ 10 meV/c2 we find ga gae < 8.1 × 10−23 GeV−1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission.
Background: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study.
Patients and methods: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA).
Results: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS.
Conclusion: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.