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Beyond CEN.PK : parallel engineering of selected S. cerevisiae strains reveals that superior chassis strains require different engineering approaches for limonene production
No full textGenetically engineered microbes are increasingly utilized to produce a broad range of high-value compounds. However, most studies start with only a very narrow group of genetically tractable type strains that have not been selected for maximum titers or industrial robustness. In this study, we used high-throughput screening and parallel metabolic engineering to identify and optimize Saccharomyces cerevisiae chassis strains for the production of limonene, a monoterpene with applications in flavors, fragrances, and biofuels. We screened 921 genetically and phenotypically distinct S. cerevisiae strains for limonene tolerance and lipid content to identify optimal chassis strains for precision fermentation of limonene. In parallel, we also evaluated 16 different plant limonene synthases. Our results revealed that two of the selected strains showed approximately a 2-fold increase in titers compared to CEN.PK2-1C, the type strain that is often used as a chassis for limonene production, with the same genetic modifications in the mevalonate pathway. Intriguingly, the most effective engineering strategy proved strain-specific. Metabolic profiling revealed that this difference is likely explained by differences in native mevalonate production. Ultimately, by using strain-specific engineering strategies, we achieved 844 mg/L in a new strain, 40% higher than the titer (605 mg/L) achieved by CEN.PK2-1C. Our findings demonstrate the potential of leveraging genetic diversity in S. cerevisiae for monoterpene bioproduction and highlight the necessity for tailoring metabolic engineering strategies to specific strains.Genetically engineered microbes are increasingly utilized to produce a broad range of high-value compounds. However, most studies start with only a very narrow group of genetically tractable type strains that have not been selected for maximum titers or industrial robustness. In this study, we used high-throughput screening and parallel metabolic engineering to identify and optimize Saccharomyces cerevisiae chassis strains for the production of limonene, a monoterpene with applications in flavors, fragrances, and biofuels. We screened 921 genetically and phenotypically distinct S. cerevisiae strains for limonene tolerance and lipid content to identify optimal chassis strains for precision fermentation of limonene. In parallel, we also evaluated 16 different plant limonene synthases. Our results revealed that two of the selected strains showed approximately a 2-fold increase in titers compared to CEN.PK2-1C, the type strain that is often used as a chassis for limonene production, with the same genetic modifications in the mevalonate pathway. Intriguingly, the most effective engineering strategy proved strain-specific. Metabolic profiling revealed that this difference is likely explained by differences in native mevalonate production. Ultimately, by using strain-specific engineering strategies, we achieved 844 mg/L in a new strain, 40% higher than the titer (605 mg/L) achieved by CEN.PK2-1C. Our findings demonstrate the potential of leveraging genetic diversity in S. cerevisiae for monoterpene bioproduction and highlight the necessity for tailoring metabolic engineering strategies to specific strains.A
Pan-influenza B control with single-domain antibodies directed against hemagglutinin and neuraminidase
No full textInfluenza B-virussen zijn verantwoordelijk voor seizoensgebonden griepepidemieën. Het gelijktijdig circuleren van verschillende lijnen van influenza B-virussen, namelijk B/Victoria- en B/Yamagata-virussen, in combinatie met voortdurende antigene drift, bemoeilijkt het produceren van vaccins, en vereist hun regelmatige aanpassing. Antivirale middelen zijn over het algemeen minder effectief tegen influenza B-virussen dan tegen influenza A-virussen, en resistente stammen zijn reeds geïdentificeerd.Nanobodies zijn compact, potent, specifiek, en worden afgeleid van de antilichamen van kameelachtigen. We immuniseerden twee verschillende llama’s met een reeks belangrijke influenza B antigenen: hemagglutinine (HA) en neuraminidase (NA). Uit de bijbehorende immuunbibliotheek isoleerden we het HA-specifieke nanobody 69, dat influenza B virus infectie kan voorkomen door de membraanfusie te blokkeren. Het NA-specifieke nanobody 525 remt enzymactiviteit en voorkomt het vrijkomen van nieuwe virussen.Door beide nanobodies te combineren als bouwstenen, bekwamen we bispecifieke nanobodies, bv hVHH-69-525, die de virus neutralisatie kracht en breedt aanzienlijk verbeterden. De bispecifieke constructies kunnen gelijktijdig aan HA en NA binden, en door een fusie met humaan IgG1 Fc-domein kan de circulatie in vivo aanzienlijk verlengd worden. Dergelijke constructen, bv 69-525-Fc, beschermden muizen tegen een anders lethale IBV-infectie.Public defense: 2025-04-29Influenza B-virussen zijn verantwoordelijk voor seizoensgebonden griepepidemieën. Het gelijktijdig circuleren van verschillende lijnen van influenza B-virussen, namelijk B/Victoria- en B/Yamagata-virussen, in combinatie met voortdurende antigene drift, bemoeilijkt het produceren van vaccins, en vereist hun regelmatige aanpassing. Antivirale middelen zijn over het algemeen minder effectief tegen influenza B-virussen dan tegen influenza A-virussen, en resistente stammen zijn reeds geïdentificeerd.Nanobodies zijn compact, potent, specifiek, en worden afgeleid van de antilichamen van kameelachtigen. We immuniseerden twee verschillende llama’s met een reeks belangrijke influenza B antigenen: hemagglutinine (HA) en neuraminidase (NA). Uit de bijbehorende immuunbibliotheek isoleerden we het HA-specifieke nanobody 69, dat influenza B virus infectie kan voorkomen door de membraanfusie te blokkeren. Het NA-specifieke nanobody 525 remt enzymactiviteit en voorkomt het vrijkomen van nieuwe virussen.Door beide nanobodies te combineren als bouwstenen, bekwamen we bispecifieke nanobodies, bv hVHH-69-525, die de virus neutralisatie kracht en breedt aanzienlijk verbeterden. De bispecifieke constructies kunnen gelijktijdig aan HA en NA binden, en door een fusie met humaan IgG1 Fc-domein kan de circulatie in vivo aanzienlijk verlengd worden. Dergelijke constructen, bv 69-525-Fc, beschermden muizen tegen een anders lethale IBV-infectie.D
Transparent to dark-brown-black electrochromic and energy storage films based on Ni-Bi hydroxide
No full textAs Ni-based electrochromic (EC) materials have a wider band gap, low electron conductivity, and limited reactive sites, it is challenging for Ni-based EC materials to obtain high optical modulation with a realistic colored state and high coloration efficiency. This study presents Ni-Bi hydroxide (Ni-Bi-40, Ni-Bi-60, and Ni-Bi-80) for dual-functional EC and energy storage films, aiming to address challenges in Ni-based EC materials. By introducing Bi3+, which have a larger ionic radius than Ni2+, the films experience lattice strain, inducing crystalline distortions that expand interlayer spacing and enhance ion mobility. This leads to significant improvements in EC performance, with optical modulation values of 77 %, 80 %, and 60 % and transmissive colored states of 20 %, 2 %, and 0 % for Ni-Bi-40, Ni-Bi-60, and Ni-Bi-80 films, respectively. These films demonstrate high cyclic stability up to 7000 seconds and coloration efficiency of 49, 52, and 41 cm2/C. In terms of energy storage, the films achieve specific capacitance of 32.1, 58.3, and 65.4 F/cm2 at 5 mV/s for Ni-Bi-40, Ni-Bi-60, and Ni-Bi 80 films, with GCD tests yielding 83.0, 153.0, and 365.0 mF/cm2 at 8 mA/cm2, respectively. These findings highlight the potential of Ni-Bi films for advanced multifunctional applications in energy-efficient technologies.As Ni-based electrochromic (EC) materials have a wider band gap, low electron conductivity, and limited reactive sites, it is challenging for Ni-based EC materials to obtain high optical modulation with a realistic colored state and high coloration efficiency. This study presents Ni-Bi hydroxide (Ni-Bi-40, Ni-Bi-60, and Ni-Bi-80) for dual-functional EC and energy storage films, aiming to address challenges in Ni-based EC materials. By introducing Bi3+, which have a larger ionic radius than Ni2+, the films experience lattice strain, inducing crystalline distortions that expand interlayer spacing and enhance ion mobility. This leads to significant improvements in EC performance, with optical modulation values of 77 %, 80 %, and 60 % and transmissive colored states of 20 %, 2 %, and 0 % for Ni-Bi-40, Ni-Bi-60, and Ni-Bi-80 films, respectively. These films demonstrate high cyclic stability up to 7000 seconds and coloration efficiency of 49, 52, and 41 cm2/C. In terms of energy storage, the films achieve specific capacitance of 32.1, 58.3, and 65.4 F/cm2 at 5 mV/s for Ni-Bi-40, Ni-Bi-60, and Ni-Bi 80 films, with GCD tests yielding 83.0, 153.0, and 365.0 mF/cm2 at 8 mA/cm2, respectively. These findings highlight the potential of Ni-Bi films for advanced multifunctional applications in energy-efficient technologies.A
A macrozoobenthic data set of the Black Sea northwestern shelf
No full textBenthic ecological data are crucial to study and manage ecosystems. On the one hand, abiotic and species data provide complementary information to identify habitats. On the other hand, trait data, describing taxon characteristics, are required to predict anthropogenic impacts on marine ecosystems. Indeed, species traits are now widely used to understand natural selection in communities or to highlight ecosystem functions. While trait data are in growing demand, compiling them is challenging, time-consuming and there are no properly established procedures for major marine ecosystems. Here, we share a data set comprising macrozoobenthic occurrences for 215 taxa over the Black Sea northwestern shelf, between 1995 and 2017, and 27 traits documented for 127 taxa that related to life cycle and ecosystem function. In addition, we provide an abiotic data set of physical and chemical variables generated by a model or compiled from in-situ data. This data set aims to fill the functional knowledge gap in the Black Sea and offers research opportunities to future studies covering ecosystem functions, biodiversity conservation, and management.Benthic ecological data are crucial to study and manage ecosystems. On the one hand, abiotic and species data provide complementary information to identify habitats. On the other hand, trait data, describing taxon characteristics, are required to predict anthropogenic impacts on marine ecosystems. Indeed, species traits are now widely used to understand natural selection in communities or to highlight ecosystem functions. While trait data are in growing demand, compiling them is challenging, time-consuming and there are no properly established procedures for major marine ecosystems. Here, we share a data set comprising macrozoobenthic occurrences for 215 taxa over the Black Sea northwestern shelf, between 1995 and 2017, and 27 traits documented for 127 taxa that related to life cycle and ecosystem function. In addition, we provide an abiotic data set of physical and chemical variables generated by a model or compiled from in-situ data. This data set aims to fill the functional knowledge gap in the Black Sea and offers research opportunities to future studies covering ecosystem functions, biodiversity conservation, and management.A
Elusive interplay of 3D structural similarity and twinning in mechanical flexibility of luminescent organic crystals
No full textThe properties of molecular crystalline solids are critically dependent on the spatial arrangement of molecules and underlying noncovalent interactions. Here, two new isoelectronic cocrystals of a substituted carbazole-based emitter are presented, with bipyridyl ethylene and azene molecules, namely, cocrystal 1 and cocrystal 2, respectively. Though both isoelectronic cocrystals are also three-dimensional (3D) isostructural at the supramolecular level, they show similar photoluminescence properties as anticipated, but irreconcilable macroscopic mechanical properties. Upon applying external stress on their respective major crystal faces, cocrystal 1 is elastically flexible, while the 3D isostructural cocrystal 2 exhibits brittle fracture. Remarkably, elastic flexibility in cocrystal 2 can be induced through twinning-mediated crystal face modification, without any change in crystal structure.The properties of molecular crystalline solids are critically dependent on the spatial arrangement of molecules and underlying noncovalent interactions. Here, two new isoelectronic cocrystals of a substituted carbazole-based emitter are presented, with bipyridyl ethylene and azene molecules, namely, cocrystal 1 and cocrystal 2, respectively. Though both isoelectronic cocrystals are also three-dimensional (3D) isostructural at the supramolecular level, they show similar photoluminescence properties as anticipated, but irreconcilable macroscopic mechanical properties. Upon applying external stress on their respective major crystal faces, cocrystal 1 is elastically flexible, while the 3D isostructural cocrystal 2 exhibits brittle fracture. Remarkably, elastic flexibility in cocrystal 2 can be induced through twinning-mediated crystal face modification, without any change in crystal structure.A
Can higher delivery costs promote greener practices? Consumer behaviour insights from Barcelona
No full textIntroducing costs for receiving online purchases is increasingly viewed by public administrations as a strategy to mitigate the impact of business-to-consumer (B2C) distribution in urban environments. A prominent example of this approach was the Fiscal Ordinance introduced by the Barcelona City Council in 2023. Although it was subsequently annulled by the judicial system, the municipality of Barcelona, along with other municipalities, continues to explore the development of a fee aimed at encouraging consumers to collect parcels from designated pick-up points, such as local businesses or lockers. However, before implementing such regulations, it is crucial to thoroughly analyse consumer behaviour within the city, with a focus on the factors influencing changes in delivery preferences. Since consumer choices are shaped not only by individual characteristics but also by local transport infrastructure and cultural context, this paper addresses that need by presenting the results of a 2024 survey conducted with a random sample of 638 Barcelona residents. The analysis includes a review of sociodemographic characteristics, followed by a cluster analysis, chi-square tests, and multinomial logistic regression. The study identifies four distinct consumer segments: occasional male shoppers, frequent male shoppers, regular female shoppers, and occasional female shoppers. The findings suggest that while increasing home delivery costs may encourage some behavioural changes, it is unlikely to significantly influence the most frequent online shoppers in Barcelona. As such, alternative strategies should be considered to promote more sustainable last-mile logistics in the city.Introducing costs for receiving online purchases is increasingly viewed by public administrations as a strategy to mitigate the impact of business-to-consumer (B2C) distribution in urban environments. A prominent example of this approach was the Fiscal Ordinance introduced by the Barcelona City Council in 2023. Although it was subsequently annulled by the judicial system, the municipality of Barcelona, along with other municipalities, continues to explore the development of a fee aimed at encouraging consumers to collect parcels from designated pick-up points, such as local businesses or lockers. However, before implementing such regulations, it is crucial to thoroughly analyse consumer behaviour within the city, with a focus on the factors influencing changes in delivery preferences. Since consumer choices are shaped not only by individual characteristics but also by local transport infrastructure and cultural context, this paper addresses that need by presenting the results of a 2024 survey conducted with a random sample of 638 Barcelona residents. The analysis includes a review of sociodemographic characteristics, followed by a cluster analysis, chi-square tests, and multinomial logistic regression. The study identifies four distinct consumer segments: occasional male shoppers, frequent male shoppers, regular female shoppers, and occasional female shoppers. The findings suggest that while increasing home delivery costs may encourage some behavioural changes, it is unlikely to significantly influence the most frequent online shoppers in Barcelona. As such, alternative strategies should be considered to promote more sustainable last-mile logistics in the city.A
SIMULATION AND APPLICATION OF MODEL-BASED AND MODEL-FREE TRACK CONTROLLERS FOR SHIP MANOEUVRING IN SHALLOW AND CONFINED WATER
No full textLong-term safety and efficacy of bimekizumab in axial spondyloarthritis : 2-year results from two phase 3 studies
No full textObjectives Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, previously demonstrated efficacy and was well tolerated to 1 year in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA). Here, we report bimekizumab safety and efficacy to 2 years. Methods Patients completing week 52 in the phase 3 studies BE MOBILE 1 (nr-axSpA; NCT03928704) and 2 (r-axSpA; NCT03928743) were eligible for an ongoing open-label extension (OLE; NCT04436640). All OLE patients received subcutaneous bimekizumab 160 mg every 4 weeks. Safety outcomes for patients who received >= 1 bimekizumab dose, and efficacy outcomes for all randomized patients, are reported to week 104. Results In the OLE (weeks 52 - 104), 70.8% (367/518) of patients reported >= 1 treatment-emergent adverse event (TEAE). Most frequent TEAEs [exposure-adjusted incidence rate per 100 patient-years (EAIR/100PY)] were SARS-CoV-2 (COVID-19) infection (25.2), nasopharyngitis (11.0) and oral candidiasis (5.4). Fungal infection EAIR/100PY was 11.8 (majority Candida infections: 6.8; most mild/moderate, none serious/systemic). Inflammatory bowel disease and uveitis rates were low; no major adverse cardiovascular events or deaths occurred. TEAE incidence rate was generally similar across weeks 0 - 52 and 52 - 104. At week 104, >50% of randomized patients (N = 586) achieved Assessment of SpondyloArthritis international Society 40% response (ASAS40); similar to 60% achieved Axial Spondyloarthritis Disease Activity Score (ASDAS) low disease activity (30% achieved ASDAS inactive disease (57% of patients achieving MRI remission. Results In the OLE (weeks 52 - 104), 70.8% (367/518) of patients reported >= 1 treatment-emergent adverse event (TEAE). Most frequent TEAEs [exposure-adjusted incidence rate per 100 patient-years (EAIR/100PY)] were SARS-CoV-2 (COVID-19) infection (25.2), nasopharyngitis (11.0) and oral candidiasis (5.4). Fungal infection EAIR/100PY was 11.8 (majority Candida infections: 6.8; most mild/moderate, none serious/systemic). Inflammatory bowel disease and uveitis rates were low; no major adverse cardiovascular events or deaths occurred. TEAE incidence rate was generally similar across weeks 0 - 52 and 52 - 104. At week 104, >50% of randomized patients (N = 586) achieved Assessment of SpondyloArthritis international Society 40% response (ASAS40); similar to 60% achieved Axial Spondyloarthritis Disease Activity Score (ASDAS) low disease activity (30% achieved ASDAS inactive disease (57% of patients achieving MRI remission. Conclusions The safety profile of bimekizumab remained consistent with prior reports, with no new safety signals identified. 1-year efficacy was sustained to 2 years across patients with nr-axSpA and r-axSpA.Objectives Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, previously demonstrated efficacy and was well tolerated to 1 year in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA). Here, we report bimekizumab safety and efficacy to 2 years. Methods Patients completing week 52 in the phase 3 studies BE MOBILE 1 (nr-axSpA; NCT03928704) and 2 (r-axSpA; NCT03928743) were eligible for an ongoing open-label extension (OLE; NCT04436640). All OLE patients received subcutaneous bimekizumab 160 mg every 4 weeks. Safety outcomes for patients who received >= 1 bimekizumab dose, and efficacy outcomes for all randomized patients, are reported to week 104. Results In the OLE (weeks 52 - 104), 70.8% (367/518) of patients reported >= 1 treatment-emergent adverse event (TEAE). Most frequent TEAEs [exposure-adjusted incidence rate per 100 patient-years (EAIR/100PY)] were SARS-CoV-2 (COVID-19) infection (25.2), nasopharyngitis (11.0) and oral candidiasis (5.4). Fungal infection EAIR/100PY was 11.8 (majority Candida infections: 6.8; most mild/moderate, none serious/systemic). Inflammatory bowel disease and uveitis rates were low; no major adverse cardiovascular events or deaths occurred. TEAE incidence rate was generally similar across weeks 0 - 52 and 52 - 104. At week 104, >50% of randomized patients (N = 586) achieved Assessment of SpondyloArthritis international Society 40% response (ASAS40); similar to 60% achieved Axial Spondyloarthritis Disease Activity Score (ASDAS) low disease activity (30% achieved ASDAS inactive disease (57% of patients achieving MRI remission. Results In the OLE (weeks 52 - 104), 70.8% (367/518) of patients reported >= 1 treatment-emergent adverse event (TEAE). Most frequent TEAEs [exposure-adjusted incidence rate per 100 patient-years (EAIR/100PY)] were SARS-CoV-2 (COVID-19) infection (25.2), nasopharyngitis (11.0) and oral candidiasis (5.4). Fungal infection EAIR/100PY was 11.8 (majority Candida infections: 6.8; most mild/moderate, none serious/systemic). Inflammatory bowel disease and uveitis rates were low; no major adverse cardiovascular events or deaths occurred. TEAE incidence rate was generally similar across weeks 0 - 52 and 52 - 104. At week 104, >50% of randomized patients (N = 586) achieved Assessment of SpondyloArthritis international Society 40% response (ASAS40); similar to 60% achieved Axial Spondyloarthritis Disease Activity Score (ASDAS) low disease activity (30% achieved ASDAS inactive disease (57% of patients achieving MRI remission. Conclusions The safety profile of bimekizumab remained consistent with prior reports, with no new safety signals identified. 1-year efficacy was sustained to 2 years across patients with nr-axSpA and r-axSpA.A
Shattered Peace, Silenced Justice: Absence of accountability fuels Ethiopia’s cycle of violence
No full textEthiopia has remained a locus of protracted violence, state repression, insurgent conflict, and rampant abductions ever since it was engulfed in turmoil, especially after 2018. A striking feature of the ongoing crisis in the country is the systemic lack of accountability for atrocities committed by both state and non-state actors.Ethiopia has remained a locus of protracted violence, state repression, insurgent conflict, and rampant abductions ever since it was engulfed in turmoil, especially after 2018. A striking feature of the ongoing crisis in the country is the systemic lack of accountability for atrocities committed by both state and non-state actors.