We present the structural and functional characterization of a single-stranded DNA-binding protein (SSB-M5) identified from a hot spring metagenome in Vatnajökull National Park, Iceland. This small protein (136 aa; 15,695 Da) shares 100% amino acid sequence identity with two previously uncharacterized SSBs from hyperthermophilic Fervidobacterium species. Functional complementation assay demonstrated that SSB-M5 can substitute for Escherichia coli SSB in an ssb- mutant strain, confirming its biological activity. A recombinant C-terminally His-tagged SSB-M5 was overproduced, purified to homogeneity, and subjected to structural, biochemical, and biophysical analysis. The crystal structure revealed that SSB-M5 forms a dimer through a crystallographic twofold axis, with each monomer contributing to a large antiparallel β-sheet. The flat surfaces of the β-sheets from the two dimers are packed together via a second crystallographic twofold axis, forming a tetramer that serves as the functional unit of the SSB-M5. Electrophoretic mobility shift assays showed that SSB-M5, after heat treatment up to 100°C, forms stable DNA-protein complexes with the (dT)40 oligo. Quantitative analyses revealed that SSB-M5 binds (dT)70 oligonucleotide with very high affinity (KD = 72 ± 6 pM). Hill analysis indicated cooperative binding, yielding an EC50 of 141 pM and a Hill coefficient of 2. Moreover, inclusion of SSB-M5 in PCR reactions significantly enhanced amplification by eliminating non-specific products. Together, these findings identify SSB-M5 as a hyperthermostable, high-affinity single-stranded DNA-binding protein with potential applications in molecular biology and biotechnology.

During the autumn, winter and early spring of 2022/2023, Europe faced rapidly increasing energy prices and threats of power cuts. The situation was consequently labelled an “energy crisis”, and one sector that was severely affected was households. In response to the situation, European households made efforts to reduce and time-shift their energy use to mitigate the effects of the crisis. Considering that domestic energy practices are often difficult to change, particularly in the long term, we find this effect of the energy crisis on households important to understand more deeply. In this paper, we use social practice theory to investigate how Swedish households responded to the crisis and what changes they made in terms of re-configurations of their practices. The aim was to contribute knowledge on how households adapt to a changing energy system with volatile prices, limitations in electric power, and threats of energy crisis. We conducted two rounds of semi-structured interviews with 9 households in single-family houses in the middle and south of Sweden during and after the crisis, in total 18 interviews, to examine what re-configurations of practices emerged and which persisted over time. The results show that significant changes were apparent in primarily the practice domains of heating and hygiene. While some of these changes were temporary, other re-configurations of energy practices persisted beyond the months of crisis and high prices, indicating that meanings of frugality and sufficiency were strengthened. Our results demonstrate that households were reminded of certain electricity use that is otherwise typically backgrounded in homes and that the energy crisis stimulated re-configuration and re-examination of norms as well as reflection on electricity use in general. Finally, we discuss the effects of the energy crisis on household practices in comparison with other crises and disruptions, and point to the importance of communicating clearly with households about the societal effects of their efforts, in order to manage the legacy of this crisis for similar future crisis situations.

We have previously described a new series of selective and orally available galectin-1 inhibitors resulting in the thiazole-containing glycomimetic GB1490. Here, we show that the introduction of polar substituents to the thiazole ring results in galectin-1-specific compounds with low nM affinities. X-ray structural analysis of a new ligand-galectin-1 complex shows changes in the binding mode and ligand-protein hydrogen bond interactions compared to the GB1490-galectin-1 complex. These new high affinity ligands were further optimized with respect to affinity and ADME properties resulting in the galectin-1-selective GB1908 (K d galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC50 = 850 nM). Pharmacokinetic experiments in mice revealed that a dose of 30 mg/kg b.i.d. results in free levels of GB1908 in plasma over galectin-1 K d for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model.

Flexible resources aids in enhancing the resilience of a renewable dominated power system. Space heating systems equipped with heat pumps is one such flexible resource. With this background, the current study deals with the quantification of flexibility potential of space heating systems in houses equipped with various heat pump types. A heat pump model is represented using a vapour compression heat pump cycle. This model is integrated with a thermal model of a house to estimate electricity consumption, for maintaining the indoor temperature at a set value, as flexibility quantification depends on electricity consumption. In addition to this, flexibility potential is quantified by, analysing and incorporating the results on minimum acceptable indoor temperature from twelve interviews with households owning heat pumps, into the integrated model. The results from interviews reveal that, there is an uncertainty in minimum acceptable indoor temperature, as it is dependant on a number of factors such as frequency and duration of interruption, access to additional heating and motivation to be flexible. Hence, to quantify flexibility using thermal simulations, the indoor temperature is reduced from 20 degrees C to values between 18 degrees C and 15 degrees C, based on minimum acceptable temperatures stated in the interviews. The flexibility potential is quantified in terms of an instantaneous reduction in electric power and reduction in electric energy. By reducing the indoor temperature from 20 degrees C to the aforementioned values at an outdoor ambient temperature of-5 degrees C, in about a million single family houses in southern half of Sweden, an instantaneous reduction in electric power is estimated to be 1.6 GW, for the power system with 23 GW plannable power. Additionally, considering the recovery of the indoor temperature to 20 degrees C in 24 h, electric energy reduction is found to be between 4.06 GWh and 7.4 GWh, when the reference indoor temperature is reduced to values between 18 degrees C and 15 degrees C respectively, over 17.25 h. Furthermore, with time the amount of flexibility offered reduces, becomes negative during the recovery period and finally reaches zero, when the indoor temperature is restored. The results reveal that space heating systems in houses equipped with heat pumps have the potential to enhance the resilience of the power grid during severe grid disturbances.

AbstractDe novo drug design aims to generate molecules from scratch that possess specific chemical and pharmacological properties. We present a computational approach utilizing interactome-based deep learning for ligand- and structure-based generation of drug-like molecules. This method capitalizes on the unique strengths of both graph neural networks and chemical language models, offering an alternative to the need for application-specific reinforcement, transfer, or few-shot learning. It enables the “zero-shot" construction of compound libraries tailored to possess specific bioactivity, synthesizability, and structural novelty. In order to proactively evaluate the deep interactome learning framework for protein structure-based drug design, potential new ligands targeting the binding site of the human peroxisome proliferator-activated receptor (PPAR) subtype gamma are generated. The top-ranking designs are chemically synthesized and computationally, biophysically, and biochemically characterized. Potent PPAR partial agonists are identified, demonstrating favorable activity and the desired selectivity profiles for both nuclear receptors and off-target interactions. Crystal structure determination of the ligand-receptor complex confirms the anticipated binding mode. This successful outcome positively advocates interactome-based de novo design for application in bioorganic and medicinal chemistry, enabling the creation of innovative bioactive molecules.

Galectin-8 contains two different carbohydrate recognition domains (CRDs). Selective inhibitors for at least one CRD are desirable for galectin-8 biology studies and potentially for pharmacological purposes. Structure-guided design led to the discovery of potent and selective glycomimetic-heterocycle hybrid ligands, with a 4-(p-bromophenyl)phthalazinone derivative displaying a 34 mu M K-d for galectin-8N (N-terminal CRD), no binding to galectin-8C (C-terminal CRD), -1, -3, -4N, -7, -9C, or -9N, and >40-fold selectivity over galectin-4C. Selectivity was achieved with the halogenated 4-phenylphthalazinone moiety occupying a galectin-8N-specific sub-pocket. A 1.30 & Aring; resolution X-ray structure revealed the phthalazinone moiety stacking with Arg45 and the 4-bromophenyl moiety stacking both Arg59 and Tyr141 of galectin-8N. Physicochemical and in vitro ADME studies revealed a desirable LogD, which also translated to good passive permeability. The chemical, microsome, and plasma stability support these compounds as promising tool compounds and candidates for hit-to-lead optimization.

Abstract Background In affluent countries, essential infrastructures like power systems are often taken for granted and thus invisible to ordinary people. However, because of energy transitions and climate impacts, the power system in countries such as Sweden is changing. For example, variable renewable power sources and increasing demand call for a potential need to be able to deal with changing conditions including disruptions at an end-use level, which makes the energy system come to the foreground. As argued in the paper, deeper knowledge about people’s sensemaking of a changing energy system is needed to support households in taking new roles. In this study, 12 interviews were conducted with people from 7 households in detached houses in Sweden participating in a trial with remote-controlled heat pumps.The aim was to investigate how householders make sense of the changing power system and possible power deficit scenarios in the future. Social representations theory and the concept of household energy resilience were used as theoretical lenses.Results Householders direct their understanding of power deficiency and changes in power supply at four different levels: household level, supplier level, national system level, and finally as a shared responsibility between the three. These insights reveal opportunities where households anticipate taking more active roles in a changing enery system – however they also identify responsibilities that other energy actors need to communicate clearly that they are taking on, to support households and the energy transition overall.Conclusions Our results show that there is potential for more active and engaged electricity end-users, beyond for example flexibility programs. However, households’ active participation, including becoming more energy resilient, is conditioned by challenges of value, involvement, and reciprocity, which are important to address as households are opening the “black box” that is the power system. The results will be of interest to professionals involved in electricity supply-related matters including suppliers, policymakers, and researchers.

Background 4-1BB (CD137) is a co-stimulatory receptor highly expressed on tumor reactive effector T cells and NK cells, which upon stimulation prolongs persistence of tumor reactive effector T and NK cells within the tumor and induces long-lived memory T cells. 4-1BB agonistic antibodies have been shown to induce strong anti-tumor effects that synergize with immune checkpoint inhibitors. The first generation of 4-1BB agonists was, however, hampered by dose-limiting toxicities resulting in suboptimal dose levels or poor agonistic activity. Methods ATOR-1017 (evunzekibart), a second-generation Fc-gamma receptor conditional 4-1BB agonist in IgG4 format, was designed to overcome the limitations of the first generation of 4-1BB agonists, providing strong agonistic effect while minimizing systemic immune activation and risk of hepatoxicity. The epitope of ATOR-1017 was determined by X-ray crystallography, and the functional activity was assessed in vitro and in vivo as monotherapy or in combination with anti-PD1. Results ATOR-1017 binds to a unique epitope on 4-1BB enabling ATOR-1017 to activate T cells, including cells with an exhausted phenotype, and NK cells, in a cross-linking dependent, FcγR-conditional, manner. This translated into a tumor-directed and potent anti-tumor therapeutic effect in vivo, which was further enhanced with anti-PD-1 treatment. Conclusions These preclinical data demonstrate a strong safety profile of ATOR-1017, together with its potent therapeutic effect as monotherapy and in combination with anti-PD1, supporting further clinical development of ATOR-1017.

Abstract 4–1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4–1BB on tumor-specific cytotoxic T cells makes 4–1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4–1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4–1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4–1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4–1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4–1BB–mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.

De novo drug design aims to generate molecules from scratch that possess specific chemical and pharmacological properties. We present a computational approach utilizing interactome-based deep learning for ligand- and structure-based generation of drug-like molecules. This method capitalizes on the unique strengths of both graph neural networks and chemical language models, offering an alternative to the need for application-specific reinforcement, transfer, or few-shot learning. It allows for the construction of compound libraries tailored to possess specific bioactivity, synthesizability, and structural novelty. In order to proactively evaluate the deep interactome learning framework for structure-based drug design, potential new ligands targeting the binding site of the human peroxisome proliferator-activated receptor (PPAR) subtype gamma were generated. The top-ranking designs were chemically synthesized and biophysically and biochemically characterized. Potent PPAR partial agonists were identified, demonstrating favorable activity and the desired selectivity profiles for both nuclear receptors and off-target interactions. Crystal structure determination of the ligand-receptor complex confirmed the anticipated binding mode. This successful outcome positively advocates interactome-based de novo design for application in bioorganic and medicinal chemistry, enabling the creation of innovative bioactive molecules.

Climate change is increasing the risk for extreme weather events such as heatwaves, including in northern countries like Sweden, which until recent years has had limited experiences of coping with extreme heat. Based on predictions that Sweden will be more frequently exposed to heatwaves in the future, it is imperative to increase the societal resilience and adaptation measures. This paper presents a qualitative interview study involving 19 participants and their experiences of caring for vulnerable people during the heatwave in 2018. The participants represent four different organizations (working directly or indirectly with vulnerable people) in two municipalities in Sweden, including preschools, homes for the elderly, homecare services, and care homes for people with functional impairments, which were all impacted during the heatwave. This study contributes new empirical insights about the heatwave in 2018 and, in particular, similarities and differences in both experiences and adaptation measures across the four organizations. The findings show how both staff and vulnerable people suffered from the consequences of heat which increased vulnerability, how some organizations lacked enough (qualified) staff to secure routines, and that few evaluations and formal changes were done after the heatwave.

A new series of orally available α-d-galactopyranosides with high affinity and specificity toward galectin-1 have been discovered. High affinity and specificity were achieved by changing six-membered aryl-triazolyl substituents in a series of recently published galectin-3-selective α-d-thiogalactosides (e.g., GB1107 Kd galectin-1/3 3.7/0.037 μM) for five-membered heterocycles such as thiazoles. The in vitro pharmacokinetic properties were optimized, resulting in several galectin-1 inhibitors with favorable properties. One compound, GB1490 (Kd galectin-1/3 0.4/2.7 μM), was selected for further characterization toward a panel of galectins showing a selectivity of 6- to 320-fold dependent on galectin. The X-ray structure of GB1490 bound to galectin-1 reveals the compound bound in a single conformation in the carbohydrate binding site. GB1490 was shown to reverse galectin-1-induced apoptosis of Jurkat cells at low μM concentrations. No cell cytotoxicity was observed for GB1490 up to 90 μM in the A549 cells. In pharmacokinetic studies in mice, GB1490 showed high oral bioavailability (F% > 99%).

The 30+ unique ligands of the TGFβ family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specificity can be accomplished by using the extracellular domains of both the type I and type II receptor to mimic the naturally occurring signaling complex. Here, we report the structure of one "type II-type I-Fc" fusion, ActRIIB-Alk4-Fc, in complex with two TGFβ family ligands, ActA, and GDF11, providing a snapshot of this therapeutic platform. The study reveals that extensive contacts are formed by both receptors, replicating the ternary signaling complex, despite the inherent low affinity of Alk4. Our study shows that low-affinity type I interactions support altered ligand specificity and can be visualized at the molecular level using this platform.

Residential solar panels are increasingly popular, yet women are largely invisible as customers and users. This creates barriers for reaching gender equality and climate goals where increased renewable energy is key. We present results from a norm-critical study drawing on 10 interviews with solar industry representatives and focus groups with 28 women, either owning solar panels or in the process of buying. The study aims to critically analyze current gender norms related to technology, market, and use, as well as to identify difficulties for women's solar panel engagement. The study shows how women at different touchpoints in the process of buying and having solar panels both navigate and negotiate an ongoing gendering of this technology, despite the industry attempts to present solar panels as gender neutral. While the study focuses on residential solar panels, the contribution is relevant for wider HCI, e.g. work related to smart home technologies.

This article presents findings from a qualitative in-depth analysis of a four-year Swedish national policy initiative where six public agencies were commissioned to produce a strategic plan for a transition towards a fossil-free transport sector. The aim of the article is to provide empirically grounded insights on principles and practices of importance for building transformative capacity in strategic, long-term transport planning. In the analysis, the concepts stewarding, unlocking, transforming and orchestrating are applied to explore and discuss transformative features of the policy initiative. Altogether, several elements of transformative capacity were developed through the process. Of specific importance was the establishment of an open and explorative approach to carrying out the commission, and ways in which the organizations involved started to challenge dominant perspectives and analytical practices in conventional transport planning. Shared principles and practices for analysis and assessment were developed, which allowed for a broadened consideration of climate mitigation measures. However, due to a lack of coordination with formalized planning settings and a lack of political decisions to sustain the commission, there are yet no signs of the work influencing conventional transport planning. Even so, gained experience and insights from this case can inform future change-oriented initiatives.

The first structure of a novel archaeal-like Holliday junction-resolving enzyme originating from a thermophilic phage was determined and its function in cleaving X-shaped dsDNA was demonstrated. Furthermore, a novel signature motif for Holliday junction-resolving enzymes originating from thermophilic bacteriophages is proposed.

A transition to renewable energy increases the risks of disruptions when electricity supply does not meet demand. HCI has explored how digital technologies can mitigate such problems in households through support for reducing or shifting electricity use. However, faster transitions may be possible if some disturbances can be acceptable and households are supported in adapting to them. In this paper, we present a study of 21 Swedish households and their experiences of and ideas on how to manage disruptions in electricity supply. We call this perspective household energy resilience and identify three strategies for resilience: (1) response diversity, i.e., diversity in ways of carrying out normally electricity-dependent practices, (2) creating opportunities to develop resilience, and (3) building community energy resilience. Furthermore, we suggest how HCI can support these strategies, both by providing tools to increase resilience and by carefully designing technology and services to be more resilient in themselves.

Residential solar panels are increasingly popular, yet women are largely invisible as customers and users. This creates barriers for reaching gender equality and climate goals where increased renewable energy is key. We present results from a norm-critical study drawing on 10 interviews with solar industry representatives and focus groups with 28 women, either owning solar panels or in the process of buying. The study aims to critically analyze current gender norms related to technology, market, and use, as well as to identify difficulties for women's solar panel engagement. The study shows how women at different touchpoints in the process of buying and having solar panels both navigate and negotiate an ongoing gendering of this technology, despite the industry attempts to present solar panels as gender neutral. While the study focuses on residential solar panels, the contribution is relevant for wider HCI, e.g. work related to smart home technologies.