3D-printed machines that manipulate microscopic objects using capillary forces.

Objects that deform a liquid interface are subject to capillary forces, which can be harnessed to assemble the objects1-4. Once assembled, such structures are generally static. Here we dynamically modulate these forces to move objects in programmable two-dimensional patterns. We 3D-print devices containing channels that trap floating objects using repulsive capillary forces5,6, then move these devices vertically in a water bath. Because the channel cross-sections vary with height, the trapped objects can be steered in two dimensions. The device and interface therefore constitute a simple machine that converts vertical to lateral motion. We design machines that translate, rotate and separate multiple floating objects and that do work on submerged objects through cyclic vertical motion. We combine these elementary machines to make centimetre-scale compound machines that braid micrometre-scale filaments into prescribed topologies, including non-repeating braids. Capillary machines are distinct from mechanical, optical or fluidic micromanipulators in that a meniscus links the object to the machine. Therefore, the channel shapes need only be controlled on the scale of the capillary length (a few millimetres), even when the objects are microscopic. Consequently, such machines can be built quickly and inexpensively. This approach could be used to manipulate micrometre-scale particles or to braid microwires for high-frequency electronics.

Condensed Matter Systems Exposed to Radiation: Multiscale Theory, Simulations, and Experiment.

This roadmap reviews the new, highly interdisciplinary research field studying the behavior of condensed matter systems exposed to radiation. The Review highlights several recent advances in the field and provides a roadmap for the development of the field over the next decade. Condensed matter systems exposed to radiation can be inorganic, organic, or biological, finite or infinite, composed of different molecular species or materials, exist in different phases, and operate under different thermodynamic conditions. Many of the key phenomena related to the behavior of irradiated systems are very similar and can be understood based on the same fundamental theoretical principles and computational approaches. The multiscale nature of such phenomena requires the quantitative description of the radiation-induced effects occurring at different spatial and temporal scales, ranging from the atomic to the macroscopic, and the interlinks between such descriptions. The multiscale nature of the effects and the similarity of their manifestation in systems of different origins necessarily bring together different disciplines, such as physics, chemistry, biology, materials science, nanoscience, and biomedical research, demonstrating the numerous interlinks and commonalities between them. This research field is highly relevant to many novel and emerging technologies and medical applications.

Learning to learn by using nonequilibrium training protocols for adaptable materials.

Evolution in time-varying environments naturally leads to adaptable biological systems that can easily switch functionalities. Advances in the synthesis of environmentally responsive materials therefore open up the possibility of creating a wide range of synthetic materials which can also be trained for adaptability. We consider high-dimensional inverse problems for materials where any particular functionality can be realized by numerous equivalent choices of design parameters. By periodically switching targets in a given design algorithm, we can teach a material to perform incompatible functionalities with minimal changes in design parameters. We exhibit this learning strategy for adaptability in two simulated settings: elastic networks that are designed to switch deformation modes with minimal bond changes and heteropolymers whose folding pathway selections are controlled by a minimal set of monomer affinities. The resulting designs can reveal physical principles, such as nucleation-controlled folding, that enable such adaptability.

Publisher Correction: Heterochromatin drives compartmentalization of inverted and conventional nuclei.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Heterochromatin drives compartmentalization of inverted and conventional nuclei.

The nucleus of mammalian cells displays a distinct spatial segregation of active euchromatic and inactive heterochromatic regions of the genome1,2. In conventional nuclei, microscopy shows that euchromatin is localized in the nuclear interior and heterochromatin at the nuclear periphery1,2. Genome-wide chromosome conformation capture (Hi-C) analyses show this segregation as a plaid pattern of contact enrichment within euchromatin and heterochromatin compartments3, and depletion between them. Many mechanisms for the formation of compartments have been proposed, such as attraction of heterochromatin to the nuclear lamina2,4, preferential attraction of similar chromatin to each other1,4-12, higher levels of chromatin mobility in active chromatin13-15 and transcription-related clustering of euchromatin16,17. However, these hypotheses have remained inconclusive, owing to the difficulty of disentangling intra-chromatin and chromatin-lamina interactions in conventional nuclei18. The marked reorganization of interphase chromosomes in the inverted nuclei of rods in nocturnal mammals19,20 provides an opportunity to elucidate the mechanisms that underlie spatial compartmentalization. Here we combine Hi-C analysis of inverted rod nuclei with microscopy and polymer simulations. We find that attractions between heterochromatic regions are crucial for establishing both compartmentalization and the concentric shells of pericentromeric heterochromatin, facultative heterochromatin and euchromatin in the inverted nucleus. When interactions between heterochromatin and the lamina are added, the same model recreates the conventional nuclear organization. In addition, our models allow us to rule out mechanisms of compartmentalization that involve strong euchromatin interactions. Together, our experiments and modelling suggest that attractions between heterochromatic regions are essential for the phase separation of the active and inactive genome in inverted and conventional nuclei, whereas interactions of the chromatin with the lamina are necessary to build the conventional architecture from these segregated phases.

Cell-type specific anti-cancerous effects of nitro-oleic acid and its combination with gamma irradiation.

Nitro-fatty acids (NFAs) are endogenous lipid mediators capable of post-translational modifications of selected regulatory proteins. Here, we investigated the anti-cancerous effects of nitro-oleic acid (NO2OA) and its combination with gamma irradiation on different cancer cell lines. The effects of NO2OA on cell death, cell cycle distribution, or expression of p21 and cyclin D1 proteins were analyzed in cancer (A-549, HT-29 and FaDu) or normal cell lines (HGF, HFF-1). Dose enhancement ratio at 50 % survival fraction (DERIC50) was calculated for samples pre-treated with NO2OA followed by gamma irradiation. NO2OA suppressed viability and induced apoptotic cell death. These effects were cell line specific but not in general selective for cancer cells. HT-29 cell line exerted higher sensitivity toward NO2OA treatment among cancer cell lines tested: induction of cell cycle arrest in the G2/M phase was associated with an increase in p21 and a decrease in cyclin D1 expression. Pre-treatment of HT-29 cells with NO2OA prior irradiation showed a significantly increased DERIC50, demonstrating radiosensitizing effects. In conclusion, NO2OA exhibited potential for combined chemoradiotherapy. Our results encourage the development of new NFAs with improved features for cancer chemoradiation.

Importance of temporary and permanent snow for new second homes.

This study investigates empirically how natural snow depth and permanent snow affect the number of new second homes in Norway. One out of four Norwegian municipalities is partly covered by glaciers and permanent snow. In the winter seasons of 1983-2020, there is a decline in snow depth from 50 to 35 cm on average (based on 41 popular second-home areas in the mountains). Results of the fixed effects Poisson estimator with spatial elements show that there is a significant and positive relationship between natural snow depth in the municipality and the number of second homes started. There is also a significant and negative relationship between the number of new second homes in the municipality and a scarcity of snow in the surrounding municipalities. However, the magnitude of both effects is small. Estimates also show a strong positive relationship between the proportion of surface covered by permanent snow or glaciers in the municipality and new second homes. This implies that a decline in permanent snow and glaciers may make these areas less attractive for the location of second homes.

A threat to the natural World Heritage site rarely happens alone.

This study contributes an empirical investigation of the likelihood that different external threats to a UNESCO Natural World Heritage Site occur in combination with each other when site characteristics and location are controlled for. For the purpose of the analysis, the World Heritage database and the UNESCO State of Conservation Reports are used and the nine most frequently appearing external threats are identified. These databases include 6852 site-year observations and 3316 threats over the period 1979-2023. The most commonly identified external threats are illegal activities, with eleven percent of all observations and mining with six percent. Transport infrastructure, tourism and visitor pressure are also common threats. Estimation results based on the multivariate Probit (equation system) model demonstrate that there are strong positive correlations between many pairs of the nine external threats. Most apparent are the links between illegal activities and loss of identity, social cohesion, changes in local population and community, water infrastructure (dams) and farming, as well as illegal activities and land conversion. There are also clear links between tourism and infrastructure. This emphasises that the various threats seldom appear in isolation from each other. Results also highlight that the threats have different drivers. Among the determinants, site characteristics and location are the most important ones. The likelihood of threats is highest for Natural Heritage Sites covered by forests or those in marine and coastal areas, Africa as well as the Arab region. It is also possible to identify a general increase in threats over time, although with a diminishing rate of growth towards the period 2015-2019. Contrary to this development and the general downturn in threats during the Covid-19 pandemic period of 2020-2023, pressure from tourism continues to grow. Methodologically, the results emphasize the need for multivariate Probit models when research goes beyond analyses of descriptive statistics and single equation approaches.

Spatial-Temporal Genome Regulation in Stress-Response and Cell-Fate Change.

Complex functioning of the genome in the cell nucleus is controlled at different levels: (a) the DNA base sequence containing all relevant inherited information; (b) epigenetic pathways consisting of protein interactions and feedback loops; (c) the genome architecture and organization activating or suppressing genetic interactions between different parts of the genome. Most research so far has shed light on the puzzle pieces at these levels. This article, however, attempts an integrative approach to genome expression regulation incorporating these different layers. Under environmental stress or during cell development, differentiation towards specialized cell types, or to dysfunctional tumor, the cell nucleus seems to react as a whole through coordinated changes at all levels of control. This implies the need for a framework in which biological, chemical, and physical manifestations can serve as a basis for a coherent theory of gene self-organization. An international symposium held at the Biomedical Research and Study Center in Riga, Latvia, on 25 July 2022 addressed novel aspects of the abovementioned topic. The present article reviews the most recent results and conclusions of the state-of-the-art research in this multidisciplinary field of science, which were delivered and discussed by scholars at the Riga symposium.

Threat Perception and Adaptive Capacity of Natural World Heritage Site Management.

This study offers new insights into the largest threats to natural and mixed World Heritage sites in developed countries as considered by their management. In addition to this, the capacity of the management to deal with threats is examined. An Ordered Probit model is used that distinguishes three groups of threats and four categories of adaptive capacity of the management. Data originate from the 2014 UNESCO Periodic Report II for sites in economically advanced countries (Europe, North America, Australia, New Zealand, Japan and South Korea) linked to the World Heritage Site database. Estimation results reveal that the probability of a major threat to World Heritage sites is perceived to be highest in the category of climate change and extreme weather events, followed by local conditions affecting the physical structure (temperature, rain, dust). Sites in tropical climates are perceived as significantly more threatened, as are those earlier listed as in danger. The likelihood of perceiving a major threat is highest in Turkey, Italy, Norway and North America. Threats related to climate change are those the management has the lowest capacity to deal with when other important aspects are controlled for. Large and natural areas have a higher perceived administrative capacity to deal with threats than others.

Spatial influence on the distribution of downhill skiers in Sweden.

This study investigates empirically how natural snow depth affects the number of downhill skiers. Data include the number of skier visits for the 32 largest ski resorts in Sweden from the 1998/1999 to the 2018/2019 seasons. Results of spatial dynamic estimations show that an increase in natural snow depth in the ski area has a significant negative impact on the number of skier visits in the short term, although the magnitude is small. This implies that a snow deficit leads to increased demand for downhill skiing both directly and indirectly (in the neighbouring areas). The variable snow depth in the neighbouring ski areas is not significantly different from zero, indicating that no spatial substitution takes place. There is, however, a strong positive relationship between skier visits to neighbouring areas, revealing that ski resorts are complements rather than substitutes. The long-term influence of snow depth is not significant, implying that the ski business is independent of variations in snow depth. Instead, the number of skier visits is mainly determined by past visits, revealing a high degree of persistence.

Digital indicators of interest in natural world heritage sites.

Due to their remoteness or boundless nature, activities at Natural Heritage Sites are difficult to monitor. In this study, two digital measures of the interest in Natural Word Heritage Sites are compared: one ex ante based on the number of Wikipedia page views of the site and another ex post derived from actual visitation as measured by the number of Instagram posts. The entire UNESCO database, which includes 248 Natural World Heritage Sites is linked to the 2.8 million Wikipedia page views, the 58 million Instagram posts and the Köppen extreme climate zone categories. Quantile regressions reveal that the main association in common for the two indicators is the risk of the site losing its inscription. Presence in the UNESCO Danger list is associated with reduced interest in a site, particularly in the number of Instagram posts and in the top quartile of Wikipedia views. Years since inscription is also an important explanatory variable, especially for the Instagram posts and the Wikipedia views in the top quartile. The UNESCO selection criterion of outstanding beauty only relates to the Instagram posts. Climate zone is mainly linked to the ex post variable and its upper quartile, where the sites with the most attention are found. Wikipedia views are also negatively associated with sites in Africa, the Arab countries and Latin America. Elevation, size of the area as well as kind of site are all variables not significant. There is a significant correlation between the two outcome variables with a coefficient of 0.5. While the Instagram posts relate clearly to actual visits, the Wikipedia page views is considered a possible leading indicator of future interest in a site.

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours.

BACKGROUND: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin. METHODS: Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W). RESULTS: Thirty-one patients received berzosertib (90-210 mg/m2) and cisplatin (40-75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2 (days 2 and 9) and cisplatin 75 mg/m2 (day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy. CONCLUSIONS: Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting. CLINICAL TRIALS IDENTIFIER: NCT02157792.

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours.

BACKGROUND: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. METHODS: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. RESULTS: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. CONCLUSIONS: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. CLINICAL TRIAL IDENTIFIER: NCT02157792.

Time-varying impact of snow depth on tourism in selected regions.

This study uses a time-varying model that provides new evidence on the changing relationship between domestic overnight stays of selected winter sport destinations and natural snow conditions. A Kalman filter method combined with wavelet-based multiresolution analysis (MRA) is employed to investigate the relationships in intervals between 2 and 4 and up to 16-32 months. The model is applied to domestic overnight stays for selected mountain regions in Sweden (Dalarna and Jämtland), Norway (Buskerud, Hedmark, Hordaland and Oppland) and Austria (Salzburg and Tyrol). Results show that the sensitivity of domestic overnight stays on natural snow conditions varies markedly depending on location, time period and frequency band window used in the estimation. The medium-run relation for Tyrol and Salzburg is significantly declining over time, while in Norway and Sweden, the same relationship is generally volatile and not significant at the end of the sample period. In the short run, none of the regions exhibits a link between domestic overnight stays and snow depth fluctuations.

The Staircase Drive-A Novel Actuator Design Optimised for Daisy-Chaining and Minimum Stress Load Coupling.

This work presents a novel type of actuator that improves over the standard cantilever by permitting daisy-chaining while minimising stress to the joint connecting to the load. A detailed structural and functional comparison of the proposed device against the cantilever actuator as a baseline is given, led by a brief revision of the cantilever actuator as the state-of-the-art that highlights its limitations with respect to daisy-chaining and the stress it inherently creates within the joint connecting to the load when attempting out-of-plane displacement without rotation. Simulations of both devices' performance confirm that the newly proposed device yields the targeted displacement profile that both enables the daisy-chaining of such a device into a higher-order actuator for increased displacement and reduce stress in the joint with the load. This comes at the cost of reduced maximum displacement compared to the cantilever, which can be overcome by daisy-chaining. The proposed device's performance is further evaluated on the basis of manufactured prototypes measured by means of a laser scanning vibrometer. The prototype was manufactured on a 150 µm alumina substrate, and both electrodes and piezoelectric layer were deposited in a thick-film printing process.

Nitro-Oleic Acid Inhibits Stemness Maintenance and Enhances Neural Differentiation of Mouse Embryonic Stem Cells via STAT3 Signaling.

Nitro-oleic acid (NO2-OA), pluripotent cell-signaling mediator, was recently described as a modulator of the signal transducer and activator of transcription 3 (STAT3) activity. In our study, we discovered new aspects of NO2-OA involvement in the regulation of stem cell pluripotency and differentiation. Murine embryonic stem cells (mESC) or mESC-derived embryoid bodies (EBs) were exposed to NO2-OA or oleic acid (OA) for selected time periods. Our results showed that NO2-OA but not OA caused the loss of pluripotency of mESC cultivated in leukemia inhibitory factor (LIF) rich medium via the decrease of pluripotency markers (NANOG, sex-determining region Y-box 1 transcription factor (SOX2), and octamer-binding transcription factor 4 (OCT4)). The effects of NO2-OA on mESC correlated with reduced phosphorylation of STAT3. Subsequent differentiation led to an increase of the ectodermal marker orthodenticle homolog 2 (Otx2). Similarly, treatment of mESC-derived EBs by NO2-OA resulted in the up-regulation of both neural markers Nestin and ß-Tubulin class III (Tubb3). Interestingly, the expression of cardiac-specific genes and beating of EBs were significantly decreased. In conclusion, NO2-OA is able to modulate pluripotency of mESC via the regulation of STAT3 phosphorylation. Further, it attenuates cardiac differentiation on the one hand, and on the other hand, it directs mESC into neural fate.

Elucidation of the Clustered Nano-Architecture of Radiation-Induced DNA Damage Sites and Surrounding Chromatin in Cancer Cells: A Single Molecule Localization Microscopy Approach.

In cancer therapy, the application of (fractionated) harsh radiation treatment is state of the art for many types of tumors. However, ionizing radiation is a "double-edged sword"-it can kill the tumor but can also promote the selection of radioresistant tumor cell clones or even initiate carcinogenesis in the normal irradiated tissue. Individualized radiotherapy would reduce these risks and boost the treatment, but its development requires a deep understanding of DNA damage and repair processes and the corresponding control mechanisms. DNA double strand breaks (DSBs) and their repair play a critical role in the cellular response to radiation. In previous years, it has become apparent that, beyond genetic and epigenetic determinants, the structural aspects of damaged chromatin (i.e., not only of DSBs themselves but also of the whole damage-surrounding chromatin domains) form another layer of complex DSB regulation. In the present article, we summarize the application of super-resolution single molecule localization microscopy (SMLM) for investigations of these structural aspects with emphasis on the relationship between the nano-architecture of radiation-induced repair foci (IRIFs), represented here by γH2AX foci, and their chromatin environment. Using irradiated HeLa cell cultures as an example, we show repair-dependent rearrangements of damaged chromatin and analyze the architecture of γH2AX repair clusters according to topological similarities. Although HeLa cells are known to have highly aberrant genomes, the topological similarity of γH2AX was high, indicating a functional, presumptively genome type-independent relevance of structural aspects in DSB repair. Remarkably, nano-scaled chromatin rearrangements during repair depended both on the chromatin domain type and the treatment. Based on these results, we demonstrate how the nano-architecture and topology of IRIFs and chromatin can be determined, point to the methodological relevance of SMLM, and discuss the consequences of the observed phenomena for the DSB repair network regulation or, for instance, radiation treatment outcomes.

5-Nitro-2,4-Dichloropyrimidine as an Universal Model for Low-Energy Electron Processes Relevant for Radiosensitization.

We report experimental results of low-energy electron interactions with.

In Vitro Comparison of Passive and Active Clinical Proton Beams.

Nowadays, the irradiation methodology in proton therapy is switching from the use of passively scattered beams to active pencil beams due to the possibility of more conformal dose distributions. The dose rates of active pencil beams are much higher than those of passive beams. The purpose of this study was to investigate whether there is any difference in the biological effectiveness of these passive and active irradiation modes. The beam qualities of double scattering and pencil beam scanning were measured dosimetrically and simulated using the Monte Carlo code. Using the medulloblastoma cell line DAOY, we performed an in vitro comparison of the two modes in two positions along the dose-deposition curve plateau and inside the Bragg peak. We followed the clonogenic cell survival, apoptosis, micronuclei, and γH2AX assays as biological endpoints. The Monte Carlo simulations did not reveal any difference between the beam qualities of the two modes. Furthermore, we did not observe any statistically significant difference between the two modes in the in vitro comparison of any of the examined biological endpoints. Our results do not show any biologically relevant differences related to the different dose rates of passive and active proton beams.