bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased lengthening frequency does not adversely affect the EOSQ scores in magnetically controlled growing rod surgeries in 133 subjects followed to final fusion
Authors: Saw Sheryl Zhi Wen , Wei Jack Zijian , Cheung Jason Pui Yin , Kwan Kenny Yat Hong ,   Pediatric Spine Study Group, Cheung Kenneth Man Chee
Published: July 2024

Purpose

Magnetically Controlled Growing Rod (MCGR) allows frequent outpatient rod lengthening when treating Early Onset Scoliosis (EOS) patients. But there is lack of expert consensus on the optimal MCGR lengthening interval. EOS 24-Item Questionnaire (EOSQ) is validated for assessing health-related quality of life (HrQOL), family burden, and satisfaction. This is the first study assessing how MCGR lengthening intervals affects patient-perceived outcomes.

Methods

This is a multicentred cohort study with subjects recruited from 2012 to 2018 and followed till fusion. EOS subjects who underwent MCGR surgeries were grouped into high, medium or low lengthening interval subgroups based on 16 and 20 week cut-offs. Repeated measure analysis was performed on EOSQ’s specified 12 domains. EOSQ results were taken: before index surgery, after index surgery, and prior to definitive treatment. Demographic, clinical and radiographic data were included in model adjustment.

Results

133 subjects with mean follow-up of 3.5 (± 1.3) years were included, with 60 males and 73 females; 45 idiopathic, 23 congenital, 38 neuromuscular, and 27 syndromic patients. Mean Cobb angle at surgery was 67° (± 22°) with mean age of 8.3 (± 2.5) years. Between groups, clinical and radiographic parameters were comparable. Higher EOSQ scores in medium lengthening interval subgroup was present in fatigue (p = 0.019), emotion (p = 0.001), and parental impact (p = 0.049) domains, and overall score (p = 0.046). Trendline contrast between subgroups were present in general health (p = 0.006) and physical function (p = 0.025) domains.

Conclusion

Patient-perceived outcome improvements appear similar between lengthening interval subgroups. All MCGR lengthening intervals were tolerated by patients and family, with no negative impact observed.

Level of evidence

Prognostic Level III.
Application of Histopathology Image Analysis Using Deep Learning Networks
Authors: Hossain Md Shamim , Armstrong Leisa J. , Cook David M. , Zaenker Pauline
Published: July 2024

As the rise in cancer cases, there is an increasing demand to develop accurate and rapid diagnostic tools for early intervention. Pathologists are looking to augment manual analysis with computer-based evaluation to develop more efficient cancer diagnostics reports. The processing of these reports from manual evaluation is time-consuming, where the pathologists focus on accurately segmenting individual cancer cells, a vital step in analysis. This paper describes the design and validation of an application which has been developed based on deep learning networks. The application includes a workflow of image pre-processing followed by synthetic image generation, which is crucial due to the lack of training data in pathology settings. The next steps are the segmentation of nuclei regions and overlapping nuclei splitting. An improved approach has been considered based on a cycle-consistent GAN network for synthetic image generation. The synthetic images were utilized in a modified U-net network. Accurately outlining the individual nucleus border assisted an automated system that split the nuclei cluster into the individual nucleus. The SSIM and PSNR values of synthetic images corresponding to original were 0.204 and 10.610. The DSC value of the network trained by the synthetic data was 0.984 which was higher than the network trained by original images (0.805). The developed application provided better individual nuclei segmentation performance, where the average accuracy of different group images was 0.97. This higher accuracy suggests the benefit of using synthetic images in a situation to avoid the scarcity of labeled histopathology images in deep networks.
The Role of Cold Pools in Modulating Convective Organization During the MJO
Authors: Tang Mingyue , Torri Giuseppe , Sakaeda Naoko
Published: July 2024

In this study, we investigate the role of cold pools in modulating convective organization throughout the Madden‐Julian Oscillation (MJO) life cycle using a modeling approach that combines Eulerian and Lagrangian techniques. First, we conduct a simulation using the soundings and forcing of the DYNAMO/AMIE campaign. The simulation shows a lag of several days between the precipitation rate peak time associated with MJO and the highest convective organization time. Second, to analyze the role of cold pools, we consider a series of 2‐day simulations conducted at different stages of the MJO. The simulation results suggest that cold pools are larger and last longer during the mature stages of the MJO, possibly because of decreased environmental surface latent heat fluxes and stronger downdrafts. These lead to the formation of moist rings at the leading edges of cold pools, facilitating the formation of more convective cores and increasing the degree of convective organization.
Contribution of Mesoscale Convective Systems to Floods in the East Asian Summer Monsoon Region
Authors: Ding Tian , Zhou Tianjun , Guo Zhun , Yang Yuan , Zou Liwei , Chen Xiaolong
Published: July 2024

The quantitative relationship between Mesoscale Convective Systems (MCSs) and floods over East Asia has not been established. In this study, MCSs are clustered into four types with Self‐Organizing Map approach. Floods in June‐August of 2000–2021 are linked with different types of MCS by automated algorithms we constructed. We find that among the major floods (potential flood peak periods), 91% (87%) are related to MCS, 65% (78%) are dominated by MCS, and 38% (20%) are dominated by multi‐types of MCS. Types 1 and 2 MCS have higher flood‐inducing efficiencies than common MCS (Type‐4). Type‐1 MCS, characterized by the least number (2% of the total number), the largest precipitation volume, longest lifetime, slowest moving, strongest precipitation, can most efficiently produce floods. Type‐2 MCS, characterized by the second largest precipitation volume, more numerous than Type‐1 particularly over land, can induce floods not only relatively efficiently but also more frequently than Type‐1.
Southern Hemisphere Circumpolar Wavenumber‐4 Pattern Simulated in SINTEX‐F2 Coupled Model
Authors: Senapati Balaji , Morioka Yushi , Behera Swadhin K. , Dash Mihir K.
Published: July 2024

Interannual sea surface temperature (SST) variations in the subtropical‐midlatitude Southern Hemisphere are often associated with a circumpolar wavenumber‐4 (W4) pattern. This study is the first attempt to successfully simulate the SST‐W4 pattern using a state‐of‐the‐art coupled model called SINTEX‐F2 and clarify the underlying physical processes. It is found that the SST variability in the southwestern subtropical Pacific (SWSP) plays a key role in triggering atmospheric variability and generating the SST‐W4 pattern during austral summer (December‐February). In contrast, the tropical SST variability has a very limited effect. The anomalous convection and associated divergence over the SWSP induce atmospheric Rossby waves confined in the westerly jet. Then, the synoptic disturbances circumnavigate the subtropical Southern Hemisphere, establishing an atmospheric W4 pattern. The atmospheric W4 pattern has an equivalent barotropic structure in the troposphere, and it interacts with the upper ocean, causing variations in mixed layer depth due to latent heat flux (LHF) anomalies. As incoming climatological solar radiation goes into a thinner (thicker) mixed layer, the shallower (deeper) mixed layer promotes surface warming (cooling). This leads to positive (negative) SST anomalies, developing the SST‐W4 pattern during austral summer. Subsequently, anomalous entrainment due to the temperature difference between the mixed layer and the water below the mixed layer, anomalous LHF, and disappearance of the overlying atmospheric W4 pattern cause the decay of the SST‐W4 pattern during austral autumn. These results indicate that accurate simulation of the atmospheric forcing and the associated atmosphere‐ocean interaction is essential to capture the SST‐W4 pattern in coupled models.
Impact of Data Assimilation in Sensitive Features on the Predictability of the 2012 Great Arctic Cyclone
Authors: Chen Zhihong , Johnson Aaron , Wang Xuguang
Published: July 2024

The Great Arctic Cyclone 2012 (AC12) is used to understand the role of initial condition errors in the predictability at 2–3‐day forecast range of a high‐impact summer Arctic Cyclone (AC). Ensemble sensitivity analysis (ESA) is first performed to identify potentially sensitive regions of the cyclone evolution using an ensemble baseline forecast with conventional in situ observations assimilated. A pseudo‐observation method is then introduced to investigate impacts of hypothetical observations in these sensitive but unobserved regions. In the baseline experiments with in situ observations assimilated, the forecasted AC12 reaches its peak intensity 18 hr earlier than in the verifying Global Forecast System Analysis (GFS‐ANL) and the cyclone track is biased toward the southwest. Using ESA, the time of peak intensity and the cyclone track error are identified to be sensitive to the upstream trough, downstream ridge, and the tropopause polar vortex (TPV) to the northeast (NE TPV) of the AC12. These features were not observed by the in situ observation networks. To examine the impact of the observation gaps, pseudo‐observations drawn from GFS‐ANL are assimilated. Pseudo‐observations sample the three features separately to study the impact of the initial condition error on the predictability of AC12. The cyclone peak intensity timing error and track error are greatly reduced when the initial condition error is reduced near the NE TPV. A southward expansion of the NE TPV and the corresponding southward shifting low‐level front lead the forecasted AC12 to progress to the east, which better agrees with the verifying GFS‐ANL.
Land Surface Modeling as a Tool to Explore Sustainable Irrigation Practices in Mediterranean Fruit Orchards
Authors: Dombrowski O. , Brogi C. , Hendricks Franssen H.‐J. , Pisinaras V. , Panagopoulos A. , Swenson S. , Bogena H.
Published: July 2024

Irrigation strongly influences land‐atmosphere processes from regional to global scale. Therefore, an accurate representation of irrigation is crucial to understand these interactions and address water resources issues. While irrigation schemes are increasingly integrated into land surface models, their evaluation and further development remains challenging due to data limitations. This study assessed the representation of field‐scale irrigation using the Community Land Model version 5 (CLM5) through comparison of observed and simulated soil moisture, transpiration and crop yield. Irrigation was simulated by (a) adjusting the current irrigation routine and (b) by implementing a novel irrigation data stream that allows to directly use observed irrigation amounts and schedules. In a following step, the effect of different irrigation scenarios at the regional scale was simulated by using this novel data stream. At the plot scale, the novel irrigation data stream performed better in representing observed SM dynamics compared to the current irrigation routine. Nonetheless, simplifications in crop and irrigation representation and uncertainty in the relation between water stress and yield currently limit the ability of CLM5 for field‐scale irrigation scheduling. Still, the simulations revealed valuable insights into model performance that can inform and improve the modeling beyond the field scale. At regional scale, the simulations identified irrigation priorities and potential water savings. Furthermore, application of LSMs such as CLM5 can help to study the effects of irrigation beyond water availability, for example, on energy fluxes and climate, thus providing a powerful tool to assess the broader implications of irrigation at larger scale.
Quartz Dissolution Effects on Flow Channelization and Transport Behavior in Three‐Dimensional Fracture Networks
Authors: Hyman Jeffrey D. , Navarre‐Sitchler Alexis , Sweeney Matthew R. , Pachalieva Aleksandra , Carey James W. , Viswanathan Hari S.
Published: July 2024

We perform a set of reactive transport simulations in three‐dimensional fracture networks to characterize the impact of geochemical reactions on flow channelization. Flow channelization, a frequently observed phenomenon in porous and fractured subsurface rock formations, results from the spatially variable hydraulic resistance offered by a geological structure. In addition to geo‐structural features such as network connectivity, geometry, and hydraulic resistance, geochemical reactions, for example, dissolution and precipitation, can dynamically inhibit or enhance flow channelization. These geochemical processes can change the fracture permeability leading to increased flow channelization, which are localized connected regions of high volumetric flow rates that are seemingly ubiquitous in the subsurface. In our simulations, fractures partially filled with quartz are gradually dissolved until quasi‐steady state conditions are obtained. We compare the flow field's initial unreacted and final dissolved states in terms of flow and transport observations. We observe that the dissolved fracture networks provide less resistance to flow and exhibit increased flow channelization when compared to their unreacted counterparts. However, there is substantial variability in the magnitude of these changes which implies that the channelization strongly depends on the network structure. In turn, we identify the interplay between the particular network structure and the impact of geochemical dissolution on flow channelization. The presented results indicate that geological systems that have been weathering or reactive for longer times in older landscapes are likely to have increased flow channelization compared to their equivalent but younger counterparts, which implies a time dependence on flow channelization in fractured media.
Southwest Pacific Ocean Warming Driven by Circulation Changes
Authors: Sutton P. J. H. , Rickard G. J. , Roemmich D. H.
Published: July 2024

An area of ocean centered on 179°E, 46°S has warmed to full depth since 2006, with surface warming around 5 times the global rate. This Subtropical Front area is associated with a confluence of warm, salty, subtropical water from the north carried in a western boundary current and cold, fresh, subantarctic water from the south carried in the northernmost branch of the Antarctic Circumpolar Current. Temperature and salinity changes observed from Argo floats indicate that the Subtropical Frontal Zone has moved west ∼120 km, creating this area of strong warming analogous to changes in extension regions of other western boundary currents. The warming is a result of changes in the local flows of subantarctic water, evident in satellite altimeter data and 1,000 m Argo trajectories, which in turn likely result from changes in meridional ocean heat content and winds. The warming has placed this biologically‐significant region in almost perpetual marine heatwave conditions.
Unexpected Global Structure of Quasi‐4‐Day Wave With Westward Zonal Wavenumber 2 During the February 2023 Unusual Major Sudden Stratospheric Warming With Elevated Stratopause
Authors: Qin Yusong , Gu Sheng‐Yang , Dou Xiankang , Wei Yafei
Published: July 2024

During February 2023, the quasi‐4‐day wave (Q4DW) with westward zonal wavenumber 2 (W2) reached its largest amplitude of ∼400 m in the Southern Hemisphere (SH) geopotential height observations since 2004, which occurred simultaneously with an Arctic major sudden stratospheric warming (SSW) with an elevated stratopause (ES). However, the Q4DW‐W2 perturbations in the Northern Hemisphere (NH) were unexpectedly suppressed despite the unstable Arctic stratosphere and mesosphere during the 2023 ES‐SSW. Diagnostic analysis shows that the westward winds at ∼54°N–70°N in the upper stratosphere of ∼‐79 m/s during the 2023 ES‐SSW were the strongest during boreal winters over the past two decades, which benefited from the onset of a preceding minor SSW at the end of January. The strongest westward wind generated a wave geometry configuration of full reflection for Q4DW‐W2 in the NH, while the Q4DW‐W2 enhancement in the SH was induced by the in‐situ amplification of the surviving seeding perturbations.
Antarctic Bottom Water Warming, Freshening, and Contraction in the Eastern Bellingshausen Basin
Authors: Johnson Gregory C. , Mahmud A. K. M. Sadman , Macdonald Alison M. , Twining Benjamin S.
Published: July 2024

Antarctic Bottom Water has been warming in recent decades throughout most of the oceans and freshening in regions close to its Indian and Pacific sector sources. We assess warming rates on isobars in the eastern Pacific sector of the Southern Ocean using CTD data collected from shipboard surveys from the early 1990s through the late 2010s together with CTD data collected from Deep Argo floats deployed in the region in January 2023. We show cooling and freshening in the temperature‐salinity relation for water colder than ∼0.4°C. We further find a recent acceleration in the regional bottom water warming rate vertically averaged for pressures exceeding 3,700 dbar, with the 2017/18 to 2023/24 trend of 7.5 (±0.9) m°C yr−1 nearly triple the 1992/95 to 2023/24 trend of 2.8 (±0.2) m°C yr−1. The 0.2°C isotherm descent rate for these same time periods nearly quadruples from 7.8 to 28 m yr−1.
SHARP Shock Database
Authors: Ganushkina N. Y. , van de Kamp M. , Hoppe T. , Dubyagin S. , Gedalin M. , Dimmock A. , Lalti A. , Khotyaintsev Y. V. , Graham D. B. , Vink J. , Russell C. T.
Published: July 2024

Despite more than half a century of Collisionless shock (CS) research, our understanding of the processes of the shock energy dissipation into the charge particle heating and acceleration remains incomplete. To help to address the problem of the rate of the data analysis on CSs being well below of the rate of the data acquisition, an open‐source high‐level database of shocks and a centralized source of advanced tools for the purpose of analyzing shock structure and dynamics have been developed. The database is called SHARP shock database by the name of the project SHARP (Shocks: structure, AcceleRation, dissiPation) funded by the European Union's Horizon 2020 program. The SHARP shock database contains shock crossings and corresponding parameters obtained from Cluster and MMS (Magnetospheric Multiscale) missions for terrestrial bow shocks, THEMIS (Time History of Events and Macroscale Interactions during Substorms)/ARTEMIS (Acceleration, Reconnection, Turbulence and Electrodynamics of the Moon's Interaction with the Sun) missions for interplanetary shocks, and MAVEN (Mars Atmosphere and Volatile EvolutioN) and VEX (Venus Express) missions for shocks at non‐magnetized planets. The SHARP shock database can be accessed via https://sharp.fmi.fi/shock‐database/.
Seasonal Carbon Dioxide Concentrations and Fluxes Throughout Denmark's Stream Network
Authors: Martinsen Kenneth Thorø , Sand‐Jensen Kaj , Bergmann Victor , Skjærlund Tobias , Kjær Johan Emil , Koch Julian
Published: July 2024

Streams are important freshwater habitats in large‐scale carbon budgets because of their high CO2 fluxes which are driven by high CO2 concentrations and surface‐water turbulence. High CO2 concentrations are promoted by terrestrial carbon inputs, groundwater flow, and internal respiration, all of which vary greatly across space and time. We used environmental monitoring data to calculate CO2 concentrations along with a wide range of predictor variables including outputs from a national hydrological model and trained machine learning models to predict spatially distributed seasonal CO2 concentrations in Danish streams. We found that streams were supersaturated in dissolved CO2 (mean = 118 μM) and higher during autumn and winter than during spring and summer. The best model, a Random Forest model, scored R2 = 0.46, MAE = 46.0 μM, and ⍴ = 0.72 on a test set. The most important predictor variables were catchment slope, seasonality, height above nearest drainage, and depth to groundwater, highlighting the importance of landscape morphometry and soil‐groundwater‐stream connectivity. Stream CO2 fluxes determined from the predicted concentrations and gas transfer velocities estimated using empirical relationships averaged 253 mmol m−2 d−1, and the annual emissions were 513 Gg CO2 from the national stream network (area = 139 km2). Our analysis presents a framework for modeling seasonal CO2 concentrations and estimating fluxes at a national scale by means of large‐scale hydrological model outputs. Future efforts should consider further improving the temporal resolution, direct measurements of fluxes and gas transfer velocities, and seasonal variation in stream surface area.
PARP inhibition with rucaparib alone followed by combination with atezolizumab: Phase Ib COUPLET clinical study in advanced gynaecological and triple-negative breast cancers
Authors: Kristeleit Rebecca , Leary Alexandra , Oaknin Ana , Redondo Andres , George Angela , Chui Stephen , Seiller Aicha , Liste-Hermoso Mario , Willis Jenna , Shemesh Colby S. , Xiao Jim , Lin Kevin K. , Molinero Luciana , Guan Yinghui , Ray-Coquard Isabelle , Mileshkin Linda
Published: July 2024

Background

Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC).

Methods

After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy.

Results

The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab.

Conclusions

In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens.

Clinical trial registration

ClinicalTrials.gov (NCT03101280).
The effect of four loading intravitreal aflibercept injections on macular fluid in treatment-naïve neovascular age-related macular degeneration
Authors: Chandra Shruti , Raimondi Raffaele , Lim Alicia , Mohan Amy , Melmane Sneha , Menon Geeta , Chandran Manju , Sivaprasad Sobha , Burton Benjamin J. L. , Kotagiri Ajay
Published: July 2024

Purpose

To evaluate the effect of four versus three loading aflibercept injections on macular fluid resolution and visual acuity (VA) in exudative neovascular AMD (nAMD).

Methods

Multicentre, retrospective cohort study of treatment naïve nAMD eyes undergoing 3 versus 4 loading doses of aflibercept. Change in VA and fluid resolution on optical coherence tomography (OCT), were evaluated at 8 weeks post loading. The primary outcome was proportion of patients with no intraretinal (IRF) and/or subretinal (SRF) fluid at central 1 mm and whole macula at 8 weeks after loading. Data were summarised with mean ± SD for continuous variables, and n (%) for categorical variables.

Results

Data from 995 patients was analysed (355 patients − 4 loading doses and 640–3 loading doses). At 8 weeks post 4 loading doses proportion of eyes with neither IRF nor SRF, no IRF and no SRF were 62.8%, 88.7% and 79.2% at fovea versus 56.1%, 87.9% and 69.9% in the whole macula, respectively. Fluid resolution at both fovea and macula were significantly higher in eyes with 4 loading injections versus 3 (p = 0.0001). The mean VA change was +4.0 (±11.3) and +5.4(±13.3) letters for 3 and 4 loading doses groups (p = 0.09).

Conclusion

Four loading dose injections of aflibercept results in higher proportion of eyes with total fluid resolution in the central subfield and total macular scan when compared to those receiving 3 loading dose injections at 8 weeks post loading phase. However, the better drying effect of 4th loading dose does not translate into better short-term VA outcomes.
Human navigation strategies and their errors result from dynamic interactions of spatial uncertainties
Authors: Kessler Fabian , Frankenstein Julia , Rothkopf Constantin A.
Published: July 2024

Goal-directed navigation requires continuously integrating uncertain self-motion and landmark cues into an internal sense of location and direction, concurrently planning future paths, and sequentially executing motor actions. Here, we provide a unified account of these processes with a computational model of probabilistic path planning in the framework of optimal feedback control under uncertainty. This model gives rise to diverse human navigational strategies previously believed to be distinct behaviors and predicts quantitatively both the errors and the variability of navigation across numerous experiments. This furthermore explains how sequential egocentric landmark observations form an uncertain allocentric cognitive map, how this internal map is used both in route planning and during execution of movements, and reconciles seemingly contradictory results about cue-integration behavior in navigation. Taken together, the present work provides a parsimonious explanation of how patterns of human goal-directed navigation behavior arise from the continuous and dynamic interactions of spatial uncertainties in perception, cognition, and action.
An in-situ peptide-antibody self-assembly to block CD47 and CD24 signaling enhances macrophage-mediated phagocytosis and anti-tumor immune responses
Authors: Zhang Weiqi , Zeng Yinghua , Xiao Qiuqun , Wu Yuanyuan , Liu Jiale , Wang Haocheng , Luo Yuting , Zhan Jie , Liao Ning , Cai Yanbin
Published: July 2024

Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8+ T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate. The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency.
Chemically tailored block copolymers for highly reliable sub-10-nm patterns by directed self-assembly
Authors: Maekawa Shinsuke , Seshimo Takehiro , Dazai Takahiro , Sato Kazufumi , Hatakeyama-Sato Kan , Nabae Yuta , Hayakawa Teruaki
Published: July 2024

While block copolymer (BCP) lithography is theoretically capable of printing features smaller than 10 nm, developing practical BCPs for this purpose remains challenging. Herein, we report the creation of a chemically tailored, highly reliable, and practically applicable block copolymer and sub-10-nm line patterns by directed self-assembly. Polystyrene-block-[poly(glycidyl methacrylate)-random-poly(methyl methacrylate)] (PS-b-(PGMA-r-PMMA) or PS-b-PGM), which is based on PS-b-PMMA with an appropriate amount of introduced PGMA (10–33 mol%) is quantitatively post-functionalized with thiols. The use of 2,2,2-trifluoroethanethiol leads to polymers (PS-b-PGFMs) with Flory–Huggins interaction parameters (χ) that are 3.5–4.6-times higher than that of PS-b-PMMA and well-defined higher-order structures with domain spacings of less than 20 nm. This study leads to the smallest perpendicular lamellar domain size of 12.3 nm. Furthermore, thin-film lamellar domain alignment and vertical orientation are highly reliably and reproducibly obtained by directed self-assembly to yield line patterns that correspond to a 7.6 nm half-pitch size.
Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response
Authors: Coulton Alexander , Murai Jun , Qian Danwen , Thakkar Krupa , Lewis Claire E. , Litchfield Kevin
Published: July 2024

The paradigm for macrophage characterization has evolved from the simple M1/M2 dichotomy to a more complex model that encompasses the broad spectrum of macrophage phenotypic diversity, due to differences in ontogeny and/or local stimuli. We currently lack an in-depth pan-cancer single cell RNA-seq (scRNAseq) atlas of tumour-associated macrophages (TAMs) that fully captures this complexity. In addition, an increased understanding of macrophage diversity could help to explain the variable responses of cancer patients to immunotherapy. Our atlas includes well established macrophage subsets as well as a number of additional ones. We associate macrophage composition with tumour phenotype and show macrophage subsets can vary between primary and metastatic tumours growing in sites like the liver. We also examine macrophage-T cell functional cross talk and identify two subsets of TAMs associated with T cell activation. Analysis of TAM signatures in a large cohort of immune checkpoint inhibitor-treated patients (CPI1000 + ) identify multiple TAM subsets associated with response, including the presence of a subset of TAMs that upregulate collagen-related genes. Finally, we demonstrate the utility of our data as a resource and reference atlas for mapping of novel macrophage datasets using projection. Overall, these advances represent an important step in both macrophage classification and overcoming resistance to immunotherapies in cancer.
Using real-time modelling to inform the 2017 Ebola outbreak response in DR Congo
Authors: Thompson R. , Hart W. , Keita M. , Fall I. , Gueye A. , Chamla D. , Mossoko M. , Ahuka-Mundeke S. , Nsio-Mbeta J. , Jombart T. , Polonsky J.
Published: July 2024

Important policy questions during infections disease outbreaks include: i) How effective are particular interventions?; ii) When can resource-intensive interventions be removed? We used mathematical modelling to address these questions during the 2017 Ebola outbreak in Likati Health Zone, Democratic Republic of the Congo (DRC). Eight cases occurred before 15 May 2017, when the Ebola Response Team (ERT; co-ordinated by the World Health Organisation and DRC Ministry of Health) was deployed to reduce transmission. We used a branching process model to estimate that, pre-ERT arrival, the reproduction number was$$R=1.49$$R=1.49(95% credible interval$$({{{{\mathrm{0.67,2.81}}}}})$$(0.67, 2.81)). The risk of further cases occurring without the ERT was estimated to be 0.97 (97%). However, no cases materialised, suggesting that the ERT’s measures were effective. We also estimated the risk of withdrawing the ERT in real-time. By the actual ERT withdrawal date (2 July 2017), the risk of future cases without the ERT was only 0.01, indicating that the ERT withdrawal decision was safe. We evaluated the sensitivity of our results to the estimated$$R$$Rvalue and considered different criteria for determining the ERT withdrawal date. This research provides an extensible modelling framework that can be used to guide decisions about when to relax interventions during future outbreaks.
Water quality management could halve future water scarcity cost-effectively in the Pearl River Basin
Authors: Baccour Safa , Goelema Gerwin , Kahil Taher , Albiac Jose , van Vliet Michelle T. H. , Zhu Xueqin , Strokal Maryna
Published: July 2024

Reducing water scarcity requires both mitigation of the increasing water pollution and adaptation to the changing availability and demand of water resources under global change. However, state-of-the-art water scarcity modeling efforts often ignore water quality and associated biogeochemical processes in the design of water scarcity reduction measures. Here, we identify cost-effective options for reducing future water scarcity by accounting for water quantity and quality in the highly water stressed and polluted Pearl River Basin in China under various socio-economic and climatic change scenarios based on the Shared Socio-economic Pathways (SSPs) and Representative Concentration Pathways (RCPs). Our modeling approach integrates a nutrient model (MARINA-Nutrients) with a cost-optimization procedure, considering biogeochemistry and human activities on land in a spatially explicit way. Results indicate that future water scarcity is expected to increase by a factor of four in most parts of the Pearl River Basin by 2050 under the RCP8.5-SSP5 scenario. Results also show that water quality management options could half future water scarcity in a cost-effective way. Our analysis could serve as an example of water scarcity assessment for other highly water stressed and polluted river basins around the world and inform the design of cost-effective measures to reduce water scarcity.
Clustering induces switching between phoretic and osmotic propulsion in active colloidal rafts
Authors: Boniface Dolachai , Leyva Sergi G. , Pagonabarraga Ignacio , Tierno Pietro
Published: July 2024

Active particles driven by chemical reactions are the subject of intense research to date due to their rich physics, being intrinsically far from equilibrium, and their multiple technological applications. Recent attention in this field is now shifting towards exploring the fascinating dynamics of active and passive mixtures. Here we realize active colloidal rafts, composed of a single catalytic particle encircled by several shells of passive microspheres, and assembled via light-activated chemophoresis. We show that the cluster propulsion mechanism transits from diffusiophoretic to diffusioosmotic as the number of colloidal shells increases. Using the Lorentz reciprocal theorem, we demonstrate that in large clusters self-propulsion emerges by considering the hydrodynamic flow via the diffusioosmotic response of the substrate. The dynamics in our active colloidal rafts are governed by the interplay between phoretic and osmotic effects. Thus, our work highlights their importance in understanding the rich physics of active catalytic systems.
Generation of precision microstructures based on reconfigurable photoresponsive hydrogels for high-resolution polymer replication and microoptics
Authors: Zhu Pang , Song Qingchuan , Bhagwat Sagar , Mayoussi Fadoua , Goralczyk Andreas , Nekoonam Niloofar , Sanjaya Mario , Hou Peilong , Tisato Silvio , Kotz-Helmer Frederik , Helmer Dorothea , Rapp Bastian E.
Published: July 2024

Microstructured molds are essential for fabricating various components ranging from precision optics and microstructured surfaces to microfluidics. However, conventional fabrication technology such as photolithography requires expensive equipment and a large number of processing steps. Here, we report a facile method to fabricate micromolds based on a reusable photoresponsive hydrogel: Uniform micropatterns are engraved into the hydrogel surface using photo masks under UV irradiation within a few minutes. Patterns are replicated using polydimethylsiloxane with minimum feature size of 40 μm and smoothness of Rq ~ 3.4 nm. After replication, the patterns can be fully erased by light thus allowing for reuse as a new mold without notable loss in performance. Utilizing greyscale lithography, patterns with different height levels can be produced within the same exposure step. We demonstrate the versatility of this method by fabricating diffractive optical elements devices and a microlens array and microfluidic device with 100 µm wide channels.
Epigenetic maintenance of adult neural stem cell quiescence in the mouse hippocampus via Setd1a
Authors: Zhao Ting , Hong Yan , Yan Bowen , Huang Suming , Ming Guo-li , Song Hongjun
Published: July 2024

Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether long-lasting epigenetic modifications maintain NSC quiescence over the long term in the adult DG is not well-understood. Here we show that mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, develop an enlarged DG with more dentate granule cells after young adulthood. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promotes their activation and neurogenesis, which is countered by inhibition of the histone demethylase LSD1. Mechanistically, RNA-sequencing and CUT & RUN analyses of cultured quiescent adult NSCs reveal Setd1a deletion-induced transcriptional changes and many Setd1a targets, among which down-regulation of Bhlhe40 promotes quiescent NSC activation in the adult DG in vivo. Together, our study reveals a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.
Engineered droplet-forming peptide as photocontrollable phase modulator for fused in sarcoma protein
Authors: Chuang Hao-Yu , He Ruei-Yu , Huang Yung-An , Hsu Wan-Ting , Cheng Ya-Jen , Guo Zheng-Rong , Wali Niaz , Hwang Ing-Shouh , Shie Jiun-Jie , Huang Joseph Jen-Tse
Published: July 2024

The assembly and disassembly of biomolecular condensates are crucial for the subcellular compartmentalization of biomolecules in the control of cellular reactions. Recently, a correlation has been discovered between the phase transition of condensates and their maturation (aggregation) process in diseases. Therefore, modulating the phase of condensates to unravel the roles of condensation has become a matter of interest. Here, we create a peptide-based phase modulator, JSF1, which forms droplets in the dark and transforms into amyloid-like fibrils upon photoinitiation, as evidenced by their distinctive nanomechanical and dynamic properties. JSF1 is found to effectively enhance the condensation of purified fused in sarcoma (FUS) protein and, upon light exposure, induce its fibrilization. We also use JSF1 to modulate the biophysical states of FUS condensates in live cells and elucidate the relationship between FUS phase transition and FUS proteinopathy, thereby shedding light on the effect of protein phase transition on cellular function and malfunction.
Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia
Authors: Liang Jing , Wan Yang , Gao Jie , Zheng Lingyue , Wang Jingwei , Wu Peng , Li Yue , Wang Bingrui , Wang Ding , Ma Yige , Shen Biao , Lv Xue , Wang Di , An Na , Ma Xiaoli , Geng Guangfeng , Tong Jingyuan , Liu Jinhua , Chen Guo , Gao Meng , Kurita Ryo , Nakamura Yukio , Zhu Ping , Yin Hang , Zhu Xiaofan , Shi Lihong
Published: July 2024

Inherited non-hemolytic anemia is a group of rare bone marrow disorders characterized by erythroid defects. Although concerted efforts have been made to explore the underlying pathogenetic mechanisms of these diseases, the understanding of the causative mutations are still incomplete. Here we identify in a diseased pedigree that a gain-of-function mutation in toll-like receptor 8 (TLR8) is implicated in inherited non-hemolytic anemia. TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage. Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells. TLR8 inhibition improves erythropoiesis in RPS19+/− HuDEP2 cells and CD34+ cells from healthy donors and inherited non-hemolytic anemic patients. Collectively, we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia.
ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells
Authors: Huang Tu-Xiong , Huang Hui-Si , Dong Shao-Wei , Chen Jia-Yan , Zhang Bin , Li Hua-Hui , Zhang Tian-Tian , Xie Qiang , Long Qiao-Yun , Yang Yang , Huang Lin-Yuan , Zhao Pan , Bi Jiong , Lu Xi-Feng , Pan Fan , Zou Chang , Fu Li
Published: July 2024

Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-β1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-β1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.
Tetrafluoroisopropylation of alkenes and alkynes enabled by photocatalytic consecutive difluoromethylation with CF2HSO2Na
Authors: Hong Yuwei , Qiu Jiayan , Wu Zhenzhen , Xu Sangxuan , Zheng Hanliang , Zhu Gangguo
Published: July 2024

Direct assembly of complex fluorinated motifs from simple fluorine sources is an attractive frontier of synthetic chemistry. Reported herein is an unconventional protocol for achieving tetrafluoroisopropylation by using commercially available CF2HSO2Na as a convenient source of the tetrafluoroisopropyl [(CF2H)2CH] group, which finds widespread applications in life science and material science. Visible-light-induced hydrotetrafluoroisopropylation of alkenes and carbotetrafluoroisopropylation of alkynes have been thus developed. Various structurally diverse α-tetrafluoroisopropyl carbonyls and cyclopentanones are selectively constructed under mild conditions. A photocatalytic triple difluoromethylation cascade, driven by consecutive reductive radical/polar crossover processes, leads to the direct assembly of a tetrafluoroisopropyl moiety from CF2HSO2Na. This C1-to-C3fluoroalkylation protocol provides a practical strategy for the rapid construction of polyfluorinated compounds that are otherwise difficult to access, thus significantly enhancing the boundary of fluoroalkylation chemistry.
Technological evolution of large-scale blue hydrogen production toward the U.S. Hydrogen Energy Earthshot
Authors: Wu Wanying , Zhai Haibo , Holubnyak Eugene
Published: July 2024

Hydrogen potentially has a crucial role in the U.S. transition to a net-zero emissions economy. Learning from large-scale hydrogen projects will boost technological evolution and innovation toward the U.S. Hydrogen Energy Earthshot. We apply experience curves to estimate the evolving costs of blue hydrogen production and to further examine the economic effect on technological evolution of the Inflation Reduction Act’s tax credits for carbon sequestration and clean hydrogen. Learning-by-doing alone can decrease the production cost of blue hydrogen. Without tax incentives, however, it is hard for blue hydrogen production to reach the cost target of $1/kg H2. Here we show that the breakeven cumulative production capacity required for gas-based blue hydrogen to reach the $1/kg H2 target highly depends on tax credit, natural gas price, inflation rate, and learning rates. We make recommendations for hydrogen hub development and for accelerating technological progress toward the Hydrogen Energy Earthshot.
Methanogenesis in the presence of oxygenic photosynthetic bacteria may contribute to global methane cycle
Authors: Ye Jie , Zhuang Minghan , Hong Mingqiu , Zhang Dong , Ren Guoping , Hu Andong , Yang Chaohui , He Zhen , Zhou Shungui
Published: July 2024

Accumulating evidences are challenging the paradigm that methane in surface water primarily stems from the anaerobic transformation of organic matters. Yet, the contribution of oxygenic photosynthetic bacteria, a dominant species in surface water, to methane production remains unclear. Here we show methanogenesis triggered by the interaction between oxygenic photosynthetic bacteria and anaerobic methanogenic archaea. By introducing cyanobacterium Synechocystis PCC6803 and methanogenic archaea Methanosarcina barkeri with the redox cycling of iron, CH4 production was induced in coculture biofilms through both syntrophic methanogenesis (under anoxic conditions in darkness) and abiotic methanogenesis (under oxic conditions in illumination) during the periodic dark-light cycles. We have further demonstrated CH4 production by other model oxygenic photosynthetic bacteria from various phyla, in conjunction with different anaerobic methanogenic archaea exhibiting diverse energy conservation modes, as well as various common Fe-species. These findings have revealed an unexpected link between oxygenic photosynthesis and methanogenesis and would advance our understanding of photosynthetic bacteria’s ecological role in the global CH4 cycle. Such light-driven methanogenesis may be widely present in nature.
Tyrosol blocks E. coli anaerobic biofilm formation via YbfA and FNR to increase antibiotic susceptibility
Authors: Choi Ha-Young , Kim Won-Gon
Published: July 2024

Bacteria within mature biofilms are highly resistant to antibiotics than planktonic cells. Oxygen limitation contributes to antibiotic resistance in mature biofilms. Nitric oxide (NO) induces biofilm dispersal; however, low NO levels stimulate biofilm formation, an underexplored process. Here, we introduce a mechanism of anaerobic biofilm formation by investigating the antibiofilm activity of tyrosol, a component in wine. Tyrosol inhibits E. coli and Pseudomonas aeruginosa biofilm formation by enhancing NO production. YbfA is identified as a target of tyrosol and its downstream targets are sequentially determined. YbfA activates YfeR, which then suppresses the anaerobic regulator FNR. This suppression leads to decreased NO production, elevated bis-(3’−5’)-cyclic dimeric GMP levels, and finally stimulates anaerobic biofilm formation in the mature stage. Blocking YbfA with tyrosol treatment renders biofilm cells as susceptible to antibiotics as planktonic cells. Thus, this study presents YbfA as a promising antibiofilm target to address antibiotic resistance posed by biofilm-forming bacteria, with tyrosol acting as an inhibitor.