bluuebunny/crossref_metadata_2025 huggingface dataset:
Small subsets with large sumset: Beyond the Cauchy–Davenport bound
Authors: Fox Jacob , Luo Sammy , Pham Huy Tuan , Zhou Yunkun
Published: February 2024

For a subset
$A$
of an abelian group
$G$
, given its size
$|A|$
, its doubling
$\kappa =|A+A|/|A|$
, and a parameter
$s$
which is small compared to
$|A|$
, we study the size of the largest sumset
$A+A'$
that can be guaranteed for a subset
$A'$
of
$A$
of size at most
$s$
. We show that a subset
$A'\subseteq A$
of size at most
$s$
can be found so that
$|A+A'| = \Omega (\!\min\! (\kappa ^{1/3},s)|A|)$
. Thus, a sumset significantly larger than the Cauchy–Davenport bound can be guaranteed by a bounded size subset assuming that the doubling
$\kappa$
is large. Building up on the same ideas, we resolve a conjecture of Bollobás, Leader and Tiba that for subsets
$A,B$
of
$\mathbb{F}_p$
of size at most
$\alpha p$
for an appropriate constant
$\alpha \gt 0$
, one only needs three elements
$b_1,b_2,b_3\in B$
to guarantee
$|A+\{b_1,b_2,b_3\}|\ge |A|+|B|-1$
. Allowing the use of larger subsets
$A'$
, we show that for sets
$A$
of bounded doubling, one only needs a subset
$A'$
with
$o(|A|)$
elements to guarantee that
$A+A'=A+A$
. We also address another conjecture and a question raised by Bollobás, Leader and Tiba on high-dimensional analogues and sets whose sumset cannot be saturated by a bounded size subset.
IASCAR: Incremental Answer Set Counting by Anytime Refinement
Authors: FICHTE JOHANNES K. , GAGGL SARAH ALICE , HECHER MARKUS , RUSOVAC DOMINIK
Published: February 2024

Answer set programming (ASP) is a popular declarative programming paradigm with various applications. Programs can easily have many answer sets that cannot be enumerated in practice, but counting still allows quantifying solution spaces. If one counts under assumptions on literals, one obtains a tool to comprehend parts of the solution space, so-called answer set navigation. However, navigating through parts of the solution space requires counting many times, which is expensive in theory. Knowledge compilation compiles instances into representations on which counting works in polynomial time. However, these techniques exist only for conjunctive normal form (CNF) formulas, and compiling ASP programs into CNF formulas can introduce an exponential overhead. This paper introduces a technique to iteratively count answer sets under assumptions on knowledge compilations of CNFs that encode supported models. Our anytime technique uses the inclusion–exclusion principle to improve bounds by over- and undercounting systematically. In a preliminary empirical analysis, we demonstrate promising results. After compiling the input (offline phase), our approach quickly (re)counts.
‘Working With the Whole Person’: Employability Keyworker Experiences of Supporting People Furthest From the Labour Market
Authors: Irvine Annie , McKenzie Joe , Brass Christine , Kelley Alex
Published: February 2024

This article explores the experiences of keyworkers within a third-sector employability programme targeted at people furthest from work. Using semi-structured qualitative interviews, the study investigated keyworker perspectives on effective elements of programme design, and what made the critical difference for those who did move into employment. Echoing previous research, findings confirmed the value of a holistic and personalised approach founded upon a consistent and long-term relationship of trust and support, through which programme participants developed the confidence and self-belief that was critical to progression towards employment. However, critical attention to the keyworker perspective offers novel insights, bringing to light challenges in defining role parameters and maintaining personal-professional boundaries in the interests of keyworkers and programme participants. We contribute to the body of research on employability practitioner perspectives, revealing that the strengths of person-centred support may simultaneously present tensions and wellbeing risks, where role parameters are very broadly defined.
Optimizing geriatric palliative care in Egypt: Comprehensive patient and family perspectives
Authors: Ibrahim Ateya Megahed , Zaghamir Donia Elsaid Fathi , Sultan Sultan Hosny Maher , Ibrahim Fatma Magdi , Abdel-Aziz Hassanat Ramadan
Published: February 2024

Objectives

In Egypt, palliative care for geriatric patients is understudied, necessitating exploration for service optimization. Amidst rising chronic illnesses and aging, understanding perspectives of geriatric patients and families is crucial for targeted improvements. This study aims to explore geriatric patients’ and their families’ perspectives on palliative care in Egypt, seeking opportunities to optimize service delivery for the elderly.

Methods

Employing a cross-sectional design with 110 geriatric patients and an equal number of family caregivers from the Damietta Oncology Institute and the pain treatment clinics for cancer patients at Zagazig University Hospital, the study focuses on a specialized pain clinic. Validated tools (Palliative Care Outcome Scale, Family Satisfaction with End-of-Life Care [FAMCARE] Scale, Edmonton Symptom Assessment System [ESAS], Caregiver Strain Index [CSI]) assess quality of life, family satisfaction, symptom severity, and caregiver strain.

Results

Geriatric patients (mean age: 65.0 ± 8.1 years; 45.5% male, 55.5% female) have diverse diagnoses (e.g., breast cancer 22%). Palliative care outcomes reveal challenges: low emotional well-being (2.6 ± 0.0) and alarming overall quality of life (1.8 ± 0.0). Family dissatisfaction (FAMCARE) is pervasive (total mean score 2.6 ± 0.5). Symptom severity (ESAS) is high, and caregiver strain (CSI) is notable (8.5 ± 2.2).

Significance of the results

The findings underscore the significance of the challenges faced by geriatric patients and caregivers in palliative care. Patients confront considerable symptom burdens and emotional distress, while caregivers experience notable strain. Urgently needed are targeted interventions designed to enhance patient well-being, alleviate caregiver burden, and elevate satisfaction. The critical importance of implementing these interventions promptly is highlighted, as they are instrumental in improving the overall care experience for geriatric patients and their caregivers. Moreover, the results underscore the imperative of developing comprehensive support mechanisms to address the intricate dimensions of palliative care, ultimately contributing to a more compassionate and effective care continuum.
Unveiling the Global Extent of Land Subsidence: The Sinking Crisis
Authors: Davydzenka Tsimur , Tahmasebi Pejman , Shokri Nima
Published: February 2024

Land subsidence, referring to the vertical sinking of land surface, is a significant geohazard posing serious risks to security of infrastructure, natural resources, built environment, and businesses in numerous places worldwide. Using deep learning approaches combined with more than 46,000 subsidence data, we predicted global land subsidence based on 23 environmental parameters. The generated global map of land subsidence covers historically documented and new subsiding areas. We estimate that more than 6.3 million square kilometers of the global land is influenced by significant subsidence rates. That includes 231,000 square kilometers of urban and dense settlement areas and a population of nearly 2 billion. The model revealed a positive correlation between the intensity of groundwater abstraction and the subsidence rate. Our results offer new insights regarding potential hotspots of land subsidence and provide the information required to devise necessary action plans and develop effective policies to mitigate this growing challenge worldwide.
The Effect of Intracrystalline Water on the Mechanical Properties of Olivine at Room Temperature
Authors: Kumamoto Kathryn M. , Hansen Lars N. , Breithaupt Thomas , Wallis David , Li Bo‐Shiuan , Armstrong David E. J. , Goldsby David L. , Li Yang (Will) , Warren Jessica M. , Wilkinson Angus J.
Published: February 2024

The effect of small concentrations of intracrystalline water on the strength of olivine is significant at asthenospheric temperatures but is poorly constrained at lower temperatures applicable to the shallow lithosphere. We examined the effect of water on the yield stress of olivine during low‐temperature plasticity using room‐temperature Berkovich nanoindentation. The presence of water in olivine (1,600 ppm H/Si) does not affect hardness or yield stress relative to dry olivine (≤40 ppm H/Si) outside of uncertainty but may slightly reduce Young’s modulus. Differences between water‐bearing and dry crystals in similar orientations were minor compared to differences between dry crystals in different orientations. These observations suggest water content does not affect the strength of olivine at low homologous temperatures. Thus, intracrystalline water does not play a role in olivine deformation at these temperatures, implying that water does not lead to weakening in the coldest portions of the mantle.
Paleoproterozoic Reworking of Archean Crust and Extreme Back‐Arc Metamorphism in the Enigmatic Southern Trans‐Hudson Orogen
Authors: Hillenbrand Ian W. , Gilmer Amy K. , Williams Michael L. , Souders A. Kate , Jercinovic Michael J. , Lowers Heather A. , Vazquez Jorge A.
Published: February 2024

The crustal evolution of the southernmost ∼2000–1800 Ma Trans‐Hudson orogen (THO) is enigmatic due to burial by Phanerozoic sediments. We provide new insights through petrochronologic analysis of a paragneiss drill core sample. Detrital zircon age peaks at 2625, 2340, and 1880 Ma and Hf isotopes suggest Paleoproterozoic arc development proximal to Archean source(s). Phase equilibria modeling and ternary feldspar thermometry suggest peak conditions of ≥1 GPa, ≥900°C, the first recognition of extreme, ultra‐high temperature metamorphism in the THO. The largely isobaric P‐T path, rapid heating rate, and ∼20 Myr duration (1872–1850 Ma) of peak conditions suggest that this metamorphism occurred in a back‐arc tectonic setting. The sample records post‐peak (1850–1815 Ma) mid‐crustal residence, slow cooling, and exhumation. Further retrogression occurred during Proterozoic regional exhumation (1630–1470 Ma) and Phanerozoic (360–220 Ma) reheating and/or fluid influx. Evidence for Paleoproterozoic arc(s) supports geophysical data for Archean cratonic and Paleoproterozoic arc crust in this region.
Aerosol Deposition and Snow Accumulation Processes From Beryllium‐7 Measurements in the Central Arctic Ocean: Results From the MOSAiC Expedition
Authors: Stephens Mark P. , Marsay Chris M. , Schneebeli Martin , Landing William M. , Buck Clifton S. , Geibert Walter
Published: February 2024

We use a tracer method involving the cosmogenic radioisotope beryllium‐7 (half‐life = 53.3 days) to follow the deposition of aerosols and the fate of snow on the MOSAiC ice floe during winter and spring 2019–2020. When examined alongside data from earlier studies in the Arctic Ocean that covered summer and fall, Be‐7 inventories indicate a summertime peak for aerosol Be‐7 deposition fluxes coinciding with seasonal minima boundary‐level aerosol concentrations, which suggests that deposition fluxes are primarily controlled by precipitation. This conclusion is supported by the linear relationship between Be‐7 fluxes and precipitation rates derived from data from the MOSAiC and SHEBA expeditions. Inventories of Be‐7 within the snow column exhibited evidence of significant redistribution. Be‐7 deficits, relative to the flux, were observed in areas of level sea ice while excess Be‐7 was found associated with deformed ice features such as pressure ridges, leading to the following estimates for the distribution of snow on the ice floe in May 2020: 75–93% of the snow mass is found on deformed sea ice with the remainder on level ice. Furthermore, uncertainties associated with measurements of Be‐7 concentrations within the ocean mixed layer would allow for losses of snow through open leads of up to approximately 20% of the flux. Our snow distribution estimates agree with data from repeat snow depth transect measurements. These results suggest that Be‐7 can be a useful tool in studying snow redistribution.
Elucidating Dissolved Organic Sulfur in the Coastal Environment by Improved Online Liquid Chromatography Coupled to FT‐ICR Mass Spectrometry
Authors: Chen Shuang , Qi Yulin , Xie Qiaorong , Ma Chao , Zhong Shujun , Wu Libin , Fu Pingqing
Published: February 2024

Dissolved organic sulfur (DOS) is an important component of dissolved organic matter (DOM) and widely exists at the land‐atmosphere interface. However, the characterization of DOS at the molecular level among different environmental samples in coastal regions has not been sufficiently focused. Here, we investigated DOS in aerosol, rainwater, and river water samples in Shanghai using an improved method–online liquid chromatography coupled to Fourier transform ion cyclotron resonance mass spectrometry (LC‐FT‐ICR MS). This system is utilized to separate DOS from complicated environmental matrices. The results showed that the average relative abundance of DOS in three different environmental media (aerosol, rainwater, and river water samples) accounted for 16.8%, 21.9% and 13.1%, respectively. The common molecules of the three mediums in coastal Shanghai contain an abundance of aromatic and aliphatic DOS of anthropogenic origin in addition to the natural sources of sea spray. Notably, results from a new structural classification scheme for DOS demonstrate that anthropogenic sulfonates and their derivatives are widely spread, although their molecular diversity in different medium was recorded due to complex environmental conditions and diverse sources.
Revealing the Influencing Factors of an Oxygenated Volatile Organic Compounds (OVOCs) Source Apportionment Model: A Case Study of a Dense Urban Agglomeration in the Winter
Authors: Zou Y. , Guan X. H. , Flores R. M. , Yan X. L. , Fan L. Y. , Deng T. , Deng X. J. , Ye D. Q.
Published: February 2024

Understanding sources of oxygenated volatile organic compounds (OVOCs) in the atmosphere still has large uncertainties. In this study, an improved OVOC source apportionment model was developed by principal component analysis and multiple linear regression based on the online monitoring of nonmethane hydrocarbons (NMHCs) and OVOCs in a dense urban agglomeration in the winter. The modeled concentrations were in good agreement with the measured concentrations (R2 = 0.56–0.97). The concentrations of major OVOCs, except for 2‐methylacrolein, were greatly affected by anthropogenic sources (15.8%–76.8%) and secondary generation (0.0%–51.7%), while transport and natural sources contributed to 0.0%–26.8% and 0.0%–32.0%, respectively. The selection of isoprene as the natural tracer led to an underestimation of the OVOC species from primary emission and an overestimation from natural sources. In addition, photochemical reactions significantly reduced the simulation accuracy of the model for NMHCs in the afternoon, with the R2 of 0.60 ± 0.23, which was lower than the overall value of 0.82 ± 0.11. However, the R2 for OVOCs (0.83 ± 0.14) did not decrease significantly in the afternoon due to the compensation of secondary oxidation. Furthermore, the concentration gradient distribution of the species gradually changes from a normal distribution to an exponential normal distribution with a decrease in concentration, the accuracy of the model was influenced by the degree of matching between tracer and species concentration gradient as species concentration change. Developing models with additional tracers at different concentration levels may enhance the robustness of the OVOC source apportionment model without increasing its complexity.
Modeling the Flow and Geomorphic Heterogeneity Induced by Salt Marsh Vegetation Patches Based on Convolutional Neural Network UNet‐Flow
Authors: Chen Zhipeng , Luo Feng , Li Ruijie , Zhang Chi
Published: February 2024

The two‐way interactions between biological and physical processes, bio‐geomorphic feedback, play a vital role in landscape formation and evolution in salt marshes. Patchy vegetation represents a typical form of scale‐dependent feedback in salt marshes and is primarily responsible for the formation of efficient drainage networks. The intuitive manifestation of scale‐dependent feedback is the heterogeneity of flow and landscape. Process‐based modeling is an essential tool for exploring flow heterogeneity, but calculations for small spatial scales and over long time frames can be prohibitively costly. In this study, we proposed a deep learning model architecture, UNet‐Flow, based on convolutional neural networks (CNNs), which is used to build a surrogate model to simulate a flow field induced by salt marsh patchy vegetation. After optimizing and evaluating the model, we discovered that UNet‐Flow exhibits a speed improvement of over four orders of magnitude compared to single‐process simulations using the free surface flow model TELEMAC‐2D, with acceptable levels of error. Furthermore, we proposed an approach that combines the process‐based model SISYPHE with the deep learning method to model geomorphic heterogeneity. After numerous simulations of flow heterogeneity modeling using UNet‐Flow, we obtained a significant logarithmic relationship between scale‐dependent feedback strength and vegetation stem density, and an ascending‐descending trend in feedback strength was observed as the number or surface area of vegetation patches increased. Finally, we investigated the relationship between geomorphic heterogeneity and vegetation‐related variables. This study represents a noteworthy effort to study bio‐geomorphology using deep learning methods.
Regional Low Flow Hydrology: Model Development and Evaluation
Authors: Chagas Vinícius B. P. , Chaffe Pedro L. B. , Blöschl Günter
Published: February 2024

Low flows result from the interplay of climatic variability and catchment storage dynamics, but it is unclear which of these variables is more relevant for explaining low flow spatial patterns. Here, we develop a new conceptual model that integrates process‐based hydrological knowledge with statistics and test it for 1,400 Brazilian catchments. Through comparative hydrology, we isolate the low flow generating mechanisms and estimate their components using linear model trees. The model explains 58% of the spatial variance in 7‐day minimum annual flows (Qmin) based on climate and catchment characteristics. The primary Qmin controls depend on the spatial scale of analysis. Catchment characteristics govern Qmin up to the continental scale (107 km2), where their relative importance matches that of climate. At subcontinental scales, catchment characteristics are twice as important as climate in predicting Qmin, suggesting that low flows are governed by the catchment's capacity to attenuate the climatic variability through water storage. Geological properties are the most important catchment characteristics, particularly bedrock type, lithology and topographic slope, determining streamflow recession rates in the dry season. Soil properties, primarily soil class and depth, are half as important as geology. Climate impacts Qmin mainly through mean annual rainfall minus evaporation, representing the potential groundwater recharge, while dry‐season length has the lowest impact. These results hold mainly for highly seasonal and snow‐free climates. Low flow hydrology that combines statistics with process understanding offers a promising framework for understanding regional low flow generating mechanisms and could support other estimation models than that presented here.
Nanotechnology’s frontier in combatting infectious and inflammatory diseases: prevention and treatment
Authors: Huang Yujing , Guo Xiaohan , Wu Yi , Chen Xingyu , Feng Lixiang , Xie Na , Shen Guobo
Published: February 2024

Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases, which continuously pose one of the most serious threats to human health, attributed to factors such as the emergence of new pathogens, increasing drug resistance, changes in living environments and lifestyles, and the aging population. Despite rapid advancements in mechanistic research and drug development for these diseases, current treatments often have limited efficacy and notable side effects, necessitating the development of more effective and targeted anti-inflammatory therapies. In recent years, the rapid development of nanotechnology has provided crucial technological support for the prevention, treatment, and detection of inflammation-associated diseases. Various types of nanoparticles (NPs) play significant roles, serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability. NPs can also directly combat pathogens and inflammation. In addition, nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases. This review categorizes and characterizes different types of NPs, summarizes their applications in the prevention, treatment, and detection of infectious and inflammatory diseases. It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects. In conclusion, nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.
CD4+ T cells produce IFN-I to license cDC1s for induction of cytotoxic T-cell activity in human tumors
Authors: Lei Xin , de Groot Daniël C. , Welters Marij J. P. , de Wit Tom , Schrama Ellen , van Eenennaam Hans , Santegoets Saskia J. , Oosenbrug Timo , van der Veen Annemarthe , Vos Joris L. , Zuur Charlotte L. , de Miranda Noel F. C. C. , Jacobs Heinz , van der Burg Sjoerd H. , Borst Jannie , Xiao Yanling
Published: February 2024

CD4+ T cells can "help” or "license” conventional type 1 dendritic cells (cDC1s) to induce CD8+ cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently identified cDC1s with a transcriptomic imprint of CD4+ T-cell help, specifically in T-cell-infiltrated human cancers, and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy. Here, we delineate the mechanism of cDC1 licensing by CD4+ T cells in humans. Activated CD4+ T cells produce IFNβ via the STING pathway, which promotes MHC-I antigen (cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses. In cooperation with CD40 ligand (L), IFNβ also optimizes the costimulatory and other functions of cDC1s required for CTL response induction. IFN-I-producing CD4+ T cells are present in diverse T-cell-infiltrated cancers and likely deliver “help” signals to CTLs locally, according to their transcriptomic profile and colocalization with “helped/licensed” cDCs and tumor-reactive CD8+ T cells. In agreement with this scenario, the presence of IFN-I-producing CD4+ T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.
Multi-molecular hyperspectral PRM-SRS microscopy
Authors: Zhang Wenxu , Li Yajuan , Fung Anthony A. , Li Zhi , Jang Hongje , Zha Honghao , Chen Xiaoping , Gao Fangyuan , Wu Jane Y. , Sheng Huaxin , Yao Junjie , Skowronska-Krawczyk Dorota , Jain Sanjay , Shi Lingyan
Published: February 2024

Lipids play crucial roles in many biological processes. Mapping spatial distributions and examining the metabolic dynamics of different lipid subtypes in cells and tissues are critical to better understanding their roles in aging and diseases. Commonly used imaging methods (such as mass spectrometry-based, fluorescence labeling, conventional optical imaging) can disrupt the native environment of cells/tissues, have limited spatial or spectral resolution, or cannot distinguish different lipid subtypes. Here we present a hyperspectral imaging platform that integrates a Penalized Reference Matching algorithm with Stimulated Raman Scattering (PRM-SRS) microscopy. Using this platform, we visualize and identify high density lipoprotein particles in human kidney, a high cholesterol to phosphatidylethanolamine ratio inside granule cells of mouse hippocampus, and subcellular distributions of sphingosine and cardiolipin in human brain. Our PRM-SRS displays unique advantages of enhanced chemical specificity, subcellular resolution, and fast data processing in distinguishing lipid subtypes in different organs and species.
Elastic properties and tensile strength of 2D Ti3C2Tx MXene monolayers
Authors: Rong Chao , Su Ting , Li Zhenkai , Chu Tianshu , Zhu Mingliang , Yan Yabin , Zhang Bowei , Xuan Fu-Zhen
Published: February 2024

Two-dimensional (2D) transition metal nitrides and carbides (MXenes), represented by Ti3C2Tx, have broad applications in flexible electronics, electromechanical devices, and structural membranes due to their unique physical and chemical properties. Despite the Young’s modulus of 2D Ti3C2Tx has been theoretically predicted to be 0.502 TPa, which has not been experimentally confirmed so far due to the measurement is extremely restricted. Here, by optimizing the sample preparation, cutting, and transfer protocols, we perform the direct in-situ tensile tests on monolayer Ti3C2Tx nanosheets using nanomechanical push-to-pull equipment under a scanning electron microscope. The effective Young’s modulus is 0.484 ± 0.013 TPa, which is much closer to the theoretical value of 0.502 TPa than the previously reported 0.33 TPa by the disputed nanoindentation method, and the measured elastic stiffness is ~948 N/m. Moreover, during the process of tensile loading, the monolayer Ti3C2Tx shows an average elastic strain of ~3.2% and a tensile strength as large as ~15.4 GPa. This work corrects the previous reports by nanoindentation method and demonstrates that the Ti3C2Tx indeed keeps immense potential for broad range of applications.
Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate
Authors: Thambyrajah Roshana , Maqueda Maria , Neo Wen Hao , Imbach Kathleen , Guillén Yolanda , Grases Daniela , Fadlullah Zaki , Gambera Stefano , Matteini Francesca , Wang Xiaonan , Calero-Nieto Fernando J. , Esteller Manel , Florian Maria Carolina , Porta Eduard , Benedito Rui , Göttgens Berthold , Lacaud Georges , Espinosa Lluis , Bigas Anna
Published: February 2024

Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium (HE) in the aorta- gonads-and mesonephros (AGM) region and reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling mechanisms that distinguish HSCs from HPCs are unknown. Notch signaling is essential for arterial specification, IAHC formation and HSC activity, but current studies on how Notch segregates these different fates are inconsistent. We now demonstrate that Notch activity is highest in a subset of, GFI1 + , HSC-primed HE cells, and is gradually lost with HSC maturation. We uncover that the HSC phenotype is maintained due to increasing levels of NOTCH1 and JAG1 interactions on the surface of the same cell (cis) that renders the NOTCH1 receptor from being activated. Forced activation of the NOTCH1 receptor in IAHC activates a hematopoietic differentiation program. Our results indicate that NOTCH1-JAG1 cis-inhibition preserves the HSC phenotype in the hematopoietic clusters of the embryonic aorta.
Tumor histoculture captures the dynamic interactions between tumor and immune components in response to anti-PD1 in head and neck cancer
Authors: Basak Nandini Pal , Jaganathan Kowshik , Das Biswajit , Muthusamy Oliyarasi , M Rajashekar , Malhotra Ritu , Samal Amit , Nath Moumita , MS Ganesh , Shankar Amritha Prabha , BV Prakash , Pillai Vijay , BV Manjula , C Jayaprakash , K Vasanth , K Gowri Shankar , Govindan Sindhu , V Syamkumar , Juby  , R Koushika , Bhowal Chandan , Kumar Upendra , K Govindaraj , Malhotra Mohit , Sankaran Satish
Published: February 2024

Dynamic interactions within the tumor micro-environment drive patient response to immune checkpoint inhibitors. Existing preclinical models lack true representation of this complexity. Using a Head and Neck cancer patient derived TruTumor histoculture platform, the response spectrum of 70 patients to anti-PD1 treatment is investigated in this study. With a subset of 55 patient samples, multiple assays to characterize T-cell reinvigoration and tumor cytotoxicity are performed. Based on levels of these two response parameters, patients are stratified into five sub-cohorts, with the best responder and non-responder sub-cohorts falling at extreme ends of the spectrum. The responder sub-cohort exhibits high T-cell reinvigoration, high tumor cytotoxicity with T-cells homing into the tumor upon treatment whereas immune suppression and tumor progression pathways are pre-dominant in the non-responders. Some moderate responders benefit from combination of anti-CTLA4 with anti-PD1, which is evident from better cytotoxic T-cell: T-regulatory cell ratio and enhancement of tumor cytotoxicity. Baseline and on-treatment gene expression signatures from this study stratify responders and non-responders in unrelated clinical datasets.
Superexchange-stabilized long-distance Cu sites in rock-salt-ordered double perovskite oxides for CO2 electromethanation
Authors: Zhu Jiawei , Zhang Yu , Chen Zitao , Zhang Zhenbao , Tian Xuezeng , Huang Minghua , Bai Xuedong , Wang Xue , Zhu Yongfa , Jiang Heqing
Published: February 2024

Cu-oxide-based catalysts are promising for CO2electroreduction (CO2RR) to CH4, but suffer from inevitable reduction (to metallic Cu) and uncontrollable structural collapse. Here we report Cu-based rock-salt-ordered double perovskite oxides with superexchange-stabilized long-distance Cu sites for efficient and stable CO2-to-CH4conversion. For the proof-of-concept catalyst of Sr2CuWO6, its corner-linked CuO6and WO6octahedral motifs alternate in all three crystallographic dimensions, creating sufficiently long Cu-Cu distances (at least 5.4 Å) and introducing marked superexchange interaction mainly manifested by O-anion-mediated electron transfer (from Cu to W sites). In CO2RR, the Sr2CuWO6exhibits significant improvements (up to 14.1 folds) in activity and selectivity for CH4, together with well boosted stability, relative to a physical-mixture counterpart of CuO/WO3. Moreover, the Sr2CuWO6is the most effective Cu-based-perovskite catalyst for CO2methanation, achieving a remarkable selectivity of 73.1% at 400 mA cm−2for CH4. Our experiments and theoretical calculations highlight the long Cu-Cu distances promoting *CO hydrogenation and the superexchange interaction stabilizing Cu sites as responsible for the superb performance.
Data encoding for healthcare data democratization and information leakage prevention
Authors: Thakur Anshul , Zhu Tingting , Abrol Vinayak , Armstrong Jacob , Wang Yujiang , Clifton David A.
Published: February 2024

The lack of data democratization and information leakage from trained models hinder the development and acceptance of robust deep learning-based healthcare solutions. This paper argues that irreversible data encoding can provide an effective solution to achieve data democratization without violating the privacy constraints imposed on healthcare data and clinical models. An ideal encoding framework transforms the data into a new space where it is imperceptible to a manual or computational inspection. However, encoded data should preserve the semantics of the original data such that deep learning models can be trained effectively. This paper hypothesizes the characteristics of the desired encoding framework and then exploits random projections and random quantum encoding to realize this framework for dense and longitudinal or time-series data. Experimental evaluation highlights that models trained on encoded time-series data effectively uphold the information bottleneck principle and hence, exhibit lesser information leakage from trained models.
Orthogonal inducible control of Cas13 circuits enables programmable RNA regulation in mammalian cells
Authors: Ding Yage , Tous Cristina , Choi Jaehoon , Chen Jingyao , Wong Wilson W.
Published: February 2024

RNA plays an indispensable role in mammalian cell functions. Cas13, a class of RNA-guided ribonuclease, is a flexible tool for modifying and regulating coding and non-coding RNAs, with enormous potential for creating new cell functions. However, the lack of control over Cas13 activity has limited its cell engineering capability. Here, we present the CRISTAL (Control of RNA with Inducible SpliT CAs13 Orthologs and Exogenous Ligands) platform. CRISTAL is powered by a collection (10 total) of orthogonal split inducible Cas13 effectors that can be turned ON or OFF via small molecules in multiple cell types, providing precise temporal control. Also, we engineer Cas13 logic circuits that can respond to endogenous signaling and exogenous small molecule inputs. Furthermore, the orthogonality, low leakiness, and high dynamic range of our inducible Cas13d and Cas13b enable the design and construction of a robust incoherent feedforward loop, leading to near-perfect and tunable adaptation response. Finally, using our inducible Cas13 effectors, we achieve simultaneous multiplexed control of multiple genes in vitro and in mice. Together, our CRISTAL design represents a powerful platform for precisely regulating RNA dynamics to advance cell engineering and elucidate RNA biology.
Ultrathin, ultralight dual-scale fibrous networks with high-infrared transmittance for high-performance, comfortable and sustainable PM0.3 filter
Authors: Yang Yuchen , Li Xiangshun , Zhou Zhiyong , Qiu Qiaohua , Chen Wenjing , Huang Jianying , Cai Weilong , Qin Xiaohong , Lai Yuekun
Published: February 2024

Highly permeable particulate matter (PM) can carry various bacteria, viruses and toxics and pose a serious threat to public health. Nevertheless, current respirators typically sacrifice their thickness and base weight for high-performance filtration, which inevitably causes wearing discomfort and significant consumption of raw materials. Here, we show a facile yet massive splitting eletrospinning strategy to prepare an ultrathin, ultralight and radiative cooling dual-scale fiber membrane with about 80% infrared transmittance for high-protective, comfortable and sustainable air filter. By tailoring antibacterial surfactant-triggered splitting of charged jets, the dual-scale fibrous filter consisting of continuous nanofibers (44 ± 12 nm) and submicron-fibers (159 ± 32 nm) is formed. It presents ultralow thickness (1.49 μm) and base weight (0.57 g m−2) but superior protective performances (about 99.95% PM0.3 removal, durable antibacterial ability) and wearing comfort of low air resistance, high heat dissipation and moisture permeability. Moreover, the ultralight filter can save over 97% polymers than commercial N95 respirator, enabling itself to be sustainable and economical. This work paves the way for designing advanced and sustainable protective materials.
Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
Authors: Ferrari Mathieu , Righi Matteo , Baldan Vania , Wawrzyniecka Patrycja , Bulek Anna , Kinna Alexander , Ma Biao , Bughda Reyisa , Akbar Zulaikha , Srivastava Saket , Gannon Isaac , Robson Mathew , Sillibourne James , Jha Ram , El-Kholy Mohamed , Amin Oliver Muhammad , Kokalaki Evangelia , Banani Mohammed Amin , Hussain Rehan , Day William , Lim Wen Chean , Ghongane Priyanka , Hopkins Jade R. , Jungherz Dennis , Herling Marco , Welin Martin , Surade Sachin , Dyson Michael , McCafferty John , Logan Derek , Cordoba Shaun , Thomas Simon , Sewell Andrew , Maciocia Paul , Onuoha Shimobi , Pule Martin
Published: February 2024

Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN), complementing the antibody previously described by our laboratory with unique TRBC1 specificity (Jovi-1) in targeting broader spectrum of T cell malignancies clonally expressing either of the two chains. This permits generation of paired reagents (chimeric antigen receptor-T cells) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies.
Dynamic X-ray imaging with screen-printed perovskite CMOS array
Authors: Liu Yanliang , Gao Chaosong , Li Dong , Zhang Xin , Zhu Jiongtao , Wu Meng , Liu Wenjun , Shi Tongyu , He Xingchen , Wang Jiahong , Huang Hao , Sheng Zonghai , Liang Dong , Yu Xue-Feng , Zheng Hairong , Sun Xiangming , Ge Yongshuai
Published: February 2024

High performance X-ray detector with ultra-high spatial and temporal resolution are crucial for biomedical imaging. This study reports a dynamic direct-conversion CMOS X-ray detector assembled with screen-printed CsPbBr3, whose mobility-lifetime product is 5.2 × 10−4 cm2 V–1 and X-ray sensitivity is 1.6 × 104 µC Gyair–1 cm–2. Samples larger than 5 cm$$\times$$
×
10 cm can be rapidly imaged by scanning this detector at a speed of 300 frames per second along the vertical and horizontal directions. In comparison to traditional indirect-conversion CMOS X-ray detector, this perovskite CMOS detector offers high spatial resolution (5.0 lp mm−1) X-ray radiographic imaging capability at low radiation dose (260 nGy). Moreover, 3D tomographic images of a biological specimen are also successfully reconstructed. These results highlight the perovskite CMOS detector’s potential in high-resolution, large-area, low-dose dynamic biomedical X-ray and CT imaging, as well as in non-destructive X-ray testing and security scanning.
Annexins—a family of proteins with distinctive tastes for cell signaling and membrane dynamics
Authors: Gerke Volker , Gavins Felicity N. E. , Geisow Michael , Grewal Thomas , Jaiswal Jyoti K. , Nylandsted Jesper , Rescher Ursula
Published: February 2024

Annexins are cytosolic proteins with conserved three-dimensional structures that bind acidic phospholipids in cellular membranes at elevated Ca2+levels. Through this they act as Ca2+-regulated membrane binding modules that organize membrane lipids, facilitating cellular membrane transport but also displaying extracellular activities. Recent discoveries highlight annexins as sensors and regulators of cellular and organismal stress, controlling inflammatory reactions in mammals, environmental stress in plants, and cellular responses to plasma membrane rupture. Here, we describe the role of annexins as Ca2+-regulated membrane binding modules that sense and respond to cellular stress and share our view on future research directions in the field.
Cortical astrocyte N-methyl-D-aspartate receptors influence whisker barrel activity and sensory discrimination in mice
Authors: Ahmadpour Noushin , Kantroo Meher , Stobart Michael J. , Meza-Resillas Jessica , Shabanipour Shahin , Parra-Nuñez Jesus , Salamovska Tetiana , Muzaleva Anna , O’Hara Finnegan , Erickson Dustin , Di Gaetano Bruno , Carrion-Falgarona Sofia , Weber Bruno , Lamont Alana , Lavine Natalie E. , Kauppinen Tiina M. , Jackson Michael F. , Stobart Jillian L.
Published: February 2024

Astrocytes express ionotropic receptors, including N-methyl-D-aspartate receptors (NMDARs). However, the contribution of NMDARs to astrocyte-neuron interactions, particularly in vivo, has not been elucidated. Here we show that a knockdown approach to selectively reduce NMDARs in mouse cortical astrocytes decreases astrocyte Ca2+ transients evoked by sensory stimulation. Astrocyte NMDAR knockdown also impairs nearby neuronal circuits by elevating spontaneous neuron activity and limiting neuronal recruitment, synchronization, and adaptation during sensory stimulation. Furthermore, this compromises the optimal processing of sensory information since the sensory acuity of the mice is reduced during a whisker-dependent tactile discrimination task. Lastly, we rescue the effects of astrocyte NMDAR knockdown on neurons and improve the tactile acuity of the animal by supplying exogenous ATP. Overall, our findings show that astrocytes can respond to nearby neuronal activity via their NMDAR, and that these receptors are an important component for purinergic signaling that regulate astrocyte-neuron interactions and cortical sensory discrimination in vivo.
Coupling between beta band and high frequency oscillations as a clinically useful biomarker for DBS
Authors: Bočková Martina , Lamoš Martin , Chrastina Jan , Daniel Pavel , Kupcová Silvia , Říha Ivo , Šmahovská Lucia , Baláž Marek , Rektor Ivan
Published: February 2024

Beta hypersynchrony was recently introduced into clinical practice in Parkinson’s disease (PD) to identify the best stimulation contacts and for adaptive deep brain stimulation (aDBS) sensing. However, many other oscillopathies accompany the disease, and beta power sensing may not be optimal for all patients. The aim of this work was to study the potential clinical usefulness of beta power phase-amplitude coupling (PAC) with high frequency oscillations (HFOs). Subthalamic nucleus (STN) local field potentials (LFPs) from externalized DBS electrodes were recorded and analyzed in PD patients (n = 19). Beta power and HFOs were evaluated in a resting-state condition; PAC was then studied and compared with the electrode contact positions, structural connectivity, and medication state. Beta-HFO PAC (mainly in the 200–500 Hz range) was observed in all subjects. PAC was detectable more specifically in the motor part of the STN compared to beta power and HFOs. Moreover, the presence of PAC better corresponds to the stimulation setup based on the clinical effect. PAC is also sensitive to the laterality of symptoms and dopaminergic therapy, where the greater PAC cluster reflects the more affected side and medication “off” state. Coupling between beta power and HFOs is known to be a correlate of the PD “off” state. Beta-HFO PAC seems to be more sensitive than beta power itself and could be more helpful in the selection of the best clinical stimulation contact and probably also as a potential future input signal for aDBS.
Wide-field Fourier magnetic imaging with electron spins in diamond
Authors: Guo Zhongzhi , Huang You , Cai Mingcheng , Li Chunxing , Shen Mengze , Wang Mengqi , Yu Pei , Wang Ya , Shi Fazhan , Wang Pengfei , Du Jiangfeng
Published: February 2024

Wide-field magnetic imaging based on nitrogen-vacancy (NV) centers in diamond has been shown the applicability in material and biological science. However, the spatial resolution is limited by the optical diffraction limit (>200 nm) due to the optical real-space localization and readout of NV centers. Here, we report the wide-field Fourier magnetic imaging technique to improve spatial resolution beyond the optical diffraction limit while maintaining the large field of view. Our method relies on wide-field pulsed magnetic field gradient encoding of NV spins and Fourier transform under pixel-dependent spatial filters. We have improved spatial resolution by a factor of 20 compared to the optical resolution and demonstrated the wide-field super-resolution magnetic imaging of a gradient magnetic field. This technique paves a way for efficient magnetic imaging of large-scale fine structures at the nanoscale.
Agent-based modeling of the prostate tumor microenvironment uncovers spatial tumor growth constraints and immunomodulatory properties
Authors: van Genderen Maisa N. G. , Kneppers Jeroen , Zaalberg Anniek , Bekers Elise M. , Bergman Andries M. , Zwart Wilbert , Eduati Federica
Published: February 2024

Inhibiting androgen receptor (AR) signaling through androgen deprivation therapy (ADT) reduces prostate cancer (PCa) growth in virtually all patients, but response may be temporary, in which case resistance develops, ultimately leading to lethal castration-resistant prostate cancer (CRPC). The tumor microenvironment (TME) plays an important role in the development and progression of PCa. In addition to tumor cells, TME-resident macrophages and fibroblasts express AR and are therefore also affected by ADT. However, the interplay of different TME cell types in the development of CRPC remains largely unexplored. To understand the complex stochastic nature of cell-cell interactions, we created a PCa-specific agent-based model (PCABM) based on in vitro cell proliferation data. PCa cells, fibroblasts, “pro-inflammatory” M1-like and “pro-tumor” M2-like polarized macrophages are modeled as agents from a simple set of validated base assumptions. PCABM allows us to simulate the effect of ADT on the interplay between various prostate TME cell types. The resulting in vitro growth patterns mimic human PCa. Our PCABM can effectively model hormonal perturbations by ADT, in which PCABM suggests that CRPC arises in clusters of resistant cells, as is observed in multifocal PCa. In addition, fibroblasts compete for cellular space in the TME while simultaneously creating niches for tumor cells to proliferate in. Finally, PCABM predicts that ADT has immunomodulatory effects on macrophages that may enhance tumor survival. Taken together, these results suggest that AR plays a critical role in the cellular interplay and stochastic interactions in the TME that influence tumor cell behavior and CRPC development.
Immunogenicity phase II study evaluating booster capacity of nonadjuvanted AKS-452 SARS-Cov-2 RBD Fc vaccine
Authors: Alleva David G. , Feitsma Eline A. , Janssen Yester F. , Boersma Hendrikus H. , Lancaster Thomas M. , Sathiyaseelan Thillainaygam , Murikipudi Sylaja , Delpero Andrea R. , Scully Melanie M. , Ragupathy Ramya , Kotha Sravya , Haworth Jeffrey R. , Shah Nishit J. , Rao Vidhya , Nagre Shashikant , Ronca Shannon E. , Green Freedom M. , Shaw Stephen A. , Aminetzah Ari , Kruijff Schelto , Brom Maarten , van Dam Gooitzen M. , Zion Todd C.
Published: February 2024

AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60–68% responded to AKS-452 via ≥2-fold increase from days 28 to 90 and progressively decreased back to baseline by day 180 (days 28 and 90 mean fold-increases, 14.7 ± 6.3 and 8.0 ± 2.2). Similar response kinetics against RBD mutant proteins (including omicrons) were observed but with slightly reduced titers relative to WT. There was an expected strong inverse correlation between day-0 titers and the fold-increase in titers at day 28. AKS-452 enhanced neutralization potency against live virus, consistent with IgG titers. Nucleocapsid protein (Np) titers suggested infection occurred in 66% (46 of 70) of subjects, in which only 20 reported mild symptomatic COVID-19. These favorable safety and immunogenicity profiles support booster evaluation in a planned phase III universal booster study of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.