bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative analysis of hand-held and stationary ultrasound for detection of sarcopenia in acutely hospitalised older adults—a validity and reliability study
Authors: Phillip Jeppe Grabov , Minet Lisbeth Rosenbek , Smedemark Siri Aas , Ryg Jesper , Andersen-Ranberg Karen , Brockhattingen Kristoffer Kittelmann
Published: July 2024

Background and purpose

Sarcopenia is a growing health concern among geriatric patients. Early diagnostics is importance to intervene and better muscle status and thus physical function. Ultrasound can be a valuable tool for patient-near diagnostics of sarcopenia. In recent time, ultrasound devices have evolved from larger stationary devices to minor hand-held devices that are more portable. However, the literature lacks research comparing quality of the different devices. The purpose of this study was to compare hand-held ultrasound (HH-US) to stationary ultrasound (S-US) in muscle assessment for detection of sarcopenia in acutely hospitalized older adults.

Methods

A cross-sectional study using a convenience sample of acutely admitted older patients examined with both HH-US and S-US within a single session by the same examiner. Image analysis was performed using ImageJ, and was conducted by two raters: Rater 2 an experienced US examiner and Rater 1 an US examiner who received training from Rater 2. The Ultrasound sarcopenia index (USI) was used for evaluating sarcopenia. Validity and reliability of HH-US were analyzed using Cohen’s Kappa and Student’s t-test.

Results

21 participants (mean age 83.4 years, 52% female). Results showed “substantial” intra-rater reliability (κ = 0.77 for Rater 1) and ‘near-perfect’ validity (κ = 0.92 for Rater 2). Inter-rater comparisons revealed no significant differences (p < 0.05).

Conclusion

HH-US is a potential method for detection of sarcopenia in acutely hospitalized older adults.
Comparing location-specific and location-open social media data: methodological lessons from a study of blaming of minorities on Twitter during the COVID-19 pandemic
Authors: Zhang Shiyi , Tsatsou Panayiota , McLaren Lauren , Zhu Yimei
Published: July 2024

Social media platforms such as Twitter (currently X) have become important sites of public discourse and participation. Researchers have attempted to identify and collect Twitter data within a certain country or region in order to answer research questions within a particular locale. However, location information of tweets is limited. Tackling the case of public blaming of minorities on Twitter in the context of the COVID-19 pandemic in the UK, we present a method for identifying UK-based tweets and analyse two types of datasets that we collected and processed: (a) tweets with UK location-tags (labelled as location-specific data and referred to as UK datasets); and (b) tweets with UK location-tags and / or user profiles containing potential UK location information (labelled as location-open data and referred to as ALL datasets). The empirical results reveal that the overall sentiments in the two dataset types align in the same direction, but the location-specific datasets contain more extreme discourses (i.e., more positive and more negative sentiments and fewer neutral sentiments). Furthermore, in the location-specific datasets, the range of theme areas is narrower, although the themes still grasp the essence of the discussion about blaming minorities found in the larger dataset. The findings demonstrate strengths and limitations of the two dataset types and that the location-specific data can be suitable especially when the available research resources are insufficient for collecting or processing larger datasets. Nevertheless, we propose that future research may consider comparing smaller and bigger datasets to test differences between these for other topics for which specific locations may be of particular interest.
Lernen während der COVID-19-Pandemie – Selbstreguliertes Lernen in der Schule und zu Hause aus der Perspektive von Grundschülerinnen und Grundschülern
Authors: Lenzgeiger Barbara , Lohrmann Katrin , Miller Katrin
Published: July 2024

Während der COVID-19-Pandemie nahmen weniger strukturierte Lernsituationen zu Hause für Schülerinnen und Schüler situativ und zeitlich zu. Unklar ist bisher, wie Grundschülerinnen und Grundschüler in diesen Phasen ihr selbstreguliertes Lernen einschätzten. Zur Beantwortung dieser Frage wurden im Rahmen einer querschnittlich-quantitativen Studie Daten von N = 204 Grundschülerinnen und Grundschülern erhoben. Die Ergebnisse aus t‑Tests und Regressionsanalysen zeigen, dass sich die befragten Schülerinnen und Schüler zu Hause als konzentrierter und selbstregulierter lernend als in der Schule wahrnehmen. Zudem sind die wahrgenommene Konzentration und die wahrgenommene häusliche Unterstützung für das selbstregulierte Lernen zu Hause relevant. Gründe für diese Ergebnisse sowie Konsequenzen für die Aus- und Fortbildung von Lehrkräften werden diskutiert.
Study on controllability assessment of a new type of power system based on lagrangian function integrated assessment method
Authors: Zhang Wangjun , Zhao Zhongjun , Chen Yu , Wu Xiong
Published: July 2024

The complex structure and multiple controllability metrics of the new power system require a comprehensive assessment approach. We propose a controllability assessment method based on the Lagrangian function, analyzing key factors that influence controllability. Our index system includes distributed power supply utilization rate, energy storage station charge state, power factor, and voltage offset. Using Lagrange shadow price theory, we construct a guideline layer index system treating bottom indexes as constraints. We formulate an optimization function utilizing the Lagrangian shadow price theory and considering weights calculated from the bottom index’s shadow price. These weights inform primary evaluation. By combining primary evaluation results, weights, and variable coefficients using the percentage system method, we determine comprehensive evaluation results for the new power system’s controllability. Experimental results demonstrate the high reliability of this method’s evaluation indexes, indicating their effectiveness. This research provides valuable insight for the advancement of the new power system. Region 1 had the lowest overall evaluation score of 51.57 and was rated general. The overall score of Region 2 was 77.24, which was considered good. Region 3 received the highest overall score of 86.29 and was rated as excellent.

Graphical Abstract
Environment-induced information scrambling transition with charge conservations
Authors: Zhang Pengfei , Yu Zhenhua
Published: July 2024

In generic closed quantum systems, the complexity of operators increases under time evolution governed by the Heisenberg equation, reflecting the scrambling of local quantum information. However, when systems interact with an external environment, the system-environment coupling allows operators to escape from the system, inducing a dynamical transition between the scrambling phase and the dissipative phase. This transition is known as the environment-induced information scrambling transition, originally proposed in Majorana fermion systems. In this work, we advance this discovery by investigating the transition in charge-conserved systems with space-time randomness. We construct solvable Brownian Sachdev-Ye-Kitaev models of complex fermions coupled to an environment, enabling the analytical computation of operator growth. We determine the critical dissipation strength, which is proportional to $$n(1-n)$$

n
(
1
-
n
)

with n being the density of the complex fermions, arising from the suppression in the quantum Lyapunova exponent due to the Pauli blockade in the scattering process. We further analyze the density dependence of maximally scrambled operators at late time. Our results shed light on the intriguing interplay between information scrambling, dissipation, and conservation laws.
Development vision to enhance the eco-therapeutic tourism industry and its impact on urban development in Egypt
Authors: Riad Mohamed Khatab Mohamed Ahmed
Published: July 2024

This study aims to analyze the importance of eco-therapeutic tourism industry in Egypt's development and to create a strategic plan to enhance such type of tourism through collaborative efforts between various stakeholders. The goal is to align with Egypt's Vision 2030 and focus on the third Sustainable Development Goal. The research highlights the positive economic impact of tourism on Egypt's tourism infrastructure, emphasizing the importance of healing, relaxation, and rejuvenation in serene destinations. It discusses the role of infrastructure capacity, programs, and services in maximizing returns from tourism, and examines the potential for growth eco-therapeutic tourism in Egypt. The study finds a correlation between demand , marketing strategies and flexible tourism infrastructure, This research project starts by exploring the fundamental principles of eco-therapeutic tourism in Egypt. It then looks at past experiences to extract important insights. The study also evaluates the potential of health and wellness tourism in Egypt and assesses the country's current performance in this aspect. The research methodology involves using descriptive and analytical inductive methods at various stages. The study found a strong link between the demand for eco-therapeutic tourism industry in Egypt and factors related to development, such as marketing effectiveness and tourism infrastructure. It also emphasized the significance of infrastructure that is not limited to a specific location in reducing costs for providers and patients. Egypt can benefit from these factors to increase revenue and achieve significant economic returns from medical and preventive tourism resorts by relying on nearby villages and cities to reduce costs.
Hydrology Outweighs Temperature in Driving Production and Export of Dissolved Carbon in a Snowy Mountain Catchment
Authors: Kerins Devon , Sadayappan Kayalvizhi , Zhi Wei , Sullivan Pamela L. , Williams Kenneth H. , Carroll Rosemary W. H. , Barnard Holly R. , Sprenger Matthias , Dong Wenming , Perdrial Julia , Li Li
Published: July 2024

Terrestrial production and export of dissolved organic and inorganic carbon (DOC and DIC) to streams depends on water flow and biogeochemical processes in and beneath soils. Yet, understanding of these processes in a rapidly changing climate is limited. Using the watershed‐scale reactive‐transport model BioRT‐HBV and stream data from a snow‐dominated catchment in the Rockies, we show deeper groundwater flow averaged about 20% of annual discharge, rising to ∼35% in drier years. DOC and DIC production and export peaked during snowmelt and wet years, driven more by hydrology than temperature. DOC was primarily produced in shallow soils (1.94 ± 1.45 gC/m2/year), stored via sorption, and flushed out during snowmelt. Some DOC was recharged to and further consumed in the deeper subsurface via respiration (−0.27 ± 0.02 gC/m2/year), therefore reducing concentrations in deeper groundwater and stream DOC concentrations at low discharge. Consequently, DOC was primarily exported from the shallow zone (1.62 ± 0.96 gC/m2/year, compared to 0.12 ± 0.02 gC/m2/year from the deeper zone). DIC was produced in both zones but at higher rates in shallow soils (1.34 ± 1.00 gC/m2/year) than in the deep subsurface (0.36 ± 0.02 gC/m2/year). Deep respiration elevated DIC concentrations in the deep zone and stream DIC concentrations at low discharge. In other words, deep respiration is responsible for the commonly‐observed increasing DOC concentrations (flushing) and decreasing DIC concentrations (dilution) with increasing discharge.  DIC export from the shallow zone was ~66% of annual export but can drop to ∼53% in drier years. Numerical experiments suggest lower carbon production and export in a warmer, drier future, and a higher proportion from deeper flow and respiration processes. These results underscore the often‐overlooked but growing importance of deeper processes in a warming climate.
Prioritizing Forestation in China Through Incorporating Biogeochemical and Local Biogeophysical Effects
Authors: Li Yu , Zhang Pengyi , Wang Huanhuan , Ma Hui , Zhao Jie , Xu Mengyang , Wang Mengyu , Guo Chenhui , Yue Chao
Published: July 2024

Forestation is a key strategy for climate mitigation in China through its biogeochemical (BGC) effect of ecosystem carbon sequestration. Additionally, the BGC effect of forestation can be either reinforced or counteracted by concurrent biogeophysical processes (BGP effect) resulting in local land surface warming or cooling, which can be translated into CO2e (i.e., BGC effect) using a local transient climate response. Previous evaluations of the climate mitigation potential of future forestation in China have, however, focused on the BGC effect only and neglected the BGP effect, potentially leading to suboptimal forestation areas. Here, we determined priority forestation areas in China by incorporating both effects to maximize its global climate mitigation effect. Our results suggest an additional 167.2 Mha potentially suitable for forestation in China, exceeding the largest forestation target (86.8 Mha) possibly assumed by the government in 2060. The forestation‐induced BGP effect (18.7 ± 61.9 tCO2e ha−1) largely reinforces the BGC effect (458.2 ± 92.6 tCO2e ha−1) in China, yielding a total climate mitigation effect of 476.9 ± 114.2 tCO2e ha−1 over 40 years (2021–2060). Under the 2060 forestation target, considering both BGC and BGP effects will displace 17.7% (15.3 Mha) of the forestation area derived by considering the BGC effect alone. Integrating both BGC and BGP effects will lead to a CO2 uptake of 28.8 GtCO2e by 2060, 3.9 GtCO2e higher than the value obtained when considering the BGC effect only. Our results highlight the importance of considering BGP effect when making forestation policies for climate mitigation.
National‐Scale Flood Hazard Data Unfit for Urban Risk Management
Authors: Schubert Jochen E. , Mach Katharine J. , Sanders Brett F.
Published: July 2024

Extreme flooding events are becoming more frequent and costly, and impacts have been concentrated in cities where exposure and vulnerability are both heightened. To manage risks, governments, the private sector, and households now rely on flood hazard data from national‐scale models that lack accuracy in urban areas due to unresolved drainage processes and infrastructure. Here we assess the uncertainties of First Street Foundation (FSF) flood hazard data, available across the U.S., using a new model (PRIMo‐Drain) that resolves drainage infrastructure and fine resolution drainage dynamics. Using the case of Los Angeles, California, we find that FSF and PRIMo‐Drain estimates of population and property value exposed to 1%‐ and 5%‐annual‐chance hazards diverge at finer scales of governance, for example, by 4‐ to 18‐fold at the municipal scale. FSF and PRIMo‐Drain data often predict opposite patterns of exposure inequality across social groups (e.g., Black, White, Disadvantaged). Further, at the county scale, we compute a Model Agreement Index of only 24%—a ∼1 in 4 chance of models agreeing upon which properties are at risk. Collectively, these differences point to limited capacity of FSF data to confidently assess which municipalities, social groups, and individual properties are at risk of flooding within urban areas. These results caution that national‐scale model data at present may misinform urban flood risk strategies and lead to maladaptation, underscoring the importance of refined and validated urban models.
Obliquity Pacing of Deep Pacific Carbonate Chemistry During the Plio‐Pleistocene
Authors: Qin Bingbin , Xiong Zhifang , Algeo Thomas J. , Jia Qi , Nürnberg Dirk , Li Tiegang
Published: July 2024

Reconstruction of the seawater carbonate system is essential for an improved understanding of glacial‐interglacial oceanic carbon cycling and climate change. However, continuous high‐resolution ocean carbonate chemistry data are generally lacking for the Plio‐Pleistocene. Here, we present a deep Pacific carbonate ion saturation state (Δ[CO32−]) record spanning the last 5.1 Myr, reconstructed from the size‐normalized shell weight of planktonic foraminifer in the western tropical Pacific. Deep Pacific Δ[CO32−] has been modulated primarily by orbital obliquity since 5.1 Ma, during which it has exhibited in‐phase behavior with the 40‐Kyr obliquity cycle. Significantly, the amplitude of the 40‐Kyr Δ[CO32−] cycles has responded linearly to obliquity forcing throughout the Plio‐Pleistocene, independent of the late Pliocene intensification of Northern Hemisphere glaciation. We speculate that the obliquity signal in the deep Pacific Δ[CO32−] record reflects an ocean‐atmosphere circulation feedback mediated by migration of the Southern Hemisphere Westerlies.
Factors Controlling DMS Emission and Atmospheric Sulfate Aerosols in the Western Pacific Continental Sea
Authors: Yan Shi‐Bo , Xu Gao‐Bin , Zhang Hong‐Hai , Wang Jian , Xu Feng , Gao Xu‐Xu , Zhang Jia‐Wei , Wu Jin‐Wei , Yang Gui‐Peng
Published: July 2024

The western Pacific continental sea significantly influences the regulation of climate‐active gases budget and the burden of sulfate aerosols. An underway shipboard measurement device was used to determine the dimethyl sulfide (DMS) in the surface seawater and overlying atmosphere in the East China Continental Sea. The average concentration of DMS in atmosphere and seawater was 122.8 ± 86.2pptv and 6.47 ± 3.58 nmol L−1, respectively. The variation trend of surface water DMS in the western Pacific continental sea was influenced by the abundance and composition of phytoplankton under different ocean current systems, with a significant impact from eddies on DMS production in the South China Sea. By eliminating the influence of terrestrial sources and limiting air mass transport within the marine boundary layer, strong correlations were established between atmospheric DMS and air mass exposure to chlorophyll (Echl), as well as between aerosol methanesulfonic acid (MSA) and Echl. During the aerosol sampling period, the atmospheric DMS levels (1,057 ± 371 ng/m3) were significantly higher than MSA levels (46.3 ± 59.8 ng/m3) in the East China Sea, where the conversion of DMS to MSA was not affected by changes in DMS concentration. The sea‐to‐air fluxes of DMS varied over a wide range, from 0.02 to 156.0 μmol m−2 d−1, with an average of 14.35 ± 18.58 μmol m−2 d−1. Marine DMS emissions play a critical role in the formation of sulfur aerosols on the western Pacific continental shelf, accounting for 24.6 ± 7.6% (14.8%–37.8%) of the total sulfate aerosols.
Decrease in UCP1 by sustained high lipid promotes NK cell necroptosis to exacerbate nonalcoholic liver fibrosis
Authors: Gu Min , Zhang Yu , Lin Zhijie , Hu Xiangyu , Zhu Yaqin , Xiao Weiming , Jia Xiaoqin , Chen Weiwei , Lu Guotao , Gong Weijuan
Published: July 2024

Uncoupling protein 1 (UCP1) catalyzes the leak of protons across the mitochondrial inner membrane for thermogenesis. Compromised NK cell activity is involved in the occurrence of nonalcoholic liver fibrosis. Here, decreased UCP1 in NK cells was identified in patients with advanced nonalcoholic fatty liver disease. Although no obvious changes were observed in the NK cells of physiologic UCP1−/− mice (8–10 weeks old), impaired NK cell bioactivity was shown in methionine–choline-diet (MCD)-fed UCP1−/− mice and involved in the acerbation of nonalcoholic steatohepatitis (NASH) progress to liver fibrosis. Moreover, UCP1-deficient NK cells were responsible for the aggravation of liver fibrosis, as confirmed in MCD-fed UCP1flox/flox-NCR1cre mice. Acerbation of liver fibrosis was also seen in wild-type mice when their endogenous NK cells were replaced with UCP1−/− NK cells. Transcriptions of mitophagy-associated molecules in UCP1−/− NK cells were enhanced according to RNA-seq. Electron microscopic results showed mitochondrial injuries and autophagic vesicles in MCD-fed NKWT cells, PA-treated NKWT cells, or physiologic NKKO cells. However, the co-existence of UCP1 deficiency and high lipid can synergistically induce NK cell necroptosis via DRP1S616 accompanied with reduced mitophagy. Finally, The UCP1 in NK cells was downregulated when treated by sustained high PA (600 μM) via the PPARγ/ATF2 axis. Thus, persistent high-lipid treatment not only decreases UCP1 expression but also combines with reduced UCP1 to promote NK cell necroptosis, and it is involved in NASH progression to fibrosis.
ATM inhibition enhance immunotherapy by activating STING signaling and augmenting MHC Class I
Authors: Li Chunya , Wang Boyu , Tu Jingyao , Liu Chaofan , Wang Yuan , Chen Junjie , Huang Yongbiao , Liu Bo , Yuan Xianglin
Published: July 2024

Accumulating evidence supports the concept that DNA damage response targeted therapies can improve antitumor immune response by increasing the immunogenicity of tumor cells and improving the tumor immune microenvironment. Ataxia telangiectasia mutated (ATM) is a core component of the DNA repair system. Although the ATM gene has a significant mutation rate in many human cancers, including colorectal, prostate, lung, and breast, it remains understudied compared with other DDR-involved molecules such as PARP and ATR. Here, we found that either gene knockout or drug intervention, ATM inhibition activated the cGAS/STING pathway and augmented MHC class I in CRC cells, and these effects could be amplified by radiation. Furthermore, we found that MHC class I upregulation induced by ATM inhibition is dependent on the activation of the NFκB/IRF1/NLRC5 pathway and independent of STING. Animal experiments have shown increasing infiltration and cytotoxic function of T cells and better survival in ATM-deficient tumors. This work indicated that ATM nonsense mutation predicted the clinical benefits of radiotherapy combined with immune checkpoint blockade for patients with CRC. It also provides a molecular mechanism rationale for ATM-targeted agents for patients with CRC.
Progression of m6A in the tumor microenvironment: hypoxia, immune and metabolic reprogramming
Authors: Han Xuan , Zhu Yu , Ke Juan , Zhai Yufeng , Huang Min , Zhang Xin , He Hongjie , Zhang Xiaojing , Zhao Xuehong , Guo Kaikai , Li Xianglin , Han Zhongyu , Zhang Yanming
Published: July 2024

Recently, N6-methyladenosine (m6A) has aroused widespread discussion in the scientific community as a mode of RNA modification. m6A comprises writers, erasers, and readers, which regulates RNA production, nuclear export, and translation and is very important for human health. A large number of studies have found that the regulation of m6A is closely related to the occurrence and invasion of tumors, while the homeostasis and function of the tumor microenvironment (TME) determine the occurrence and development of tumors to some extent. TME is composed of a variety of immune cells (T cells, B cells, etc.) and nonimmune cells (tumor-associated mesenchymal stem cells (TA-MSCs), cancer-associated fibroblasts (CAFs), etc.). Current studies suggest that m6A is involved in regulating the function of various cells in the TME, thereby affecting tumor progression. In this manuscript, we present the composition of m6A and TME, the relationship between m6A methylation and characteristic changes in TME, the role of m6A methylation in TME, and potential therapeutic strategies to provide new perspectives for better treatment of tumors in clinical work.
Family with sequence similarity 83, member A (FAM83A) inhibits ferroptosis via the Wnt/β-catenin pathway in lung squamous cell cancer
Authors: Wang Cong , Zhang Jing , Wang Hongjiao , Chen Ruixue , Lu Ming
Published: July 2024

The function of Family With Sequence Similarity 83, Member A (FAM83A) in lung squamous cell carcinoma (LUSC) is largely unknown. Here, we detected its prognostic and regulation roles in LUSC. Bioinformatics methods were applied initially to predict the expression level and prognostic value of FAM83A mRNA in LUSC. In vitro experiments, such as western blot, colony formation and cell viability assay, lipid Reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG), and 4-hydroxy-2-nonenal (4-HNE) assay, were used to investigate its mechanism. In vivo experiments were further conducted to validate the mechanism. Results from TCGA and Oncomine databases revealed significantly higher FAM83A mRNA expression levels in LUSC than in normal lung tissue. TCGA and GEO databases and our database revealed that FAM83A expression level was an independent prognostic factor for both overall survival and progression-free survival. Besides, FAM83A was significantly associated with a higher ability of growth and clonogenicity. Mechanistically, in vitro and in vivo experiments revealed that FAM83A could promote LUSC cell growth by inhibiting ferroptosis via activating the Wnt/β-catenin signaling pathway. The rescue experiment demonstrated that inhibition of the Wnt/β-catenin pathway counteracted the function of FAM83A. FAM83A is overexpressed in LUSC and could serve as a prognosis prediction biomarker for LUSC. FAM83A promotes LUSC cell growth by inhibiting ferroptosis via activating the Wnt/β-catenin signaling pathway, which provides a new potential therapeutic target for LUSC treatment.
Structure and exfoliation mechanism of two-dimensional boron nanosheets
Authors: Chung Jing-Yang , Yuan Yanwen , Mishra Tara P. , Joseph Chithralekha , Canepa Pieremanuele , Ranjan Pranay , Sadki El Hadi S. , Gradečak Silvija , Garaj Slaven
Published: July 2024

Exfoliation of two-dimensional (2D) nanosheets from three-dimensional (3D) non-layered, non-van der Waals crystals represents an emerging strategy for materials engineering that could significantly increase the library of 2D materials. Yet, the exfoliation mechanism in which nanosheets are derived from crystals that are not intrinsically layered remains unclear. Here, we show that planar defects in the starting 3D boron material promote the exfoliation of 2D boron sheets—by combining liquid-phase exfoliation, aberration-corrected scanning transmission electron microscopy, Raman spectroscopy, and density functional theory calculations. We demonstrate that 2D boron nanosheets consist of a planar arrangement of icosahedral sub-units cleaved along the {001} planes of β-rhombohedral boron. Correspondingly, intrinsic stacking faults in 3D boron form parallel layers of faulted planes in the same orientation as the exfoliated nanosheets, reducing the {001} cleavage energy. Planar defects represent a potential engineerable pathway for exfoliating 2D sheets from 3D boron and, more broadly, the other covalently bonded materials.
Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency
Authors: Tesla Rachel , Guhl Charlotte , Werthmann Gordon C. , Dixon Danielle , Cenik Basar , Addepalli Yesu , Liang Jue , Fass Daniel M. , Rosenthal Zachary , Haggarty Stephen J. , Williams Noelle S. , Posner Bruce A. , Ready Joseph M. , Herz Joachim
Published: July 2024

Heterozygous loss-of-function mutations in the GRN gene are a major cause of hereditary frontotemporal dementia. The mechanisms linking frontotemporal dementia pathogenesis to progranulin deficiency are not well understood, and there is currently no treatment. Our strategy to prevent the onset and progression of frontotemporal dementia in patients with GRN mutations is to utilize small molecule positive regulators of GRN expression to boost progranulin levels from the remaining functional GRN allele, thus restoring progranulin levels back to normal within the brain. This work describes a series of blood-brain-barrier-penetrant small molecules which significantly increase progranulin protein levels in human cellular models, correct progranulin protein deficiency in Grn+/− mouse brains, and reverse lysosomal proteome aberrations, a phenotypic hallmark of frontotemporal dementia, more efficiently than the previously described small molecule suberoylanilide hydroxamic acid. These molecules will allow further elucidation of the cellular functions of progranulin and its role in frontotemporal dementia and will also serve as lead structures for further drug development.
Characterization of a Salmonella enterica serovar Typhimurium lineage with rough colony morphology and multidrug resistance
Authors: Xiang Ying , Zhu Kunpeng , Min Kaiyuan , Zhang Yaowen , Liu Jiangfeng , Liu Kangkang , Han Yiran , Li Xinge , Du Xinying , Wang Xin , Huang Ying , Li Xinping , Peng Yuqian , Yang Chaojie , Liu Hongbo , Liu HONGBO , Li Xiaoying , Wang Hui , Wang Chao , Wang Qi , Jia Huiqun , Yang Mingjuan , Wang Ligui , Wu Yarong , Cui Yujun , Chen Fei , Yang Haiyan , Baker Stephen , Xu Xuebin , Yang Juntao , Song Hongbin , Qiu Shaofu
Published: July 2024

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major cause of salmonellosis, and the emergence of multidrug-resistant pathovariants has become a growing concern. Here, we investigate a distinct rough colony variant exhibiting a strong biofilm-forming ability isolated in China. Whole-genome sequencing on 2,212 Chinese isolates and 1,739 publicly available genomes reveals the population structure and evolutionary history of the rough colony variants. Characterized by macro, red, dry, and rough (mrdar) colonies, these variants demonstrate enhanced biofilm formation at 28 °C and 37 °C compared to typical rdar colonies. The mrdar variants exhibit extensive multidrug resistance, with significantly higher resistance to at least five classes of antimicrobial agents compared to non-mrdar variants. This resistance is primarily conferred by an IncHI2 plasmid harboring 19 antimicrobial resistance genes. Phylogenomic analysis divides the global collections into six lineages. The majority of mrdar variants belong to sublineage L6.5, which originated from Chinese smooth colony strains and possibly emerged circa 1977. Among the mrdar variants, upregulation of the csgDEFG operons is observed, probably due to a distinct point mutation (−44G > T) in the csgD gene promoter. Pangenome and genome-wide association analyses identify 87 specific accessory genes and 72 distinct single nucleotide polymorphisms associated with the mrdar morphotype.
Catalyst-free selective oxidation of C(sp3)-H bonds in toluene on water
Authors: Lee Kyoungmun , Cho Yumi , Kim Jin Chul , Choi Chiyoung , Kim Jiwon , Lee Jae Kyoo , Li Sheng , Kwak Sang Kyu , Choi Siyoung Q.
Published: July 2024

The anisotropic water interfaces provide an environment to drive various chemical reactions not seen in bulk solutions. However, catalytic reactions by the aqueous interfaces are still in their infancy, with the emphasis being on the reaction rate acceleration on water. Here, we report that the oil-water interface activates and oxidizes C(sp3)-H bonds in toluene, yielding benzaldehyde with high selectivity (>99%) and conversion (>99%) under mild, catalyst-free conditions. Collision at the interface between oil-dissolved toluene and hydroxyl radicals spontaneously generated near the water-side interfaces is responsible for the unexpectedly high selectivity. Protrusion of free OH groups from interfacial water destabilizes the transition state of the OH-addition by forming π-hydrogen bonds with toluene, while the H-abstraction remains unchanged to effectively activate C(sp3)-H bonds. Moreover, the exposed free OH groups form hydrogen bonds with the produced benzaldehyde, suppressing it from being overoxidized. Our investigation shows that the oil-water interface has considerable promise for chemoselective redox reactions on water without any catalysts.
3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression
Authors: Mortenson Katelyn L. , Dawes Courtney , Wilson Emily R. , Patchen Nathan E. , Johnson Hailey E. , Gertz Jason , Bailey Swneke D. , Liu Yang , Varley Katherine E. , Zhang Xiaoyang
Published: July 2024

Cancer genomes are composed of many complex structural alterations on chromosomes and extrachromosomal DNA (ecDNA), making it difficult to identify non-coding enhancer regions that are hijacked to activate oncogene expression. Here, we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking. HAPI analysis of HiChIP data from 34 cancer cell lines identified enhancer hijacking events that activate both known and potentially novel oncogenes such as MYC, CCND1, ETV1, CRKL, and ID4. Furthermore, we found enhancer hijacking among multiple oncogenes from different chromosomes, often including MYC, on the same complex amplicons such as ecDNA. We characterized a MYC-ERBB2 chimeric ecDNA, in which ERBB2 heavily hijacks MYC’s enhancers. Notably, CRISPRi of the MYC promoter led to increased interaction of ERBB2 with MYC enhancers and elevated ERBB2 expression. Our HAPI analysis tool provides a robust strategy to detect enhancer hijacking and reveals novel insights into oncogene activation.
Facile access to bicyclo[2.1.1]hexanes by Lewis acid-catalyzed formal cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes
Authors: Hu Sai , Pan Yuming , Ni Dongshun , Deng Li
Published: July 2024

Saturated three-dimensional carbocycles have gained increasing prominence in synthetic and medicinal chemistry. In particular, bicyclo[2.1.1]hexanes (BCHs) have been identified as the molecular replacement for benzenes. Here, we present facile access to a variety of BCHs via a stepwise two-electron formal (3 + 2) cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes (BCBs) under Lewis acid catalysis. The reaction features wide functional group tolerance for silyl enol ethers, allowing the efficient construction of two vicinal quaternary carbon centers and a silyl-protected tertiary alcohol unit in a streamlined fashion. Interestingly, the reaction with conjugated silyl dienol ethers can provide access to bicyclo[4.1.1]octanes (BCOs) equipped with silyl enol ethers that facilitate further transformation. The utilities of this methodology are demonstrated by the late-stage modification of natural products, transformations of tertiary alcohol units on bicyclo[2.1.1]hexane frameworks, and derivatization of silyl enol ethers on bicyclo[4.1.1]octanes, delivering functionalized bicycles that are traditionally inaccessible.
Extremely large magnetoresistance in twisted intertwined graphene spirals
Authors: Zhang Yiwen , Xie Bo , Yang Yue , Wu Yueshen , Lu Xin , Hu Yuxiong , Ding Yifan , He Jiadian , Dong Peng , Wang Jinghui , Zhou Xiang , Liu Jianpeng , Wang Zhu-Jun , Li Jun
Published: July 2024

Extremely large magnetoresistance (XMR) is highly applicable in spintronic devices such as magnetic sensors, magnetic memory, and hard drives. Typically, XMR is found in Weyl semimetals characterized by perfect electron–hole symmetry or exceptionally high electric conductivity and mobility. Our study explores this phenomenon in a recently developed graphene moiré system, which demonstrates XMR owing to its topological structure and high-quality crystal formation. We investigate the electronic properties of three-dimensional intertwined twisted graphene spirals (TGS), manipulating the screw dislocation axis to achieve a rotation angle of 7.3°. Notably, at 14 T and 2 K, the magnetoresistance of these structures reaches 1.7 × 107%, accompanied by a metal–insulator transition as the temperature increases. This transition becomes noticeable when the magnetic field exceeds a minimal threshold of approximately 0.1 T. These observations suggest the possible existence of complex, correlated states within the partially filled three-dimensional Landau levels of the 3D TGS system. Our findings open up possibilities for achieving XMR by engineering the topological structure of 2D layered moiré systems.
Ca2+ transients on the T cell surface trigger rapid integrin activation in a timescale of seconds
Authors: Li Yue , Wang ShiHui , Zhang YouHua , Liu ZhaoYuan , Zheng YunZhe , Zhang Kun , Chen ShiYang , Lv XiaoYing , Huang MengWen , Pan XingChao , Zheng YaJuan , Yuan MengYa , Ge GaoXiang , Zeng Yi Arial , Lin ChangDong , Chen JianFeng
Published: July 2024

One question in lymphocyte homing is how integrins are rapidly activated to enable immediate arrest of fast rolling lymphocytes upon encountering chemokines at target vascular beds given the slow chemokine-induced integrin inside-out activation. Herein we demonstrate that chemokine CCL25-triggered Ca2+ influx induces T cell membrane-proximal external Ca2+ concentration ([Ca2+]ex) drop in 6 s from physiological concentration 1.2 mM to 0.3 mM, a critical extracellular Ca2+ threshold for inducing αLβ2 activation, triggering rapid αLβ2 activation and T cell arrest before occurrence of αLβ2 inside-out activation. Talin knockdown inhibits the slow inside-out activation of αLβ2 but not [Ca2+]ex drop-triggered αLβ2 quick activation. Blocking Ca2+ influx significantly suppresses T cell rolling-to-arrest transition and homing to skin lesions in a mouse psoriasis model, thus alleviating skin inflammation. [Ca2+]ex decrease-triggered rapid integrin activation bridges the gap between initial chemokine stimulation and slow integrin inside-out activation, ensuring immediate lymphocyte arrest and subsequent diapedesis on the right location.
LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance
Authors: Kubrak Olga , Jørgensen Anne F. , Koyama Takashi , Lassen Mette , Nagy Stanislav , Hald Jacob , Mazzoni Gianluca , Madsen Dennis , Hansen Jacob B. , Larsen Martin Røssel , Texada Michael J. , Hansen Jakob L. , Halberg Kenneth V. , Rewitz Kim
Published: July 2024

Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.
Tumor detection by analysis of both symmetric- and hemi-methylation of plasma cell-free DNA
Authors: Hua Xu , Zhou Hui , Wu Hui-Chen , Furnari Julia , Kotidis Corina P. , Rabadan Raul , Genkinger Jeanine M. , Bruce Jeffrey N. , Canoll Peter , Santella Regina M. , Zhang Zhiguo
Published: July 2024

Aberrant DNA methylation patterns have been used for cancer detection. However, DNA hemi-methylation, present at about 10% CpG dinucleotides, has been less well studied. Here we show that a majority of differentially hemi-methylated regions (DHMRs) in liver tumor DNA or plasma cells free (cf) DNA do not overlap with differentially methylated regions (DMRs) of the same samples, indicating that DHMRs could serve as independent biomarkers. Furthermore, we analyzed the cfDNA methylomes of 215 samples from individuals with liver or brain cancer and individuals without cancer (controls), and trained machine learning models using DMRs, DHMRs or both. The models incorporated with both DMRs and DHMRs show a superior performance compared to models trained with DMRs or DHMRs, with AUROC being 0.978, 0.990, and 0.983 in distinguishing control, liver and brain cancer, respectively, in a validation cohort. This study supports the potential of utilizing both DMRs and DHMRs for multi-cancer detection.
Two-dimensional and high-order directional information modulations for secure communications based on programmable metasurface
Authors: Xu Hui , Wu Jun Wei , Wang Zheng Xing , Shao Rui Wen , Yang Han Qing , Cui Tie Jun
Published: July 2024

Conventional wireless communication schemes indiscriminately transmit information into the whole space and pose inherent security risks. Recently, directional information modulation (DIM) has attracted enormous attention as a promising technology. DIM generates correct constellation symbols in the desired directions and distorts them in undesired directions, thus ensuring the security of the transmitted information. Although several DIM schemes have been reported, they suffer from defects of bulkiness, energy consumption, high cost, and inability to support two-dimensional (2D) and high-order modulations. Here, we propose a DIM scheme based on a 2-bit programmable metasurface (PM) that overcomes these defects. A fast and efficient discrete optimization algorithm is developed to optimize the digital coding sequences, and the correct constellation symbols can be generated and transmitted in multi-directional beams. As a proof-of-concept, three sets of constellation diagrams (8 phase shift keying (PSK), 16 quadrature amplitude modulation (QAM), and 64QAM) are realized in the multi-channel modes. This work provides an important route of employing DIM for ensuring physical-layer security and serves as a stepping stone toward endogenous secure communications.
Temporal pattern recognition in retinal ganglion cells is mediated by dynamical inhibitory synapses
Authors: Ebert Simone , Buffet Thomas , Sermet B.Semihcan , Marre Olivier , Cessac Bruno
Published: July 2024

A fundamental task for the brain is to generate predictions of future sensory inputs, and signal errors in these predictions. Many neurons have been shown to signal omitted stimuli during periodic stimulation, even in the retina. However, the mechanisms of this error signaling are unclear. Here we show that depressing inhibitory synapses shape the timing of the response to an omitted stimulus in the retina. While ganglion cells, the retinal output, responded to an omitted flash with a constant latency over many frequencies of the flash sequence, we found that this was not the case once inhibition was blocked. We built a simple circuit model and showed that depressing inhibitory synapses were a necessary component to reproduce our experimental findings. A new prediction of our model is that the accuracy of the constant latency requires a sufficient amount of flashes in the stimulus, which we could confirm experimentally. Depressing inhibitory synapses could thus be a key component to generate the predictive responses observed in the retina, and potentially in many brain areas.
Towards enhanced functionality of vagus neuroprostheses through in silico optimized stimulation
Authors: Ciotti Federico , John Robert , Katic Secerovic Natalija , Gozzi Noemi , Cimolato Andrea , Jayaprakash Naveen , Song Weiguo , Toth Viktor , Zanos Theodoros , Zanos Stavros , Raspopovic Stanisa
Published: July 2024

Bioelectronic therapies modulating the vagus nerve are promising for cardiovascular, inflammatory, and mental disorders. Clinical applications are however limited by side-effects such as breathing obstruction and headache caused by non-specific stimulation. To design selective and functional stimulation, we engineered VaStim, a realistic and efficient in-silico model. We developed a protocol to personalize VaStim in-vivo using simple muscle responses, successfully reproducing experimental observations, by combining models with trials conducted on five pigs. Through optimized algorithms, VaStim simulated the complete fiber population in minutes, including often omitted unmyelinated fibers which constitute 80% of the nerve. The model suggested that all Aα-fibers across the nerve affect laryngeal muscle, while heart rate changes were caused by B-efferents in specific fascicles. It predicted that tripolar paradigms could reduce laryngeal activity by 70% compared to typically used protocols. VaStim may serve as a model for developing neuromodulation therapies by maximizing efficacy and specificity, reducing animal experimentation.
Malleable, printable, bondable, and highly conductive MXene/liquid metal plasticine with improved wettability
Authors: Jiang Haojie , Yuan Bin , Guo Hongtao , Pan Fei , Meng Fanmao , Wu Yongpeng , Wang Xiao , Ruan Lingyang , Zheng Shuhuai , Yang Yang , Xiu Zheng , Li Lixin , Wu Changsheng , Gong Yongqing , Yang Menghao , Lu Wei
Published: July 2024

Integration of functional fillers into liquid metals (LM) induces rheology modification, enabling the free-form shaping of LM at the micrometer scale. However, integrating non-chemically modified low-dimensional materials with LM to form stable and uniform dispersions remain a great challenge. Herein, we propose a solvent-assisted dispersion (SAD) method that utilizes the fragmentation and reintegration of LM in volatile solvents to engulf and disperse fillers. This method successfully integrates MXene uniformly into LM, achieving better internal connectivity than the conventional dry powder mixing (DPM) method. Consequently, the MXene/LM (MLM) coating exhibits high electromagnetic interference (EMI) shielding performance (105 dB at 20 μm, which is 1.6 times that of coatings prepared by DPM). Moreover, the rheological characteristic of MLM render it malleable and facilitates direct printing and adaptation to diverse structures. This study offers a convenient method for assembling LM with low-dimensional materials, paving the way for the development of multifunctional soft devices.
Electrochromic windows with fast response and wide dynamic range for visible-light modulation without traditional electrodes
Authors: Jia Zhuofei , Sui Yiming , Qian Long , Ren Xi , Zhao Yunxiang , Yao Rui , Wang Lumeng , Chao Dongliang , Yang Cheng
Published: July 2024

Electrochromic (EC) devices represent an emerging energy-saving technology, exhibiting the capability to dynamically modulate light and heat transmittance. Despite their promising potential, the commercialization of EC devices faces substantial impediments such as high cost, intricate fabrication process, and low optical contrast inherent in conventional EC materials relying on the ion insertion/extraction mechanism. In this study, we introduce an innovative “electrode-free” electrochromic (EC) device, termed the EECD, which lacks an EC-layer on the electrodes during device assembling and in the bleached state. This device features a simplified fabrication process and delivers superior optical modulation. It achieves a high optical contrast ranging from 68-85% across the visible spectrum and boasts a rapid response time, reaching 90% coloring in just 17 seconds. In addition, EECD exhibits stable cycling for over 10,000 cycles without noticeable degradation and maintains functionality across a broad temperature range (0 °C to 50 °C). Furthermore, the fabricated large-area devices (40 cm × 40 cm) demonstrate excellent tinting uniformity, suggesting excellent scalability of this approach. Our study establishes a paradigmatic breakthrough for EC smart windows.