bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence of validity and accuracy for the Mindful Self-Care Scale-Brief among family caregivers of people with cancer in Brazil: A cross-sectional study
Authors: Garcia Ana Cláudia Mesquita , Silva Cremilson de Paula , Paiva Eliza Mara das Chagas , Meireles Everson , Nogueira Denismar Alves , Wong Claudia
Published: February 2024

Objectives

This study aimed to evaluate the evidence of validity and accuracy for the Mindful Self-Care Scale-Brief (B-MSCS) in Brazil among family caregivers of people with cancer.

Methods

This was a cross-sectional study with a sample of 203 family caregivers of people with cancer. The instruments used in this study were the following: B-MSCS, Brief Resilience Scale, and Brief Scale for Spiritual/Religious Coping. Exploratory factor analysis was carried out using the principal axis factoring method and direct oblimin oblique rotation, and confirmatory factor analysis using the robust weighted least squares means and variance adjusted estimation method and GEOMIM oblique rotation. The internal consistency of the latent factors was measured using Cronbach’s alpha coefficients.

Results

The 6-factor model showed good fit to the data, with satisfactory reliability indices and adequate representation of the scale’s internal structure. The results that can support arguments in favor of validity evidence based on internal structure for the B-MSCS-Brazilian version (BR) relate to a 19-item version which, grouped into 6 latent factors, explained 46.47% of the variance. The factor solution reproduced 79.2% of the theoretically expected structure and 5 items were excluded. The Cronbach’s alpha coefficient of the factors in the B-MSCS-BR ranged from 0.58 to 0.84. Positive religious/spiritual coping had a direct association with the B-MSCS-BR factors, with the exception of the Physical Care factor (r = 0.033, p = 0.635). Negative spiritual/religious coping was inversely associated with the Mindful Relaxation (r = −0.160, p = 0.023), Supportive Relationships (r = −0.142, p = 0.043), and Mindful Awareness factors (r = −0.140, p = 0.045). There were no associations between the B-MSCS-BR factors and resilience.

Significance of results

The findings reveal that the B-MSCS (19-item) is a valid, reliable, and culturally-appropriate instrument to examine the practice of mindful self-care by family caregivers of people with cancer in Brazil.
Impacts of Local Green's Functions on Modeling Atmospheric Loading Effects for GNSS Reference Stations
Authors: Fan Wenlan , Jiang Weiping , Li Zhao , Tao Jun , Wang Ze , He Linyu
Published: February 2024

The Green's function approach is well‐established and widely used for modeling the surface mass loading displacements. Global mean Green's functions (MGFs) are commonly applied without considering local variations of the crustal structure. Derived from the modified layered Earth structure, the local Green's functions (LGFs) are theoretically beneficial to generate more accurate deformation, since they consider interior information of the local crust. This paper analyzed the differences among MGFs from Gutenberg–Bullen A model and two sets of LGFs derived from modified PREM Earth models consolidating with two crust models TEA12 and CRUST1.0, hereafter called PREMTEA and PREMCRU, respectively. Utilizing MGFs and two sets of LGFs, we modeled the corresponding 3D atmospheric loading displacements for 984 ITRF2014 stations and compared them with the ITRF2014 residuals. The results show that LGFs from PREMTEA and PREMCRU perform well in further promoting scatter reduction for ∼72%, ∼56%, and ∼85% of stations for the Up, East and North components, respectively. The improvements for the North components are significant (up to 3.6%). In particular, stations in the east coastal areas of North America and the west edge of Greenland exhibit further promoting scatter reduction for the East components (up to ∼2.5%), while those located in west coastline of North America show better performance for the North components. Nevertheless, there are significant anomalies in northern Europe for PREMCRU, the mutation margin of which should be carefully considered when using a resolution higher than 1°. In the area around station MORP (358.31°W, 55.21°N, sited at coastline of Britain), we suggest using PREMTEA model.
On the Spatial and Temporal Evolution of EMIC Wave‐Driven Relativistic Electron Precipitation: Magnetically Conjugate Observations From the Van Allen Probes and CALET
Authors: Blum L. W. , Bruno A. , Capannolo L. , Ma Q. , Kataoka R. , Torii S. , Baishev D.
Published: February 2024

Electromagnetic ion cyclotron (EMIC) waves have been shown to be able to drive strong electron precipitation, particularly at MeV energies. However, the spatio‐temporal evolution of both the waves and the resulting precipitation is still not well understood. Here we investigate the evolution of relativistic electron precipitation driven by EMIC waves through combined observations from the Van Allen Probes and the CALorimetric Electron Telescope experiment onboard the International Space Station. Two case studies are examined where EMIC waves near the magnetic equator and precipitation at low altitude were detected in close magnetic conjunction, both of which were confined to narrow radial regions but persisted multiple hours. These observations, combined with quasilinear calculations, confirm that long‐lived EMIC waves can drive hours‐long MeV electron precipitation loss. However, the magnitude of the precipitation varied significantly during one of the events, as resonance conditions, particularly plasma density, evolved.
Mantle Structure Beneath the Damara Belt in South‐Central Africa Imaged Using Adaptively Parameterized P‐Wave Tomography
Authors: Saeidi Hesam , Hansen Samantha E. , Nyblade Andrew A. , Haag Ryan
Published: February 2024

Many seismic tomography studies have indicated that the African Large Low Velocity Province (LLVP) extends from the lower mantle beneath southern Africa into the upper mantle beneath eastern Africa; however, it has been questioned whether the LLVP structure may also extend to the north or northwest beneath south‐central Africa. Debates regarding the upper mantle structure beneath the Damara Belt contribute to this uncertainty. Some studies suggest the Damara Belt is underlain by thermally perturbed upper mantle; however, other studies indicate the region is not associated with anomalous structure. Here, we use a comprehensive P‐wave travel‐time data set and an adaptive model parameterization to develop a new tomographic model for the Damara Belt and surrounding regions. Our results show that seismically slow structure beneath the Damara Belt is relegated to depths greater than ∼1,200 km, indicating that the LLVP is not significantly affecting this region. However, further to the northeast, the LLVP structure obliquely rises and crosses the mantle transition zone near the Irumide Belt, where it then extends into the upper mantle. The seismic structure beneath the Damara Belt and neighboring areas in our model correlates well with tectonic observations at the surface, including variations in heat flow, the distribution of geothermal features, the locations of rifts, and estimates of dynamic topography.
System‐Wide Effects of Local Bed Disturbance on the Morphological Evolution of a Bifurcating Channel Network
Authors: Gao Weilun , Shao Dongdong , Wang Zheng Bing , Zhu Zhenchang , Yang Zhifeng
Published: February 2024

Deltaic channel networks are important conduits for water and material supplies to the fluvial and coastal communities. However, increasing human interventions in river deltas have altered the topology and geometry of channel networks as well as their long‐term evolution. While the morphological evolution of a single channel has received extensive studies, the system‐wide morphological responses of channel networks to local disturbances remain largely unclear. Here we investigate the morphological responses of a bifurcating channel network subject to local disturbance of channel deepening due to dredging and sand mining through idealized simulations, and further compare the results with the reference scenarios of a single channel and theoretical analysis of the phase plane. The results show that the infilling of the local deepening is associated with the erosion of the entire branch, which also causes system‐wide effects on the siltation of the other branch. The morphological responses of the bifurcating channel network consist of a relatively short stage for the infilling of the local deepening followed by a relatively long stage for recovering the equilibrium configuration of the river bifurcation. The system‐wide effects of the local disturbance arise from the altered water surface slope and water partitioning downstream of the bifurcation due to the local deepening. Also, the prolonged recovery of the equilibrium configuration is consistent with theoretical analysis, which reveals a slow evolution of the bifurcation when approaching the equilibrium. Our results can help understand the long‐term morphological responses of large‐scale complex channel networks and inform water managements under increasing human interventions.
Road Salt Legacies: Quantifying Fluxes of Chloride to Groundwater and Surface Water Across the Chicago Metropolitan Statistical Area
Authors: Van Meter K. J. , Ceisel E.
Published: February 2024

Freshwater chloride concentrations have been increasing in North American surface waters for decades, largely driven by increases in the use of road salt, which is commonly applied as a deicer. In Chicago, thousands of tons of road salt are applied to roadways each winter, and increases in surface water chloride concentrations have been noted across the region since the mid‐1960s. While much of the applied salt runs directly off to nearby waterways during snowmelt events, some percolates to groundwater, affecting public supply wells and increasing the amount of chloride released to streams as baseflow during the non‐salting season. In the present study we have developed a spatially distributed chloride mass balance across the Chicago Metropolitan Statistical Area (CMSA) for a 30‐year period (1990–2020) to better our understanding of long‐term chloride fluxes and storage. Our results show that inputs of road salt to the region increased by 33% between 1990 and 2020. During this same period, riverine chloride loads across the region increased by 60%. Despite these increases in riverine chloride export, we find that chloride is accumulating in CMSA groundwater at a rate of ∼480 ktons year−1. We show that shallow aquifers, <30 m, exhibit only seasonal chloride storage, without long‐term accumulation. In contrast, at depths below 30 m, we find chloride concentrations to be increasing over time, indicating that legacy chloride is accumulating at deeper depths in CMSA groundwater. The present results highlight the importance of legacy chloride to long‐term water quality dynamics in North American cities.
The c.1617del variant of TMEM260 is identified as the most frequent single gene determinant for Japanese patients with a specific type of congenital heart disease
Authors: Inoue Tadashi , Takase Ryuta , Uchida Keiko , Kodo Kazuki , Suda Kenji , Watanabe Yoriko , Yoshiura Koh-Ichiro , Kunimatsu Masaya , Ishizaki Reina , Azuma Kenko , Inai Kei , Muneuchi Jun , Furutani Yoshiyuki , Akagawa Hiroyuki , Yamagishi Hiroyuki
Published: February 2024

Although the molecular mechanisms underlying congenital heart disease (CHD) remain poorly understood, recent advances in genetic analysis have facilitated the exploration of causative genes for CHD. We reported that the pathogenic variant c.1617del of TMEM260, which encodes a transmembrane protein, is highly associated with CHD, specifically persistent truncus arteriosus (PTA), the most severe cardiac outflow tract (OFT) defect. Using whole-exome sequencing, the c.1617del variant was identified in two siblings with PTA in a Japanese family and in three of the 26 DNAs obtained from Japanese individuals with PTA. The c.1617del of TMEM260 has been found only in East Asians, especially Japanese and Korean populations, and the frequency of this variant in PTA is estimated to be next to that of the 22q11.2 deletion, the most well-known genetic cause of PTA. Phenotype of patients with c.1617del appears to be predominantly in the heart, although TMEM260 is responsible for structural heart defects and renal anomalies syndrome (SHDRA). The mouse TMEM260 variant (p.W535Cfs*56), synonymous with the human variant (p.W539Cfs*9), exhibited truncation and downregulation by western blotting, and aggregation by immunocytochemistry. In situ hybridization demonstrated that Tmem260 is expressed ubiquitously during embryogenesis, including in the development of cardiac OFT implicated in PTA. This expression may be regulated by a ~ 0.8 kb genomic region in intron 3 of Tmem260 that includes multiple highly conserved binding sites for essential cardiac transcription factors, thus revealing that the c.1617del variant of TMEM260 is the major single-gene variant responsible for PTA in the Japanese population.
Stromal thrombospondin 1 suppresses angiogenesis in oral submucous fibrosis
Authors: Yang Xiao , Zhao Hui , Li Rui , Chen Yang , Xu Zhi , Shang Zhengjun
Published: February 2024

A decline in mucosal vascularity is a histological hallmark of oral submucous fibrosis (OSF), a premalignant disease that is largely induced by betel quid chewing. However, the lack of available models has challenged studies of angiogenesis in OSF. Here, we found that the expression of thrombospondin 1 (THBS1), an endogenous angiostatic protein, was elevated in the stroma of tissues with OSF. Using a fibroblast-attached organoid (FAO) model, the overexpression of THBS1 in OSF was stably recapitulated in vitro. In the FAO model, treatment with arecoline, a major pathogenic component in areca nuts, enhanced the secretion of transforming growth factor (TGF)-β1 by epithelial cells, which then promoted the expression of THBS1 in fibroblasts. Furthermore, human umbilical vein endothelial cells (HUVECs) were incorporated into the FAO to mimic the vascularized component. Overexpression of THBS1 in fibroblasts drastically suppressed the sprouting ability of endothelial cells in vascularized FAOs (vFAOs). Consistently, treatment with arecoline reduced the expression of CD31 in vFAOs, and this effect was attenuated when the endothelial cells were preincubated with neutralizing antibody of CD36, a receptor of THBS1. Finally, in an arecoline-induced rat OSF model, THBS1 inhibition alleviated collagen deposition and the decline in vascularity in vivo. Overall, we exploited an assembled organoid model to study OSF pathogenesis and provide a rationale for targeting THBS1.
Mediating effect of fat mass, lean mass, blood pressure and insulin resistance on the associations of accelerometer-based sedentary time and physical activity with arterial stiffness, carotid IMT and carotid elasticity in 1574 adolescents
Authors: Agbaje Andrew O.
Published: February 2024

This study examined the mediating effect of total body fat mass, lean mass, blood pressure (BP) and insulin resistance on the associations of sedentary time (ST), light physical activity (LPA) and moderate-to-vigorous PA (MVPA) with carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT) and carotid elasticity in 1574 adolescents from the Avon Longitudinal Study of Parents and Children birth cohort, UK. ST, LPA and MVPA were assessed with ActiGraph accelerometer. ST and LPA were sex-categorised in tertiles as low (reference), moderate and high, while MVPA was categorised as <40 min/day (reference), 40–<60 min/day and ≥60 min/day. cfPWV, cIMT and carotid elasticity were measured with Vicorder and ultrasound. Fat mass and lean mass were assessed with dual-energy X-ray absorptiometry and homeostatic model assessment of insulin resistance (HOMA-IR) was computed. Mediation analyses structural equation models and linear mixed-effect models adjusted for cardiometabolic and lifestyle factors were conducted. Among 1574 adolescents [56.2% female; mean (SD) age 15.4 (0.24) years], 41% males and 17% females accumulated ≥60 min/day of MVPA. Higher ST was associated with lower cIMT partly mediated by lean mass. Higher LPA (standardized β = −0.057; [95% CI −0.101 to −0.013; p = 0.014]) and the highest LPA tertile were associated with lower cfPWV. BP had no significant mediating effect movement behaviour relations with vascular indices. Lean mass partially mediated associations of higher MVPA with higher cIMT (0.012; [0.007–0.002; p = 0.001], 25.5% mediation) and higher carotid elasticity (0.025; [0.014–0.039; p = 0.001], 28.1% mediation). HOMA-IR mediated the associations of higher MVPA with higher carotid elasticity (7.7% mediation). Engaging in ≥60 min/day of MVPA was associated with higher carotid elasticity. In conclusion, higher LPA was associated with lower arterial stiffness, but higher MVPA was associated with thicker carotid wall explained by higher lean mass.
Light-controlled soft bio-microrobot
Authors: Xiong Jianyun , Li Xing , He Ziyi , Shi Yang , Pan Ting , Zhu Guoshuai , Lu Dengyun , Xin Hongbao
Published: February 2024

Micro/nanorobots hold exciting prospects for biomedical and even clinical applications due to their small size and high controllability. However, it is still a big challenge to maneuver micro/nanorobots into narrow spaces with high deformability and adaptability to perform complicated biomedical tasks. Here, we report a light-controlled soft bio-microrobots (called “Ebot”) based on Euglena gracilis that are capable of performing multiple tasks in narrow microenvironments including intestinal mucosa with high controllability, deformability and adaptability. The motion of the Ebot can be precisely navigated via light-controlled polygonal flagellum beating. Moreover, the Ebot shows highly controlled deformability with different light illumination duration, which allows it to pass through narrow and curved microchannels with high adaptability. With these features, Ebots are able to execute multiple tasks, such as targeted drug delivery, selective removal of diseased cells in intestinal mucosa, as well as photodynamic therapy. This light-controlled Ebot provides a new bio-microrobotic tool, with many new possibilities for biomedical task execution in narrow and complicated spaces where conventional tools are difficult to access due to the lack of deformability and bio-adaptability.
Precise genome-editing in human diseases: mechanisms, strategies and applications
Authors: Zheng Yanjiang , Li Yifei , Zhou Kaiyu , Li Tiange , VanDusen Nathan J. , Hua Yimin
Published: February 2024

Precise genome-editing platforms are versatile tools for generating specific, site-directed DNA insertions, deletions, and substitutions. The continuous enhancement of these tools has led to a revolution in the life sciences, which promises to deliver novel therapies for genetic disease. Precise genome-editing can be traced back to the 1950s with the discovery of DNA’s double-helix and, after 70 years of development, has evolved from crude in vitro applications to a wide range of sophisticated capabilities, including in vivo applications. Nonetheless, precise genome-editing faces constraints such as modest efficiency, delivery challenges, and off-target effects. In this review, we explore precise genome-editing, with a focus on introduction of the landmark events in its history, various platforms, delivery systems, and applications. First, we discuss the landmark events in the history of precise genome-editing. Second, we describe the current state of precise genome-editing strategies and explain how these techniques offer unprecedented precision and versatility for modifying the human genome. Third, we introduce the current delivery systems used to deploy precise genome-editing components through DNA, RNA, and RNPs. Finally, we summarize the current applications of precise genome-editing in labeling endogenous genes, screening genetic variants, molecular recording, generating disease models, and gene therapy, including ex vivo therapy and in vivo therapy, and discuss potential future advances.
Association of emotional and behavioral problems with the development of the substantia nigra, subthalamic nucleus, and red nucleus volumes and asymmetries from childhood to adolescence: A longitudinal cohort study
Authors: Wang Yanpei , Ma Leilei , Wang Jiali , Liu Ningyu , Men Weiwei , Tan Shuping , Gao Jia-Hong , Qin Shaozheng , He Yong , Dong Qi , Tao Sha
Published: February 2024

The substantia nigra (SN), subthalamic nucleus (STN), and red nucleus (RN) have been widely studied as important biomarkers of degenerative diseases. However, how they develop in childhood and adolescence and are affected by emotional behavior has not been studied thus far. This population-based longitudinal cohort study used data from a representative sample followed two to five times. Emotional and behavioral problems were assessed with the Strengths and Difficulties Questionnaire (SDQ). Linear mixed models were used to map developmental trajectories and behavioral regulation. Using an innovative automated image segmentation technique, we quantified the volumes and asymmetries of the SN, STN and RN with 1226 MRI scans of a large longitudinal sample of 667 subjects aged 6–15 years and mapped their developmental trajectories. The results showed that the absolute and relative volumes of the bilateral SN and right STN showed linear increases, while the absolute volume of the right RN and relative volume of the bilateral RN decreased linearly, these effects were not affected by gender. Hyperactivity/inattention weakened the increase in SN volume and reduced the absolute volume of the STN, conduct problems impeded the RN volume from decreasing, and emotional symptoms changed the direction of SN lateralization. This longitudinal cohort study mapped the developmental trajectories of SN, STN, and RN volumes and asymmetries from childhood to adolescence, and found the association of emotional symptoms, conduct problems, and hyperactivity/inattention with these trajectories, providing guidance for preventing and intervening in cognitive and emotional behavioral problems.
A guardian turned rogue: TP53 promoter translocations rewire stress responses to oncogenic effectors in osteosarcoma
Authors: Herold Nikolas
Published: February 2024

Osteosarcoma is the most prevalent malignant bone tumour in children, adolescents and young adults. Despite a multitude of aberrations present in osteosarcoma genomes, no recurrent driver mutations have been identified to date. In addition, unlike for other sarcoma entities, no functional fusion proteins resulting from chromosomal rearrangements have been reported. Part of the genetic complexity of osteosarcoma might, however, be explained by the association of osteosarcoma with germline and somatic mutations of the major tumour suppressor TP53 that safeguards genomic integrity. By demonstrating that TP53 promoter translocations resulting in transcriptionally active fusion genes are a recurrent event in osteosarcoma, long-learnt paradigms are challenged by a recent publication by Saba, Difilippo et al. Osteosarcoma no longer appears to be a fusion-negative tumour, and by hardwiring cellular stress responses that transactivate the TP53 promoter to an oncogenic fusion partner, TP53 can be subverted and turned into an oncogene.
Multimodal detection of molecular residual disease in high-risk locally advanced squamous cell carcinoma of the head and neck
Authors: Sanz-Garcia Enrique , Zou Jinfeng , Avery Lisa , Spreafico Anna , Waldron John , Goldstein David , Hansen Aaron , Cho B. C. John , de Almeida John , Hope Andrew , Hosni Ali , Hahn Ezra , Perez-Ordonez Bayardo , Zhao Zhen , Smith Christopher , Zheng Yangqiao , Singaravelan Nitthusha , Bratman Scott V. , Siu Lillian L.
Published: February 2024

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4–6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection.
Single-cell multi-omics analysis of lineage development and spatial organization in the human fetal cerebellum
Authors: Yang Fuqiang , Zhao Ziqi , Zhang Dan , Xiong Yu , Dong Xinran , Wang Yuchen , Yang Min , Pan Taotao , Liu Chuanyu , Liu Kaiyi , Lin Yifeng , Liu Yongjie , Tu Qiang , Dang Yashan , Xia Mingyang , Mi Da , Zhou Wenhao , Xu Zhiheng
Published: February 2024

Human cerebellum encompasses numerous neurons, exhibiting a distinct developmental paradigm from cerebrum. Here we conducted scRNA-seq, scATAC-seq and spatial transcriptomic analyses of fetal samples from gestational week (GW) 13 to 18 to explore the emergence of cellular diversity and developmental programs in the developing human cerebellum. We identified transitory granule cell progenitors that are conserved across species. Special patterns in both granule cells and Purkinje cells were dissected multidimensionally. Species-specific gene expression patterns of cerebellar lobes were characterized and we found that PARM1 exhibited inconsistent distribution in human and mouse granule cells. A novel cluster of potential neuroepithelium at the rhombic lip was identified. We also resolved various subtypes of Purkinje cells and unipolar brush cells and revealed gene regulatory networks controlling their diversification. Therefore, our study offers a valuable multi-omics landscape of human fetal cerebellum and advances our understanding of development and spatial organization of human cerebellum.
Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice
Authors: Ranjbarvaziri Sara , Zeng Aliya , Wu Iris , Greer-Short Amara , Farshidfar Farshad , Budan Ana , Xu Emma , Shenwai Reva , Kozubov Matthew , Li Cindy , Van Pell Melissa , Grafton Francis , MacKay Charles E , Song Xiaomei , Priest James R , Argast Gretchen , Mandegar Mohammad A. , Hoey Timothy , Yang Jin
Published: February 2024

Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6’s role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in male HFpEF mouse models. Additionally, in male mice lacking Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018’s effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts on heart pathophysiology and is a promising target for HFpEF treatment.
NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress
Authors: Han Joo-Hui , Karki Rajendra , Malireddi R. K. Subbarao , Mall Raghvendra , Sarkar Roman , Sharma Bhesh Raj , Klein Jonathon , Berns Harmut , Pisharath Harshan , Pruett-Miller Shondra M. , Bae Sung-Jin , Kanneganti Thirumala-Devi
Published: February 2024

Innate immunity provides the first line of defense through multiple mechanisms, including pyrogen production and cell death. While elevated body temperature during infection is beneficial to clear pathogens, heat stress (HS) can lead to inflammation and pathology. Links between pathogen exposure, HS, cytokine release, and inflammation have been observed, but fundamental innate immune mechanisms driving pathology during pathogen exposure and HS remain unclear. Here, we use multiple genetic approaches to elucidate innate immune pathways in infection or LPS and HS models. Our results show that bacteria and LPS robustly increase inflammatory cell death during HS that is dependent on caspase-1, caspase-11, caspase-8, and RIPK3 through the PANoptosis pathway. Caspase-7 also contributes to PANoptosis in this context. Furthermore, NINJ1 is an important executioner of this cell death to release inflammatory molecules, independent of other pore-forming executioner proteins, gasdermin D, gasdermin E, and MLKL. In an in vivo HS model, mortality is reduced by deleting NINJ1 and fully rescued by deleting key PANoptosis molecules. Our findings suggest that therapeutic strategies blocking NINJ1 or its upstream regulators to prevent PANoptosis may reduce the release of inflammatory mediators and benefit patients.
Transfer learning with graph neural networks for improved molecular property prediction in the multi-fidelity setting
Authors: Buterez David , Janet Jon Paul , Kiddle Steven J. , Oglic Dino , Lió Pietro
Published: February 2024

We investigate the potential of graph neural networks for transfer learning and improving molecular property prediction on sparse and expensive to acquire high-fidelity data by leveraging low-fidelity measurements as an inexpensive proxy for a targeted property of interest. This problem arises in discovery processes that rely on screening funnels for trading off the overall costs against throughput and accuracy. Typically, individual stages in these processes are loosely connected and each one generates data at different scale and fidelity. We consider this setup holistically and demonstrate empirically that existing transfer learning techniques for graph neural networks are generally unable to harness the information from multi-fidelity cascades. Here, we propose several effective transfer learning strategies and study them in transductive and inductive settings. Our analysis involves a collection of more than 28 million unique experimental protein-ligand interactions across 37 targets from drug discovery by high-throughput screening and 12 quantum properties from the dataset QMugs. The results indicate that transfer learning can improve the performance on sparse tasks by up to eight times while using an order of magnitude less high-fidelity training data. Moreover, the proposed methods consistently outperform existing transfer learning strategies for graph-structured data on drug discovery and quantum mechanics datasets.
MarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution
Authors: Mertens Till Fabian , Liebheit Alina Tabea , Ehl Johanna , Köhler Ralf , Rakhymzhan Asylkhan , Woehler Andrew , Katthän Lukas , Ebel Gernot , Liublin Wjatscheslaw , Kasapi Ana , Triantafyllopoulou Antigoni , Schulz Tim Julius , Niesner Raluca Aura , Hauser Anja Erika
Published: February 2024

Analyzing immune cell interactions in the bone marrow is vital for understanding hematopoiesis and bone homeostasis. Three-dimensional analysis of the complete, intact bone marrow within the cortex of whole long bones remains a challenge, especially at subcellular resolution. We present a method that stabilizes the marrow and provides subcellular resolution of fluorescent signals throughout the murine femur, enabling identification and spatial characterization of hematopoietic and stromal cell subsets. By combining a pre-processing algorithm for stripe artifact removal with a machine-learning approach, we demonstrate reliable cell segmentation down to the deepest bone marrow regions. This reveals age-related changes in the marrow. It highlights the interaction between CX3CR1+ cells and the vascular system in homeostasis, in contrast to other myeloid cell types, and reveals their spatial characteristics after injury. The broad applicability of this method will contribute to a better understanding of bone marrow biology.
CCl4 emissions in eastern China during 2021–2022 and exploration of potential new sources
Authors: Li Bowei , Huang Jiahuan , Hu Xiaoyi , Zhang Lulu , Ma Mengyue , Hu Liting , Chen Di , Du Qianna , Sun Yahui , Cai Zhouxiang , Chen Ao , Li Xinhe , Feng Rui , Prinn Ronald G. , Fang Xuekun
Published: February 2024

According to the Montreal Protocol, the production and consumption of ozone-layer-depleting CCl4 for dispersive applications was globally phased out by 2010, including China. However, continued CCl4 emissions were disclosed, with the latest CCl4 emissions unknown in eastern China. In the current study, based on the atmospheric measurements of ~12,000 air samples taken at two sites in eastern China, the 2021–2022 CCl4 emissions are quantified as 7.6 ± 1.7 gigagrams per year. This finding indicates that CCl4 emissions continued after being phased out for dispersive uses in 2010. Subsequently, our study identifies potential industrial sources (manufacture of general purpose machinery and manufacture of raw chemical materials, and chemical products) of CCl4 emissions.
Phase-selective in-plane heteroepitaxial growth of H-phase CrSe2
Authors: Liu Meizhuang , Gou Jian , Liu Zizhao , Chen Zuxin , Ye Yuliang , Xu Jing , Xu Xiaozhi , Zhong Dingyong , Eda Goki , Wee Andrew T. S.
Published: February 2024

Phase engineering of two-dimensional transition metal dichalcogenides (2D-TMDs) offers opportunities for exploring unique phase-specific properties and achieving new desired functionalities. Here, we report a phase-selective in-plane heteroepitaxial method to grow semiconducting H-phase CrSe2. The lattice-matched MoSe2 nanoribbons are utilized as the in-plane heteroepitaxial template to seed the growth of H-phase CrSe2 with the formation of MoSe2-CrSe2 heterostructures. Scanning tunneling microscopy and non-contact atomic force microscopy studies reveal the atomically sharp heterostructure interfaces and the characteristic defects of mirror twin boundaries emerging in the H-phase CrSe2 monolayers. The type-I straddling band alignments with band bending at the heterostructure interfaces are directly visualized with atomic precision. The mirror twin boundaries in the H-phase CrSe2 exhibit the Tomonaga-Luttinger liquid behavior in the confined one-dimensional electronic system. Our work provides a promising strategy for phase engineering of 2D TMDs, thereby promoting the property research and device applications of specific phases.
Transient disome complex formation in native polysomes during ongoing protein synthesis captured by cryo-EM
Authors: Flügel Timo , Schacherl Magdalena , Unbehaun Anett , Schroeer Birgit , Dabrowski Marylena , Bürger Jörg , Mielke Thorsten , Sprink Thiemo , Diebolder Christoph A. , Guillén Schlippe Yollete V. , Spahn Christian M. T.
Published: February 2024

Structural studies of translating ribosomes traditionally rely on in vitro assembly and stalling of ribosomes in defined states. To comprehensively visualize bacterial translation, we reactivated ex vivo-derived E. coli polysomes in the PURE in vitro translation system and analyzed the actively elongating polysomes by cryo-EM. We find that 31% of 70S ribosomes assemble into disome complexes that represent eight distinct functional states including decoding and termination intermediates, and a pre-nucleophilic attack state. The functional diversity of disome complexes together with RNase digest experiments suggests that paused disome complexes transiently form during ongoing elongation. Structural analysis revealed five disome interfaces between leading and queueing ribosomes that undergo rearrangements as the leading ribosome traverses through the elongation cycle. Our findings reveal at the molecular level how bL9’s CTD obstructs the factor binding site of queueing ribosomes to thwart harmful collisions and illustrate how translation dynamics reshape inter-ribosomal contacts.
Distance effect of single atoms on stability of cobalt oxide catalysts for acidic oxygen evolution
Authors: Zhang Zhirong , Jia Chuanyi , Ma Peiyu , Feng Chen , Yang Jin , Huang Junming , Zheng Jiana , Zuo Ming , Liu Mingkai , Zhou Shiming , Zeng Jie
Published: February 2024

Developing efficient and economical electrocatalysts for acidic oxygen evolution reaction (OER) is essential for proton exchange membrane water electrolyzers (PEMWE). Cobalt oxides are considered promising non-precious OER catalysts due to their high activities. However, the severe dissolution of Co atoms in acid media leads to the collapse of crystal structure, which impedes their application in PEMWE. Here, we report that introducing acid-resistant Ir single atoms into the lattice of spinel cobalt oxides can significantly suppress the Co dissolution and keep them highly stable during the acidic OER process. Combining theoretical and experimental studies, we reveal that the stabilizing effect induced by Ir heteroatoms exhibits a strong dependence on the distance of adjacent Ir single atoms, where the OER stability of cobalt oxides continuously improves with decreasing the distance. When the distance reduces to about 0.6 nm, the spinel cobalt oxides present no obvious degradation over a 60-h stability test for acidic OER, suggesting potential for practical applications.
Shaping high-performance wearable robots for human motor and sensory reconstruction and enhancement
Authors: Xia Haisheng , Zhang Yuchong , Rajabi Nona , Taleb Farzaneh , Yang Qunting , Kragic Danica , Li Zhijun
Published: February 2024

Most wearable robots such as exoskeletons and prostheses can operate with dexterity, while wearers do not perceive them as part of their bodies. In this perspective, we contend that integrating environmental, physiological, and physical information through multi-modal fusion, incorporating human-in-the-loop control, utilizing neuromuscular interface, employing flexible electronics, and acquiring and processing human-robot information with biomechatronic chips, should all be leveraged towards building the next generation of wearable robots. These technologies could improve the embodiment of wearable robots. With optimizations in mechanical structure and clinical training, the next generation of wearable robots should better facilitate human motor and sensory reconstruction and enhancement.
Conserved molecular chaperone PrsA stimulates protective immunity against group A Streptococcus
Authors: Lai Chien-Yu , Xie Jia-Xun , Lai Meng-Chih , Wu Zhao-Yi , Lin Jr-Shiuan , Huang Yu-Tsung , Chi Chia-Yu , Chiang-Ni Chuan , Walker Mark J. , Chang Yung-Chi
Published: February 2024

Group A Streptococcus (GAS) is a significant human pathogen that poses a global health concern. However, the development of a GAS vaccine has been challenging due to the multitude of diverse M-types and the risk of triggering cross-reactive immune responses. Our previous research has identified a critical role of PrsA1 and PrsA2, surface post-translational molecular chaperone proteins, in maintaining GAS proteome homeostasis and virulence traits. In this study, we aimed to further explore the potential of PrsA1 and PrsA2 as vaccine candidates for preventing GAS infection. We found that PrsA1 and PrsA2 are highly conserved among GAS isolates, demonstrating minimal amino acid variation. Antibodies specifically targeting PrsA1/A2 showed no cross-reactivity with human heart proteins and effectively enhanced neutrophil opsonophagocytic killing of various GAS serotypes. Additionally, passive transfer of PrsA1/A2-specific antibodies conferred protective immunity in infected mice. Compared to alum, immunization with CFA-adjuvanted PrsA1/A2 induced higher levels of Th1-associated IgG isotypes and complement activation and provided approximately 70% protection against invasive GAS challenge. These findings highlight the potential of PrsA1 and PrsA2 as universal vaccine candidates for the development of an effective GAS vaccine.
Automated model building and protein identification in cryo-EM maps
Authors: Jamali Kiarash , Käll Lukas , Zhang Rui , Brown Alan , Kimanius Dari , Scheres Sjors H. W.
Published: February 2024

Interpreting electron cryo-microscopy (cryo-EM) maps with atomic models requires high levels of expertise and labour-intensive manual intervention in three-dimensional computer graphics programs1,2. Here we present ModelAngelo, a machine-learning approach for automated atomic model building in cryo-EM maps. By combining information from the cryo-EM map with information from protein sequence and structure in a single graph neural network, ModelAngelo builds atomic models for proteins that are of similar quality to those generated by human experts. For nucleotides, ModelAngelo builds backbones with similar accuracy to those built by humans. By using its predicted amino acid probabilities for each residue in hidden Markov model sequence searches, ModelAngelo outperforms human experts in the identification of proteins with unknown sequences. ModelAngelo will therefore remove bottlenecks and increase objectivity in cryo-EM structure determination.
The Dresden in vivo OCT dataset for automatic middle ear segmentation
Authors: Liu Peng , Steuer Svea , Golde Jonas , Morgenstern Joseph , Hu Yujia , Schieffer Catherina , Ossmann Steffen , Kirsten Lars , Bodenstedt Sebastian , Pfeiffer Micha , Speidel Stefanie , Koch Edmund , Neudert Marcus
Published: February 2024

Endoscopic optical coherence tomography (OCT) offers a non-invasive approach to perform the morphological and functional assessment of the middle ear in vivo. However, interpreting such OCT images is challenging and time-consuming due to the shadowing of preceding structures. Deep neural networks have emerged as a promising tool to enhance this process in multiple aspects, including segmentation, classification, and registration. Nevertheless, the scarcity of annotated datasets of OCT middle ear images poses a significant hurdle to the performance of neural networks. We introduce the Dresden in vivo OCT Dataset of the Middle Ear (DIOME) featuring 43 OCT volumes from both healthy and pathological middle ears of 29 subjects. DIOME provides semantic segmentations of five crucial anatomical structures (tympanic membrane, malleus, incus, stapes and promontory), and sparse landmarks delineating the salient features of the structures. The availability of these data facilitates the training and evaluation of algorithms regarding various analysis tasks with middle ear OCT images, e.g. diagnostics.
Comparison of online, offline, and hybrid hypotheses of motor sequence learning using a quantitative model that incorporate reactive inhibition
Authors: Gupta Mohan W. , Rickard Timothy C.
Published: February 2024

Two hypotheses have been advanced for when motor sequence learning occurs: offline between bouts of practice or online concurrently with practice. A third possibility is that learning occurs both online and offline. A complication for differentiating between those hypotheses is a process known as reactive inhibition, whereby performance worsens over consecutively executed sequences, but dissipates during breaks. We advance a new quantitative modeling framework that incorporates reactive inhibition and in which the three learning accounts can be implemented. Our results show that reactive inhibition plays a far larger role in performance than is appreciated in the literature. Across four groups of participants in which break times and correct sequences per trial were varied, the best overall fits were provided by a hybrid model. The version of the offline model that does not account for reactive inhibition, which is widely assumed in the literature, had the worst fits. We discuss implications for extant hypotheses and directions for future research.
First isolation and genotyping of pathogenic Leptospira spp. from Austria
Authors: Sohm Cynthia , Willixhofer Denise , Fasching Eva , Waldner Karoline , Deitzer Nicole , Steiner Janina , Jöbstl Julia , Schleicher Corina , Schwarz Marcel , Fuchs Reinhard , Bourhy Pascale , Käsbohrer Annemarie , Wittek Thomas , Firth Clair , Steinparzer Romana , Desvars-Larrive Amélie
Published: February 2024

Leptospirosis is a globally distributed zoonotic disease. The standard serological test, known as Microscopic Agglutination Test (MAT), requires the use of live Leptospira strains. To enhance its sensitivity and specificity, the usage of locally circulating strains is recommended. However, to date, no local strain is available from Austria. This study aimed to isolate circulating Leptospira strains from cattle in Austria to enhance the performances of the routine serological test for both humans and animals. We used a statistical approach combined with a comprehensive literature search to profile cattle with greater risk of leptospirosis infection and implemented a targeted sampling between November 2021 and October 2022. Urine and/or kidney tissue were sampled from 410 cattle considered at higher risk of infection. Samples were inoculated into EMJH-STAFF culture media within 2–6 h and a real-time PCR targeting the lipL32 gene was used to confirm the presence/absence of pathogenic Leptospira in each sample. Isolates were further characterised by core genome multilocus sequence typing (cgMLST). Nine out of 429 samples tested positive by PCR, from which three isolates were successfully cultured and identified as Leptospira borgpetersenii serogroup Sejroe serovar Hardjobovis, cgMLST cluster 40. This is the first report on the isolation and genotyping of local zoonotic Leptospira in Austria, which holds the potential for a significant improvement in diagnostic performance in the country. Although the local strain was identified as a cattle-adapted serovar, it possesses significant zoonotic implications. Furthermore, this study contributes to a better understanding of the epidemiology of leptospirosis in Europe.