bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding individual health-related social needs in the context of area-level social determinants of health: The case for granularity
Authors: Telzak Andrew , Levano Samantha , Haughton Jessica , Chambers Earle C. , Fiori Kevin P.
Published: April 2024

Introduction:

Screening for health-related social needs (HRSNs) within health systems is a widely accepted recommendation, however challenging to implement. Aggregate area-level metrics of social determinants of health (SDoH) are easily accessible and have been used as proxies in the interim. However, gaps remain in our understanding of the relationships between these measurement methodologies. This study assesses the relationships between three area-level SDoH measures, Area Deprivation Index (ADI), Social Deprivation Index (SDI) and Social Vulnerability Index (SVI), and individual HRSNs among patients within one large urban health system.

Methods:

Patients screened for HRSNs between 2018 and 2019 (N = 45,312) were included in the analysis. Multivariable logistic regression models assessed the association between area-level SDoH scores and individual HRSNs. Bivariate choropleth maps displayed the intersection of area-level SDoH and individual HRSNs, and the sensitivity, specificity, and positive and negative predictive values of the three area-level metrics were assessed in relation to individual HRSNs.

Results:

The SDI and SVI were significantly associated with HRSNs in areas with high SDoH scores, with strong specificity and positive predictive values (∼83% and ∼78%) but poor sensitivity and negative predictive values (∼54% and 62%). The strength of these associations and predictive values was poor in areas with low SDoH scores.

Conclusions:

While limitations exist in utilizing area-level SDoH metrics as proxies for individual social risk, understanding where and how these data can be useful in combination is critical both for meeting the immediate needs of individuals and for strengthening the advocacy platform needed for resource allocation across communities.
The military-strategic rationality of hybrid warfare: Everyday total defence under strategic non-peace in the case of Sweden
Authors: Ljungkvist Kristin
Published: April 2024

This article explores the emergence of new military-strategic rationalities in relation to conceptions of hybrid warfare in the grey zone through a case study of Sweden’s reinstatement of total defence since 2015. Through a governmentality-inspired approach, I analyse what it means for the organisation of a new total defence when one of the main threats to be dealt with is daily antagonistic but highly ambiguous hybrid attacks. I illustrate how conceptions of an ambiguous strategic non-peace entails a move beyond war preparedness into urgent demands for an everyday active total defence that hinges on a ‘martialisation’ of civilian life. This in turn run the risk of challenging fundamental democratic principles and civil liberties. The analysis contributes to an increased understanding and uncovering of the politics made possible by a military-strategic rationality geared towards hybrid threats in the grey zone – which in the Swedish case has resulted in a historically specific version of total defence that builds on a highly diffused and rather extreme form of decentralised defence.
Association between cortical thickness or surface area and divergent thinking in patients with bipolar disorder
Authors: Tu Pei-Chi , Chang Wan-Chen , Kuan Yi-Hsuan , Chen Mu-Hong , Su Tung-Ping
Published: April 2024

Objective:

Divergent thinking is a critical creative cognitive process. Its neural mechanisms have been well-studied through structural and functional imaging in healthy individuals but are less explored in patients with bipolar disorder (BD). Because of the traditional link between creativity and BD, this study investigated the structural correlates of divergent thinking in patients with BD through surface-based morphometry.

Methods:

Fifty-nine patients diagnosed with BD I or BD II (35.3 ± 8.5 years) and 56 age- and sex-matched controls (33.9 ± 7.4 years) were recruited. The participants underwent structural magnetic resonance imaging and an evaluation of divergent thinking by using the Chinese version of the Abbreviated Torrance Test for Adults (ATTA). FreeSurfer 7.0 was used to generate thickness and surface area maps for each participant. Brainwise regression of the association between cortical thickness or surface area and ATTA performance was conducted using general linear models.

Results:

Divergent thinking performance did not differ significantly between the patients with BD and the healthy controls. In these patients, total ATTA score was negatively correlated with cortical thickness in the right middle frontal gyrus, right occipital, and left precuneus but positively correlated with the surface area of the right superior frontal gyrus. By contrast, total ATTA scores and cortical thickness or surface area were not significantly correlated among the controls.

Conclusion:

The findings indicate that divergent thinking involves cerebral structures for executive control, mental imagery, and visual processing in patients with BD, and the right prefrontal cortex might be the most crucial of these structures.
The Okubo–Weiss-type topological criteria in two-dimensional magnetohydrodynamic flows
Authors: Shivamoggi B.K. , van Heijst G.J.F. , Kamp L.P.J.
Published: April 2024

The Okubo–Weiss (Okubo, Deep-Sea Res., vol. 17, issue 3, 1970, pp. 445–454; Weiss, Physica D, vol. 48, issue 2, 1991, pp. 273–294) criterion has been widely used as a diagnostic tool to divide a two-dimensional (2-D) hydrodynamical flow field into hyperbolic and elliptic regions. This paper considers extension of these ideas to 2-D magnetohydrodynamic (MHD) flows, and presents an Okubo–Weiss-type criterion to parameterize the magnetic field topology in 2-D MHD flows. This ensues via its topological connections with the intrinsic metric properties of the underlying magnetic flux manifold, and is illustrated by recasting the Okubo–Weiss-type criterion via the 2-D MHD stationary generalized Alfvénic state condition to approximate the slow-flow-variation ansatz imposed in its derivation. The Okubo–Weiss-type parameter then turns out to be related to the sign definiteness of the Gaussian curvature of the magnetic flux manifold. A similar formulation becomes possible for 2-D electron MHD flows, by using the generalized magnetic flux framework to incorporate the electron-inertia effects. Numerical simulations of quasi-stationary vortices in 2-D MHD flows in the decaying turbulence regime are then given to demonstrate that the Okubo–Weiss-type criterion is able to separate the MHD flow field into elliptic and hyperbolic field configurations very well.
Termitaria enhance soil and forest diversity in Deciduous Dipterocarp Forest, Northern Thailand
Authors: Kaewfoo Manop , Bunyavejchewin Sarayudh , Marod Dokrak , Wiwatwittaya Decha , Baillie Ian C. , Davies Stuart J. , Hallett Stephen H.
Published: April 2024

We characterised the soils and vegetation in 15 sets of four quadrats on and around mounds of Macrotermes annandalei (Isoptera, Macrotermitinae) on a plain of deep dystric clay over limestone in Deciduous Dipterocarp Forest in Northern Thailand. Termites have excavated the mounds from the deep calcareous substrate. The mound soils have darker subsoils, larger contents of clays and exchangeable cations, and higher pH values than the surrounding dystric clay loams. The thickets on the mounds are visually different from the surrounding Deciduous Dipterocarp Forest. They have few dipterocarps and are floristically similar to the regionally important Mixed Deciduous Forest. The clear visual differences are confirmed by floristic similarity, cluster, and canonical correspondence analyses for each of the tree, sapling and seedling size classes. The differences between the mound clays and surrounding red clay loams and the associations between soil and forest types are confirmed by ‘t tests’ and the significant correlations of the soil base status with the main floristic axis of the canonical correspondence analyses. Soil variability due to termites and other agents of pedoturbation can significantly contribute to short-range floristic and structural diversity in some dry tropical forests.
A genetically related cluster of Salmonella Typhimurium cases in humans associated with ruminant livestock and related food chains, United Kingdom, August 2021–December 2022
Authors: Merrick Rachel , Pulford Caisey , Rubeshkumar Polani , Seyan Parnam , Fina Laia , Sawyer Clare , Pacchiarini Nicole , Pollock Carrie , Lighthill Jonathan , Potter Tina , Harvey Nathan , Thomas Kara , Lloyd Daniel , Gherman Iulia , Mackintosh Adrienne , Lawes Joanna , Snow Lucy , Waldram Alison , Larkin Lesley , Balasegaram Sooria , Painset Anais , McCormick Jacquelyn , Elson Richard , Browning Lynda , Williams Christopher , Andrew Rachel , Mably Susan , Thomas Daniel
Published: April 2024

Following an outbreak of Salmonella Typhimurium in Wales in July 2021 associated with sheep meat and offal, further genetically related cases were detected across the UK. Cases were UK residents with laboratory-confirmed Salmonella Typhimurium in the same 5-single-nucleotide polymorphism (SNP) single-linkage cluster with specimen date between 01/08/2021–2031/12/2022. We described cases using routine (UK) and enhanced (Wales only) surveillance data. Exposures in cases in Wales were compared with non-Typhimurium Salmonella case–controls. Environmental Health Practitioners and the Food Standards Agency investigated supply chains of food premises reported by ≥2 cases. Animal, carcass, and environmental samples taken for diagnostic or monitoring purposes for gastrointestinal pathogens were included in microbiological investigations. We identified 142 cases: 75% in England, 23% in Wales and 3% in Scotland. Median age was 32 years, and 59% were male. Direct contact with sheep was associated with becoming a case (aOR: 14, 95%CI: 1.4–145) but reported by few (6/32 cases). No single food item, premises, or supplier linked all cases. Multi-agency collaboration enabled the identification of isolates in the same 5-SNP single-linkage cluster from a sheep carcass at an English abattoir and in ruminant, wildlife, poultry, and environmental samples, suggesting multiple vehicles and pathways of infection.
Guidelines for the Provision of Remote Psychological	Services
Authors: Geraldo Andreia , Dores Artemisa Rocha , Mendes-Santos Cristina , Barbosa Fernando
Published: April 2024

Abstract: Albeit the benefits of delivering psychological services remotely using digital technologies (eMental Health) were established in the literature in the past years, its integration into clinical practice was slow. The COVID-19 pandemic marked an abrupt change, with eMental Health being almost the only way to provide psychological support worldwide. New competencies were demanded from psychologists, accompanied by a growing number of guidelines to support their practices. This work’s main goal was to summarize the available guidelines for the practice of remote psychological services. A scoping literature review was conducted until March 2022. All documents that provided guidelines for the remote provision of psychological services were analyzed. A deductive thematic analysis, followed by an inductive thematic analysis, was conducted. The most unanimous result was the importance of incorporating the guidelines available for the presential provision of psychological services in eMental Health services. Additional procedures were suggested, namely, to ensure the privacy and security of the information, therapeutic boundaries and therapeutic setting, and the safety of the clients. Furthermore, aspects such as risk assessment and management, managing interruptions and exits in sessions, multicultural competence of psychologists, and specificities of remote psychological assessment shall be considered before beginning the therapeutic process. This scoping review presents a summary of the available guidelines for the provision of remote psychological services and can be used by Psychologists to make informed decisions regarding their remote practices. It highlights the need to develop specific competencies related to the remote environment, which reinforces the need for formal training and adapting the training curricula of new psychologists.
Projecting Global Mercury Emissions and Deposition Under the Shared Socioeconomic Pathways
Authors: Geyman Benjamin M. , Streets David G. , Thackray Colin P. , Olson Christine L. , Schaefer Kevin , Sunderland Elsie M.
Published: April 2024

Mercury (Hg) is a naturally occurring element that has been greatly enriched in the environment by human activities like mining and fossil fuel combustion. Despite commonalities in some carbon dioxide (CO2) and Hg emission sources, the implications of long‐range climate scenarios for anthropogenic Hg emissions have yet to be explored. Here, we present comprehensive projections of anthropogenic Hg emissions extending to the year 2300 and evaluate impacts on global atmospheric Hg deposition. Projections are based on four Shared Socioeconomic Pathways (SSPs) ranging from sustainable reductions in resource and energy intensity to rapid economic growth driven by abundant fossil fuel exploitation. There is a greater than two‐fold difference in cumulative anthropogenic Hg emissions between the lower‐bound (110 Gg) and upper‐bound (235 Gg) scenarios. Hg releases to land and water are approximately six times those of direct emissions to air (600–1,470 Gg). At their peak, anthropogenic Hg emissions reach 2,200–2,600 Mg a−1 sometime between 2010 (baseline) and 2030, depending on the SSP scenario. Coal combustion is the largest determinant of differences in Hg emissions among scenarios. Decoupling of Hg and CO2 emission sources occurs under low‐to mid‐range scenarios, though contributions from artisanal and small‐scale gold mining remain uncertain. Future Hg emissions may have lower gaseous elemental Hg (Hg0) and higher divalent Hg (HgII), resulting in a higher fraction of locally sourced Hg deposition. Projected reemissions of previously deposited anthropogenic Hg follow a similar temporal trajectory to primary emissions, amplifying the benefits of primary Hg emission reductions under the most stringent mitigation scenarios.
Improving Mercury Systematics With Molybdenum and Vanadium Enrichments: New Insights From the Cambrian‐Ordovician Boundary
Authors: Bian Leibo , Chappaz Anthony , Wang Xiaomei , Amouroux David , Schovsbo Niels Hemmingsen , Zheng Xiaowei , Sanei Hamed
Published: April 2024

The Cambro‐Ordovician interval marks a significant transition from extinction to bio‐diversification in deep time. However, the relationship of bio‐transition to volcanism, commonly characterized by mercury (Hg) systematics in sedimentary records, has not been examined. We present the first Cambro‐Ordovician Hg systematics from the Scandinavian Alum Shale. Our results show pronounced Furongian Hg enrichments, coupled with positive Δ199Hg, Δ200Hg, and Δ201Hg values and negative Δ204Hg values that we ascribe to atmospheric Hg transport over long‐distances, while Early Ordovician Hg anomalies, characterized by near‐zero mass‐independent isotope values, indicative of submarine source. Our findings are supported by two new proxies: molybdenum‐Hg and vanadium‐δ202Hg co‐variations, demonstrating Hg systematics were strongly influenced by changes in source and depositional conditions. Constrained by a synchronous atmospheric‐tectonic‐oceanic model, we hypothesize Furongian subaerial volcanism contributed to global extinction and oceanic anoxia, whereas Early Ordovician submarine volcanism concurrent with ocean water upwelling promoted the nascent bio‐diversification.
Characteristics of Daytime‐And‐Nighttime AOD Differences Over China: A Perspective From CALIOP Satellite Observations and GEOS‐Chem Model Simulations
Authors: Jiang Xiaodong , Wang Yi , Wang Lunche , Tao Minghui , Wang Jun , Zhou Meng , Bai Xuehui , Gui Lu
Published: April 2024

We use the GEOS‐Chem chemistry transport model to quantify the factors in the diel discrepancy of Aerosol Optical Depth (AOD) retrieved from Cloud‐Aerosol Lidar with Orthogonal Polarization (CALIOP) satellite observations over eastern China. The GEOS‐Chem simulation reveals that the AOD below 1 km is 58.5% larger at night than during the daytime, which is comparable to the counterpart of 41.3% from CALIOP (v4.2). Model sensitivity simulations show that the diurnal variation in wind barely impacts the AOD difference between daytime and nighttime, and the increase in AOD at nighttime is primarily caused by the lower temperature at nighttime compared to daytime. Further simulations demonstrate that the low temperature at night increases AOD primarily by increasing relative humidity, and hence particle hygroscopic growth, while the effect of temperature on chemical rate barely influences AOD. CALIOP also observes that the absolute difference in AOD above 1 km between nighttime and daytime is 0.105, while the counterpart in GEOS‐Chem simulations is −0.031. This contrast can be partly explained by the factor that the percentage of valid CALIOP retrievals below 5 km is 15%–20% greater at nighttime than in the daytime due to the CALIOP detection limit. Removing the detection limit impact decreases the difference in the CALIOP AOD above 1 km between nighttime and daytime to 0.073.
Glacier‐Fed Lakes Are Significant Sinks of Carbon Dioxide in the Southeastern Tibetan Plateau
Authors: Zhu Meizhuang , Kuang Xingxing , Song Chunlin , Feng Yuqing , He Qiule , Zou Yiguang , Zhou Hui , Zheng Chunmiao
Published: April 2024

Dissolved inorganic carbon (DIC) sources, transportation, and transition in inland water bodies have been intensively studied due to their important role in the global carbon cycle. While glacier‐fed lakes play a crucial role in global carbon cycling, related studies are limited. In this study, we investigated the spatiotemporal variability of DIC in the maritime glacier‐fed lakes of the southeastern Tibetan Plateau, identifying the carbon sources and potential controlling factors of DIC pathways The results revealed significant temporal variations in DIC and δ13C‐DIC, with averages of 7.29 ± 0.45 mg C L−1 and –8.6 ± 0.2‰ in summer, and 3.40 ± 0.54 mg C L−1 and –7.4 ± 0.6‰ in winter, respectively. Temporal variations in DIC and δ13C‐DIC were mainly controlled by carbonates weathering and silicate weathering processes. The chemical weathering reactions facilitate the consumption of dissolved CO2. Undersaturated pCO2 (120.02 ± 29.18 μatm) relative to atmospheric equilibrium suggests considerable capacity for CO2 uptake within glacier‐fed lakes system. We estimated that the maritime glacier‐fed lakes in the southeastern Tibetan Plateau absorb a total of 9.6 ± 2.7 × 10−3 Tg C‐CO2 yr−1, highlighting their significant contribution to the global carbon budget. The distinctive landscape of the glacier‐fed system and the vulnerable weathering environment result in seasonal and spatial variations of DIC concentration and δ13C‐DIC values, as well as the chemical weathering‐induced CO2 sink in glacier regions. Given the accelerated glacier retreat observed in this area, further studies on the temporal variability of DIC in the water column are urgently needed to identify the mechanisms driving the biogeochemical reactions inside glacier‐fed lake. Our study highlights the unrecognized role of maritime glacier‐fed lakes as CO2 sinks and emphasizes their significance in regional carbon budgets.
Recreating Observed Convection‐Generated Gravity Waves From Weather Radar Observations via a Neural Network and a Dynamical Atmospheric Model
Authors: Kruse C. G. , Alexander M. J. , Bramberger M. , Chattopadhyay A. , Hassanzadeh P. , Green B. , Grimsdell A. , Hoffmann L.
Published: April 2024

Convection‐generated gravity waves (CGWs) transport momentum and energy, and this momentum is a dominant driver of global features of Earth's atmosphere's general circulation (e.g., the quasi‐biennial oscillation, the pole‐to‐pole mesospheric circulation). As CGWs are not generally resolved by global weather and climate models, their effects on the circulation need to be parameterized. However, quality observations of GWs are spatiotemporally sparse, limiting understanding and preventing constraints on parameterizations. Convection‐permitting or ‐resolving simulations do generate CGWs, but validation is not possible as these simulations cannot reproduce the CGW‐forcing convection at correct times, locations, and intensities. Here, realistic convective diabatic heating, learned from full‐physics convection‐permitting Weather Research and Forecasting simulations, is predicted from weather radar observations using neural networks and a previously developed look‐up table. These heating rates are then used to force an idealized GW‐resolving dynamical model. Simulated CGWs forced in this way closely resembled those observed by the Atmospheric InfraRed Sounder in the upper stratosphere. CGW drag in these validated simulations extends 100s of kilometers away from the convective sources, highlighting errors in current gravity wave drag parameterizations due to the use of the ubiquitous single‐column approximation. Such validatable simulations have significant potential to be used to further basic understanding of CGWs, improve their parameterizations physically, and provide more restrictive constraints on tuning with confidence.
Secondary Ice Production Improves Simulations of Freezing Rain
Authors: Cholette Mélissa , Milbrandt Jason A. , Morrison Hugh , Kirk Sabrina , Lalonde Louis‐Émile
Published: April 2024

Weather forecasts and climate projections of precipitation phase and type in winter storms are challenging due to the complicated underlying microphysical and dynamical processes. In the Canadian numerical weather prediction model, explicit freezing rain (FR) at the surface is often overestimated during the winter season for situations in which snow is observed. For a case study simulated using this model with the Predicted Particle Properties (P3) microphysics scheme, the secondary ice production (SIP) process has a major impact on the surface precipitation type. Parameterized SIP substantially reduces FR due to increased collection of supercooled drops with ice particles formed by rime splintering. Hindcast simulations of 40 winter cases show that these results are systematic, and the decreased frequency of FR leads to improved forecast skill relative to observations. Thus, accounting for SIP in the model is critical for accurately simulating precipitation types.
Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation
Authors: Park Sanghyun , Ryu Won-Ji , Kim Tae Yeong , Hwang Yumi , Han Hyun Ju , Lee Jeong Dong , Kim Gun Min , Sohn Joohyuk , Kim Sang Kyum , Kim Min Hwan , Kim Joon
Published: April 2024

Transcriptional programs governed by YAP play key roles in conferring resistance to various molecular-targeted anticancer agents. Strategies aimed at inhibiting YAP activity have garnered substantial interest as a means to overcome drug resistance. However, despite extensive research into the canonical Hippo–YAP pathway, few clinical agents are currently available to counteract YAP-associated drug resistance. Here, we present a novel mechanism of YAP stability regulation by MAP3K3 that is independent of Hippo kinases. Furthermore, we identified MAP3K3 as a target for overcoming anticancer drug resistance. Depletion of MAP3K3 led to a substantial reduction in the YAP protein level in melanoma and breast cancer cells. Mass spectrometry analysis revealed that MAP3K3 phosphorylates YAP at serine 405. This MAP3K3-mediated phosphorylation event hindered the binding of the E3 ubiquitin ligase FBXW7 to YAP, thereby preventing its p62-mediated lysosomal degradation. Robust YAP activation was observed in CDK4/6 inhibitor-resistant luminal breast cancer cells. Knockdown or pharmacological inhibition of MAP3K3 effectively suppressed YAP activity and restored CDK4/6 inhibitor sensitivity. Similarly, elevated MAP3K3 expression supported the prosurvival activity of YAP in BRAF inhibitor-resistant melanoma cells. Inhibition of MAP3K3 decreased YAP-dependent cell proliferation and successfully restored BRAF inhibitor sensitivity. In conclusion, our study reveals a previously unrecognized mechanism for the regulation of YAP stability, suggesting MAP3K3 inhibition as a promising strategy for overcoming resistance to CDK4/6 and BRAF inhibitors in cancer treatment.
Loss of SREBP-1c ameliorates iron-induced liver fibrosis by decreasing lipocalin-2
Authors: Lee Eun-Ho , Lee Jae-Ho , Kim Do-Young , Lee Young-Seung , Jo Yunju , Dao Tam , Kim Kyung Eun , Song Dae-Kyu , Seo Ji Hae , Seo Young-Kyo , Seong Je Kyung , Moon Changjong , Han Eugene , Kim Mi Kyung , Ryu Seungwan , Shin Minsang , Roh Gu Seob , Jung Hye Ra , Osborne Timothy F. , Ryu Dongryeol , Jeon Tae-Il , Im Seung-Soon
Published: April 2024

Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl4), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl4-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.
Single cell analysis unveils B cell-dominated immune subtypes in HNSCC for enhanced prognostic and therapeutic stratification
Authors: Li Kang , Zhang Caihua , Zhou Ruoxing , Cheng Maosheng , Ling Rongsong , Xiong Gan , Ma Jieyi , Zhu Yan , Chen Shuang , Chen Jie , Chen Demeng , Peng Liang
Published: April 2024

Head and neck squamous cell carcinoma (HNSCC) is characterized by high recurrence or distant metastases rate and the prognosis is challenging. There is mounting evidence that tumor-infiltrating B cells (TIL-Bs) have a crucial, synergistic role in tumor control. However, little is known about the role TIL-Bs play in immune microenvironment and the way TIL-Bs affect the outcome of immune checkpoint blockade. Using single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, the study identified distinct gene expression patterns in TIL-Bs. HNSCC samples were categorized into TIL-Bs inhibition and TIL-Bs activation groups using unsupervised clustering. This classification was further validated with TCGA HNSCC data, correlating with patient prognosis, immune cell infiltration, and response to immunotherapy. We found that the B cells activation group exhibited a better prognosis, higher immune cell infiltration, and distinct immune checkpoint levels, including elevated PD-L1. A prognostic model was also developed and validated, highlighting four genes as potential biomarkers for predicting survival outcomes in HNSCC patients. Overall, this study provides a foundational approach for B cells-based tumor classification in HNSCC, offering insights into targeted treatment and immunotherapy strategies.
Phase II study of novel orally PI3Kα/δ inhibitor TQ-B3525 in relapsed and/or refractory follicular lymphoma
Authors: Wang Huaqing , Feng Jifeng , Liu Yanyan , Qian Zhengzi , Gao Da , Ran Xuehong , Zhou Hui , Liu Lihong , Wang Binghua , Fang Meiyun , Zhou Hebing , Huang Zhenqian , Tao Shi , Chen Zhuowen , Su Liping , Su Hang , Yang Yu , Xie Xiaobao , Wu Huijing , Sun Ping , Hu Guoyu , Liang Aibin , Li Zhiming
Published: April 2024

This registration study assessed clinical outcomes of TQ-B3525, the dual phosphatidylinositol-3-kinase (PI3K) α/δ inhibitor, in relapsed and/or refractory follicular lymphoma (R/R FL). This phase II study (ClinicalTrials.gov NCT04324879. Registered March 27, 2020) comprised run-in stage and stage 2. R/R FL patients after ≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease progression. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Based on results (ORR, 88.0%; duration of response [DOR], 11.8 months; progression-free survival [PFS], 12.0 months) in 25 patients at run-in stage, second stage study was initiated and included 82 patients for efficacy/safety analysis. Patients received prior-line (median, 3) therapies, with 56.1% refractory to previous last therapies; 73.2% experienced POD24 at baseline. At stage 2, ORR was 86.6% (71/82; 95% CI, 77.3–93.1%), with 28 (34.2%) complete responses. Disease control rate was 95.1% due to 7 (8.5%) stable diseases. Median time to response was 1.8 months. Among 71 responders, median DOR was not reached; 18-month DOR rate was 51.6%. with median follow-up of 13.3 months, median PFS was 18.5 (95% CI, 10.2-not estimable) months. Median overall survival (OS) was not reached by cutoff date; 24-month OS rate was estimated as 86.1%. Response rates and survival data were consistent across all subgroups. Grade 3 or higher treatment-related adverse events were observed in 63 (76.8%) cases, with neutropenia (22.0%), hyperglycemia (19.5%), and diarrhea (13.4%) being common. TQ-B3525 showed favorable efficacy and safety for R/R FL patients after ≥2 lines prior therapies.
Therapeutic role of PTEN in tissue regeneration for management of neurological disorders: stem cell behaviors to an in-depth review
Authors: Li Yue , Ma Ruishuang , Hao Xia
Published: April 2024

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) represents the initial tumor suppressor gene identified to possess phosphatase activity, governing various cellular processes including cell cycle regulation, migration, metabolic pathways, autophagy, oxidative stress response, and cellular senescence. Current evidence suggests that PTEN is critical for stem cell maintenance, self-renewal, migration, lineage commitment, and differentiation. Based on the latest available evidence, we provide a comprehensive overview of the mechanisms by which PTEN regulates activities of different stem cell populations and influences neurological disorders, encompassing autism, stroke, spinal cord injury, traumatic brain injury, Alzheimer’s disease and Parkinson’s disease. This review aims to elucidate the therapeutic impacts and mechanisms of PTEN in relation to neurogenesis or the stem cell niche across a range of neurological disorders, offering a foundation for innovative therapeutic approaches aimed at tissue repair and regeneration in neurological disorders.
Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort
Authors: Pearson Madeline , McGowan Ruth , Greene Philip , Lam Wayne , Miedzybrodzka Zofia , Berg Jonathan
Published: April 2024

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.
ATP-free in vitro biotransformation of starch-derived maltodextrin into poly-3-hydroxybutyrate via acetyl-CoA
Authors: Wei Xinlei , Yang Xue , Hu Congcong , Li Qiangzi , Liu Qianqian , Wu Yue , Xie Leipeng , Ning Xiao , Li Fei , Cai Tao , Zhu Zhiguang , Zhang Yi-Heng P. Job , Zhang Yanfei , Chen Xuejun , You Chun
Published: April 2024

In vitro biotransformation (ivBT) facilitated by in vitro synthetic enzymatic biosystems (ivSEBs) has emerged as a highly promising biosynthetic platform. Several ivSEBs have been constructed to produce poly-3-hydroxybutyrate (PHB) via acetyl-coenzyme A (acetyl-CoA). However, some systems are hindered by their reliance on costly ATP, limiting their practicality. This study presents the design of an ATP-free ivSEB for one-pot PHB biosynthesis via acetyl-CoA utilizing starch-derived maltodextrin as the sole substrate. Stoichiometric analysis indicates this ivSEB can self-maintain NADP+/NADPH balance and achieve a theoretical molar yield of 133.3%. Leveraging simple one-pot reactions, our ivSEBs achieved a near-theoretical molar yield of 125.5%, the highest PHB titer (208.3 mM, approximately 17.9 g/L) and the fastest PHB production rate (9.4 mM/h, approximately 0.8 g/L/h) among all the reported ivSEBs to date, and demonstrated easy scalability. This study unveils the promising potential of ivBT for the industrial-scale production of PHB and other acetyl-CoA-derived chemicals from starch.
An optoacoustic field-programmable perceptron for recurrent neural networks
Authors: Becker Steven , Englund Dirk , Stiller Birgit
Published: April 2024

Recurrent neural networks (RNNs) can process contextual information such as time series signals and language. But their tracking of internal states is a limiting factor, motivating research on analog implementations in photonics. While photonic unidirectional feedforward neural networks (NNs) have demonstrated big leaps, bi-directional optical RNNs present a challenge: the need for a short-term memory that (i) programmable and coherently computes optical inputs, (ii) minimizes added noise, and (iii) allows scalability. Here, we experimentally demonstrate an optoacoustic recurrent operator (OREO) which meets (i, ii, iii). OREO contextualizes the information of an optical pulse sequence via acoustic waves. The acoustic waves link different optical pulses, capturing their information and using it to manipulate subsequent operations. OREO’s all-optical control on a pulse-by-pulse basis offers simple reconfigurability and is used to implement a recurrent drop-out and pattern recognition of 27 optical pulse patterns. Finally, we introduce OREO as bi-directional perceptron for new classes of optical NNs.
Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus
Authors: Handal Tayma , Juster Sarah , Abu Diab Manar , Yanovsky-Dagan Shira , Zahdeh Fouad , Aviel Uria , Sarel-Gallily Roni , Michael Shir , Bnaya Ester , Sebban Shulamit , Buganim Yosef , Drier Yotam , Mouly Vincent , Kubicek Stefan , van den Broek Walther J. A. A. , Wansink Derick G. , Epsztejn-Litman Silvina , Eiges Rachel
Published: April 2024

Epigenetic defects caused by hereditary or de novo mutations are implicated in various human diseases. It remains uncertain whether correcting the underlying mutation can reverse these defects in patient cells. Here we show by the analysis of myotonic dystrophy type 1 (DM1)-related locus that in mutant human embryonic stem cells (hESCs), DNA methylation and H3K9me3 enrichments are completely abolished by repeat excision (CTG2000 expansion), whereas in patient myoblasts (CTG2600 expansion), repeat deletion fails to do so. This distinction between undifferentiated and differentiated cells arises during cell differentiation, and can be reversed by reprogramming of gene-edited myoblasts. We demonstrate that abnormal methylation in DM1 is distinctively maintained in the undifferentiated state by the activity of the de novo DNMTs (DNMT3b in tandem with DNMT3a). Overall, the findings highlight a crucial difference in heterochromatin maintenance between undifferentiated (sequence-dependent) and differentiated (sequence-independent) cells, thus underscoring the role of differentiation as a locking mechanism for repressive epigenetic modifications at the DM1 locus.
Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2
Authors: Schulz Vinzent , Steinhilper Ralf , Oltmanns Jonathan , Freibert Sven-A. , Krapoth Nils , Linne Uwe , Welsch Sonja , Hoock Maren H. , Schünemann Volker , Murphy Bonnie J. , Lill Roland
Published: April 2024

Maturation of iron-sulfur proteins in eukaryotes is initiated in mitochondria by the core iron-sulfur cluster assembly (ISC) complex, consisting of the cysteine desulfurase sub-complex NFS1-ISD11-ACP1, the scaffold protein ISCU2, the electron donor ferredoxin FDX2, and frataxin, a protein dysfunctional in Friedreich’s ataxia. The core ISC complex synthesizes [2Fe-2S] clusters de novo from Fe and a persulfide (SSH) bound at conserved cluster assembly site residues. Here, we elucidate the poorly understood Fe-dependent mechanism of persulfide transfer from cysteine desulfurase NFS1 to ISCU2. High-resolution cryo-EM structures obtained from anaerobically prepared samples provide snapshots that both visualize different stages of persulfide transfer from Cys381NFS1 to Cys138ISCU2 and clarify the molecular role of frataxin in optimally positioning assembly site residues for fast sulfur transfer. Biochemical analyses assign ISCU2 residues essential for sulfur transfer, and reveal that Cys138ISCU2 rapidly receives the persulfide without a detectable intermediate. Mössbauer spectroscopy assessing the Fe coordination of various sulfur transfer intermediates shows a dynamic equilibrium between pre- and post-sulfur-transfer states shifted by frataxin. Collectively, our study defines crucial mechanistic stages of physiological [2Fe-2S] cluster assembly and clarifies frataxin’s molecular role in this fundamental process.
Distinct information conveyed to the olfactory bulb by feedforward input from the nose and feedback from the cortex
Authors: Zak Joseph D. , Reddy Gautam , Konanur Vaibhav , Murthy Venkatesh N.
Published: April 2024

Sensory systems are organized hierarchically, but feedback projections frequently disrupt this order. In the olfactory bulb (OB), cortical feedback projections numerically match sensory inputs. To unravel information carried by these two streams, we imaged the activity of olfactory sensory neurons (OSNs) and cortical axons in the mouse OB using calcium indicators, multiphoton microscopy, and diverse olfactory stimuli. Here, we show that odorant mixtures of increasing complexity evoke progressively denser OSN activity, yet cortical feedback activity is of similar sparsity for all stimuli. Also, representations of complex mixtures are similar in OSNs but are decorrelated in cortical axons. While OSN responses to increasing odorant concentrations exhibit a sigmoidal relationship, cortical axonal responses are complex and nonmonotonic, which can be explained by a model with activity-dependent feedback inhibition in the cortex. Our study indicates that early-stage olfactory circuits have access to local feedforward signals and global, efficiently formatted information about odor scenes through cortical feedback.
Emerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection
Authors: Liu Chang , Das Raksha , Dijokaite-Guraliuc Aiste , Zhou Daming , Mentzer Alexander J. , Supasa Piyada , Selvaraj Muneeswaran , Duyvesteyn Helen M. E. , Ritter Thomas G. , Temperton Nigel , Klenerman Paul , Dunachie Susanna J. , Paterson Neil G. , Williams Mark A. , Hall David R. , Fry Elizabeth E. , Mongkolsapaya Juthathip , Ren Jingshan , Stuart David I. , Screaton Gavin R.
Published: April 2024

The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. Twenty eight potent antibodies are isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5, SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of BA.4/5 mAbs culminating in total loss of function with recent XBB.1.5.70 variants containing the so-called ‘FLip’ mutations at positions 455 and 456. Interestingly, activity of some mAbs is regained on the recently reported variant BA.2.86.
Neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial
Authors: Li Zhongchao , Liu Jing , Zhang Bo , Yue Jinbo , Shi Xuetao , Cui Kai , Liu Zhaogang , Chang Zhibin , Sun Zhicheng , Li Mingming , Yang Yue , Ma Zhao , Li Lei , Zhang Chengsheng , Sun Pengfei , Zhong Jingtao , Zhao Lei
Published: April 2024

Notable-HCC (NCT05185531) is a phase 1b trial, aiming to evaluate the safety and preliminary effectiveness of neoadjuvant PD-1 blockade plus stereotactic body radiotherapy (SBRT) in early-stage resectable hepatocellular carcinoma (HCC). Twenty patients with HCC of BCLC stage 0-A received 3$$\times $$
×
Gy SBRT and two cycles of tislelizumab, an anti-PD-1 monoclonal antibody before the curative HCC resection. Primary endpoints were the surgery delay, radiographic and pathological tumor response after the neoadjuvant therapy, safety and tolerability. During the neoadjuvant therapy, treatment-related adverse events (TRAEs) of grade 1-2 occurred in all 20 patients (100%), eight patients (40%) had grade 3 TRAEs, no grade 4 to 5 TRAE occurred, and all resolved without corticosteroids treatment. Per mRECIST, the objective response rate was 63.2% (12/19), with 3 complete response; the disease control rate was 100%. Two (10.5%) patients achieved complete pathological response. No surgery delay occurred. The neoadjuvant therapy did not increase the surgical difficulty or the incidence of complications. Secondary endpoints of disease-free survival and overall survival were not mature at the time of the analysis. Our pilot trial shows that neoadjuvant therapy with anti-PD-1 + SBRT is safe and promotes tumor responses in early-stage resectable HCC.
Robust compression and detection of epileptiform patterns in ECoG using a real-time spiking neural network hardware framework
Authors: Costa Filippo , Schaft Eline V. , Huiskamp Geertjan , Aarnoutse Erik J. , van’t Klooster Maryse A. , Krayenbühl Niklaus , Ramantani Georgia , Zijlmans Maeike , Indiveri Giacomo , Sarnthein Johannes
Published: April 2024

Interictal Epileptiform Discharges (IED) and High Frequency Oscillations (HFO) in intraoperative electrocorticography (ECoG) may guide the surgeon by delineating the epileptogenic zone. We designed a modular spiking neural network (SNN) in a mixed-signal neuromorphic device to process the ECoG in real-time. We exploit the variability of the inhomogeneous silicon neurons to achieve efficient sparse and decorrelated temporal signal encoding. We interface the full-custom SNN device to the BCI2000 real-time framework and configure the setup to detect HFO and IED co-occurring with HFO (IED-HFO). We validate the setup on pre-recorded data and obtain HFO rates that are concordant with a previously validated offline algorithm (Spearman’s ρ = 0.75, p = 1e-4), achieving the same postsurgical seizure freedom predictions for all patients. In a remote on-line analysis, intraoperative ECoG recorded in Utrecht was compressed and transferred to Zurich for SNN processing and successful IED-HFO detection in real-time. These results further demonstrate how automated remote real-time detection may enable the use of HFO in clinical practice.
Ultrasensitive single-step CRISPR detection of monkeypox virus in minutes with a vest-pocket diagnostic device
Authors: Wang Yunxiang , Chen Hong , Lin Kai , Han Yongjun , Gu Zhixia , Wei Hongjuan , Mu Kai , Wang Dongfeng , Liu Liyan , Jin Ronghua , Song Rui , Rong Zhen , Wang Shengqi
Published: April 2024

The emerging monkeypox virus (MPXV) has raised global health concern, thereby highlighting the need for rapid, sensitive, and easy-to-use diagnostics. Here, we develop a single-step CRISPR-based diagnostic platform, termed SCOPE (Streamlined CRISPR On Pod Evaluation platform), for field-deployable ultrasensitive detection of MPXV in resource-limited settings. The viral nucleic acids are rapidly released from the rash fluid swab, oral swab, saliva, and urine samples in 2 min via a streamlined viral lysis protocol, followed by a 10-min single-step recombinase polymerase amplification (RPA)-CRISPR/Cas13a reaction. A pod-shaped vest-pocket analysis device achieves the whole process for reaction execution, signal acquisition, and result interpretation. SCOPE can detect as low as 0.5 copies/µL (2.5 copies/reaction) of MPXV within 15 min from the sample input to the answer. We validate the developed assay on 102 clinical samples from male patients / volunteers, and the testing results are 100% concordant with the real-time PCR. SCOPE achieves a single-molecular level sensitivity in minutes with a simplified procedure performed on a miniaturized wireless device, which is expected to spur substantial progress to enable the practice application of CRISPR-based diagnostics techniques in a point-of-care setting.
Nanoparticles as an antidote for poisoned gold single-atom catalysts in sustainable propylene epoxidation
Authors: Wang Qianhong , Sang Keng , Liu Changwei , Zhang Zhihua , Chen Wenyao , Ji Te , Li Lina , Lian Cheng , Qian Gang , Zhang Jing , Zhou Xinggui , Yuan Weikang , Duan Xuezhi
Published: April 2024

The development of sustainable and anti-poisoning single-atom catalysts (SACs) is essential for advancing their research from laboratory to industry. Here, we present a proof-of-concept study on the poisoning of Au SACs, and the antidote of Au nanoparticles (NPs), with trace addition shown to reinforce and sustain propylene epoxidation. Multiple characterizations, kinetics investigations, and multiscale simulations reveal that Au SACs display remarkable epoxidation activity at a low propylene coverage, but become poisoned at higher coverages. Interestingly, Au NPs can synergistically cooperate with Au SACs by providing distinct active sites required for H2/O2 and C3H6 activations, as well as hydroperoxyl radical to restore poisoned SACs. The difference in reaction order between C3H6 and H2 (nC3H6-nH2) is identified as the descriptor for establishing the volcano curves, which can be fine-tuned by the intimacy and composition of SACs and NPs to achieve a rate-matching scenario for the formation, transfer, and consumption of hydroperoxyl. Consequently, only trace addition of Au NPs antidote (0.3% ratio of SACs) stimulates significant improvements in propylene oxide formation rate, selectivity, and H2 efficiency compared to SACs alone, offering a 56-fold, 3-fold, and 22-fold increase, respectively, whose performances can be maintained for 150 h.