bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of hospital leadership support on burnout, psychological safety, and safety climate for US infection preventionists during the coronavirus disease 2019 (COVID-19) pandemic
Authors: Gilmartin Heather M. , Saint Sanjay , Ratz David , Chrouser Kristin , Fowler Karen E. , Greene M. Todd
Published: September 2023

Objective:

To explore infection preventionists’ perceptions of hospital leadership support for infection prevention and control programs during the coronavirus disease 2019 (COVID-19) pandemic and relationships with individual perceptions of burnout, psychological safety, and safety climate.

Design:

Cross-sectional survey, administered April through December 2021.

Setting:

Random sample of non-federal acute-care hospitals in the United States.

Participants:

Lead infection preventionists.

Results:

We received responses from 415 of 881 infection preventionists, representing a response rate of 47%. Among respondents, 64% reported very good to excellent hospital leadership support for their infection prevention and control program. However, 49% reported feeling burned out from their work. Also, ∼30% responded positively for all 7 psychological safety questions and were deemed to have “high psychological safety,” and 76% responded positively to the 2 safety climate questions and were deemed to have a “high safety climate.” Our results indicate an association between strong hospital leadership support and lower burnout (IRR, 0.61; 95% CI, 0.50–0.74), higher perceptions of psychological safety (IRR, 3.20; 95% CI, 2.00–5.10), and a corresponding 1.2 increase in safety climate on an ascending Likert scale from 1 to 10 (β, 1.21; 95% CI, 0.93–1.49).

Conclusions:

Our national survey provides evidence that hospital leadership support may have helped infection preventionists avoid burnout and increase perceptions of psychological safety and safety climate during the COVID-19 pandemic. These findings aid in identifying factors that promote the well-being of infection preventionists and enhance the quality and safety of patient care.
High-subsonic boundary-layer flows of an organic vapour
Authors: Gloerfelt Xavier , Bienner Aurélien , Cinnella Paola
Published: September 2023

Boundary layers of Novec649, a low-global-warming potential fluid of interest for low-grade heat recovery, are investigated numerically by means of linear stability theory, direct numerical simulation (DNS) and large-eddy simulations (LES). This organic vapour is of interest in organic Rankine cycle (ORC) turbines and realistic thermodynamic conditions are selected. Under these conditions, the vapour behaves as a dense gas and, due to its high molecular complexity, real-gas effects occur. In addition, the fluid exhibits large and highly variable heat capacities and density- as well as temperature-dependent transport properties. More specifically we report the first direct and LES of transitional and turbulent boundary layers of Novec649 at high-subsonic conditions$M=0.9$. A controlled transition is performed by using oblique modes determined by linear stability theory extended to dense gases. An oblique-type transition is obtained as in low-speed air flows, where sinuous streaks develop by the lift-up mechanism and break down into turbulence. In the turbulent state, the profiles of dynamic flow properties (velocities, turbulent intensities, turbulent kinetic energy budgets) are little affected by the gas properties and remain very close to incompressible DNS, despite the high-subsonic flow speed. The fluctuations levels for thermodynamic properties have been quantified with respect to air flows. Notwithstanding a drastic reduction, genuine compressibility effects are present. For example, the fluctuating Mach number and the acoustic mode are characteristic of high-speed flows. The influence of forcing frequency and amplitude on the established turbulent state has been investigated using LES. An analysis of integral quantities shows a slow relaxation towards a canonical equilibrium turbulent state for all cases due to the high Reynolds numbers typical of dense gas flows. Overall the present DNS constitutes a valuable reference not only for forthcoming experiments but also for future studies of free-stream transition and loss mechanisms in ORC turbines.
Functional priority of syntax over semantics in Chinese ‘ba’ construction: evidence from eye-tracking during natural reading
Authors: Wei Yanjun , Tang Yingjuan , Privitera Adam John
Published: September 2023

Studies on sentence processing in inflectional languages support that syntactic structure building functionally precedes semantic processing. Conversely, most EEG studies of Chinese sentence processing do not support the priority of syntax. One possible explanation is that the Chinese language lacks morphological inflections. Another explanation may be that the presentation of separate sentence components on individual screens in EEG studies disrupts syntactic framework construction during sentence reading. The present study investigated this explanation using a self-paced reading experiment mimicking rapid serial visual presentation in EEG studies and an eye-tracking experiment reflecting natural reading. In both experiments, Chinese ‘ba’ sentences were presented to Chinese young adults in four conditions that differed across the dimensions of syntactic and semantic congruency. Evidence supporting the functional priority of syntax over semantics was limited to only the natural reading context, in which syntactic violations blocked the processing of semantics. Additionally, we observed a later stage of integrating plausible semantics with a failed syntax. Together, our findings extend the functional priority of syntax to the Chinese language and highlight the importance of adopting more ecologically valid methods when investigating sentence reading.
Growth rate affects blood flow rate to the tibia of the dinosaur Maiasaura
Authors: Seymour Roger S. , Caldwell Heath R. , Woodward Holly N. , Hu Qiaohui
Published: September 2023

Fossil bones were once living tissues that demanded internal blood perfusion in proportion to their metabolic requirements. Metabolic rates were primarily associated with bone growth (modeling) in the juvenile stages and with alteration and repair of existing bone affected by weight bearing and locomotion (remodeling) in later stages. This study estimates blood flow rates to the tibia shafts of the Late Cretaceous hadrosaurid Maiasaura peeblesorum, based on the size of the primary nutrient foramina in fossil bones. Foramen size quantitatively reflects arterial size and hence blood flow rate. The results showed that the bone metabolic intensity of juveniles (ca. 1 year old) was greater than fourfold higher than that of 6- to 11-year-old adults. This difference is much greater than expected from standard metabolic scaling and is interpreted as a shift from the high metabolic demands for primary bone modeling in the rapidly growing juveniles to a lower metabolic demand of adults to remodel their bones for repair of microfractures accumulated during locomotion and weight bearing. Large nutrient foramina of adults indicate a high level of cursorial locomotion characteristic of tachymetabolic endotherms. The practical value of these results is that juvenile and adult stages should be treated separately in interspecific analyses of bone perfusion in relation to body mass.
The non-autonomous Navier–Stokes–Brinkman–Forchheimer equation with Dirichlet boundary conditions: dissipativity, regularity, and attractors
Authors: Stone Dominic , Zelik Sergey
Published: September 2023

We give a comprehensive study of the 3D Navier–Stokes–Brinkman–Forchheimer equations in a bounded domain endowed with the Dirichlet boundary conditions and non-autonomous external forces. This study includes the questions related with the regularity of weak solutions, their dissipativity in higher energy spaces and the existence of the corresponding uniform attractors
Media wars: Remaking the logics of propaganda in India’s wartime cine-ecologies
Authors: Mukherjee Debashree
Published: September 2023

Recent Second World War historiography has rightly highlighted the forgotten contributions of South Asia in the Allied war effort, and the everyday meanings of the war in South Asia. The role of cinema here, however, remains largely overlooked. This article focuses on British efforts to produce war propaganda in India with the help of Indian filmmakers, through varying tactics of incentivization and coercion. Between 1940 and 1945, the British colonial administration attempted several strategies to build a local film propaganda apparatus in India but, as I demonstrate, each stage was met with differentiated forms of cooperation, reluctance, and outright refusal, finally leading to the adoption of the unlikely genre of the full-length fiction film as the main mode of war propaganda in India. Derided as frivolous and half-hearted by critics at the time, the Indian-language ‘war effort’ film is more generatively framed as a form of ‘useless cinema’ that defied the logics of propaganda and privileged ideological ambivalence. This article brings together media history, film analysis, industrial debates about supply chains and licence regimes, aesthetic concerns about subtlety, and political differences about the ideological meanings of the war to situate the Second World War within the complex cine-ecologies of India. I read films and film industrial negotiations together to add to the multi-sited story of India’s experience of the Second World War that this special issue develops.
Maternal postnatal depressive symptoms and children’s internalizing problems: The moderating role of mother–infant RSA synchrony
Authors: Lan Qili , Zhang Chen , Lunkenheimer Erika , Chang Suying , Li Zhi , Wang Li
Published: September 2023

Maternal depressive symptoms are a crucial risk factor for children’s internalizing problems, though positive mother–child relationships may buffer this risk transmission. Mother–child physiological coregulation (e.g., synchrony) has emerged as a potentially important mechanism of developmental psychopathology and may play a role in the transmission of internalizing symptoms. In this two-wave longitudinal study, we examined whether and how mother–infant physiological synchrony (of respiratory sinus arrhythmia; RSA) moderated the association between maternal postnatal depressive symptoms and children’s internalizing problems in a rural, low-SES community sample (N = 166 dyads). At 6 months, mother–infant RSA synchrony and infant negative affect were assessed during free play. Mother reported their depressive symptoms at 6 months and children’s internalizing problems at 24 months. Multilevel structural equation models indicated that mother–infant dyads demonstrated significant and positive RSA synchrony on average and RSA synchrony significantly moderated the association between maternal depressive symptoms and children’s internalizing problems even after controlling for infant negative affect. Greater maternal depressive symptoms were associated with higher child internalizing problems when RSA synchrony was lower but not when it was higher. This finding suggests that mother–infant RSA synchrony may operate as a resilience factor for the intergenerational transmission of internalizing symptoms in community samples.
An Archaeology of Traces
Authors: Routledge Bruce
Published: September 2023

Archaeology is centrally concerned with the tension between material remains in the present and a reconstructed past. This tension is captured by the concept of a trace, namely a contemporary phenomenon that references the past through some sort of epistemic intervention. Traces are deceptively complex in terms of both their epistemology and their ontology and hence worthy of detailed exploration. In particular, archaeological traces not only concern the past per se but also possess a latent quality of as yet unrealized signification. This gives archaeological traces a future orientation that is rarely considered in discussions of archaeological epistemology.
City-Level Law and Action for Climate-Resilient Development in Southern Africa
Authors: du Plessis Anél , Steyn Nicolene , Rantlo John
Published: September 2023

This article studies eight cities in four countries in the southern African region (Namibia, Zimbabwe, South Africa, and Botswana) to explore whether and how local governing authority has been channelled towards local climate-resilient development. The authors undertook a desk-based identification and review of available primary and secondary legal sources and normative documents while also drawing on scientific papers and policy documents for statistics and information about urbanization, climate change, politics, and governance in the selected countries. The analysis is interested in the law but is not strictly of a legal nature in the sense that the authors did not aim for a critical analysis of the regulatory detail in the relevant legal instruments. Instead, the article provides an evaluation of the political, de facto choices made by selected local governments as to how and to what extent to utilize their governing authority (legislative and executive) towards climate-resilient development. The authors explore if and how local government powers in the four southern African countries are currently leveraged for local climate action, and comment on the possible reasons for the status quo by comparing the four jurisdictions.
In Greek we trust! Παίζοντες μανθάνομεν
Authors: Manolidou Eugenia , Goula Sophia
Published: September 2023

This article presents the method used in Elliniki Agogi, a private small school that teaches the Ancient Greek language as an extra-curricular activity. Over the 29 years of experimenting with educational material, methods, books and exercises, teaching Ancient Greek as a living language seems like the only method that really works for the students. It is immersive, experiential, educational and fun, but most important, it makes students love what they learn; by loving, they keep wanting to come back. By coming back, they repeat. By repeating; they learn. And by learning Greek as a living language, they never forget it. This is our school's aim: to make our students love the language. Experiential learning is highly valued and applied through visits to archaeological sites, and reviving important historical events. But this is only the beginning; playing, drawing, acting, foreign exchanges, educational trips, digital programs, collaborations with foreign institutions and educational organisations come alive in Elliniki Agogi, a small school that was founded 29 years ago in Greece and has joined worldwide efforts in changing the way Greek is taught in order to promote its true, timeless, precious wisdom. In Elliniki Agogi a combination of teaching Greek as a living language and activities that include play and fun, a method as old as time, shows exactly the reason way the words ‘play’ (παιδιά) and ‘education’ (παιδεία) derive from the exact same root word: παῖς (child). Educational material is also provided in order to further enhance and deepen children's knowledge.
In Situ Optimized Substrate Witness Plates: Ground Truth for Key Processes on the Moon and Other Planets
Authors: Saxena Prabal , Morrissey Liam S. , Killen Rosemary M. , McLain Jason L. , Yeo Li Hsia , Curran Natalie M. , Abraham Nithin S. , Graham Heather V. , Tucker Orenthal J. , Sarantos Menelaos , Regberg Aaron B. , Pugel Diane E. , Needham Andrew W. , Hasegawa Mark , Wong Alfred J.
Published: September 2023

Future exploration efforts of the Moon, Mars, and other bodies are poised to focus heavily on persistent and sustainable survey and research efforts, especially given the recent interest in a long‐term sustainable human presence at the Moon. Key to these efforts understands a number of important processes on the lunar surface for both scientific and operational purposes. We discuss the potential value of in situ artificial substrate witness plates, powerful tools that can supplement familiar remote sensing and sample acquisition techniques and provide a sustainable way of monitoring processes in key locations on planetary surfaces while maintaining a low environmental footprint. These tools, which we call Biscuits, can use customized materials as wide ranging as zircon‐based spray coatings to metals potentially useable for surface structures, to target specific processes/questions as part of a small, passive witness plate that can be flexibly placed with respect to location and total time duration. We examine and discuss unique case studies to show how processes such as water presence/transport, presence and contamination of biologically relevant molecules, solar activity related effects, and other processes can be measured using Biscuits. Biscuits can yield key location sensitive, time integrated measurements on these processes to inform scientific understanding of the Moon and enable operational goals in lunar exploration. While we specifically demonstrate this on a simulated traverse and for selected examples, we stress all groups interested in planetary surfaces should consider these adaptable, low footprint, and highly informative tools for future exploration.
Our Evolving Understanding of Biological Carbon Export
Authors: Osborne Emily , Luo Jessica , Cetinić Ivona , Benway Heather , Menden-Deuer Susanne
Published: September 2023

The array of processes and organisms that make up the biological carbon pump has immense influence on Earth’s carbon cycle and climate. But there’s still much to learn about how the pump works.
Two Decades of Temperature and Specific Humidity Variance Scaling With the Atmospheric Infrared Sounder
Authors: Kahn Brian H. , Fetzer Eric J. , Teixeira Joao , Yue Qing
Published: September 2023

A two‐decade climatology of height‐resolved horizontal variance scaling exponents (𝛼) for temperature (T) and specific humidity (q) is described using Aqua Atmospheric Infrared Sounder (AIRS) sounding profiles. The AIRS Team Version 6 (V6), Version 7 (V7), and Community Long‐term Infrared Microwave Combined Atmospheric Product System (CLIMCAPS) retrieval algorithms are compared to European Centre for Medium‐Range Weather Forecasts Reanalysis v5 (ERA5) and Modern‐Era Retrospective analysis for Research and Applications, Version 2 (MERRA‐2) reanalyses. Large‐scale T exponents derived between 600 and 1,200 km (𝛼L) show close agreement between V6, V7, and CLIMCAPS algorithms. However, small‐scale q exponents derived between 150 and 400 km (𝛼S) are in poor agreement, including an unrealistically steep 𝛼S in the planetary boundary layer (PBL) in the V7 and CLIMCAPS algorithms that is caused by a combination of algorithm damping and overconstraint by the first guess fields. ERA5 and MERRA‐2 reanalyses have large values of 𝛼L and 𝛼S for both T and q that indicate reduced small‐scale variability in the reanalysis fields. Differences in 𝛼S between free‐running MERRA‐2 AMIP and MERRA‐2 are negligible, implying that suppressed small‐scale variability in reanalyses is imposed by the background model and not caused by the data assimilation process. AIRS has positively skewed T distributions in the tropical‐free troposphere that is consistent with positively buoyant air parcels in convection, and negative skewness in the PBL that is related to the existence of cold pools, behavior that is mostly absent in ERA5 and MERRA‐2. AIRS provides a global view of scale‐dependent variance and skewness that is useful for subgrid parameterization development and validation of weather and climate prediction models.
Detrital Garnet Geochronology by In Situ U‐Pb and Lu‐Hf Analysis: A Case Study From the European Alps
Authors: Mark Chris , O’Sullivan Gary , Glorie Stijn , Simpson Alexander , Andò Sergio , Barbarano Marta , Stutenbecker Laura , Daly J. Stephen , Gilbert Sarah
Published: September 2023

Detrital geochronology employing the widely‐used zircon U‐Pb proxy is biased toward igneous events and metamorphic anatexis; additionally, zircon is highly refractory and frequently polycyclic. Garnet, a rock‐forming and thus commonly occurring mineral, is predominantly metamorphic and much less refractory. Here, we report in situ U‐Pb and Lu‐Hf ages from detrital garnet hosted in ancient and modern sediments of the European Alps. Both geochronometers are biased toward the most recent garnet‐crystallizing metamorphic event in the source area, with fewer inherited ages. This likely reflects efficient removal of inherited garnet during diagenesis and metamorphism, and is in contrast to detrital zircon, apatite, and rutile U‐Pb data, which largely record pre‐Alpine ages. Neither the U‐Pb nor Lu‐Hf system in garnet exhibits a relationship between age recovery and composition. However, the Lu‐Hf system in garnet yields significantly better age recovery than the U‐Pb system. Estimated initial 238U/206Pbc values at the time of crystallization are near unity, suggesting that garnet does not significantly partition U from Pb during crystallization, at least for the generally almandine‐rich garnets analyzed in this study. Hence, Lu‐Hf geochronology of detrital garnet offers an effective method to detect and date the most recent phase of mid‐grade metamorphism in sub‐anatectic source areas, in which detrital zircon U‐Pb analysis may be of less utility.
Baseline levels of miR-223-3p correlate with the effectiveness of electroconvulsive therapy in patients with major depression
Authors: Kaurani Lalit , Besse Matthias , Methfessel Isabel , Methi Aditi , Zhou Jiayin , Pradhan Ranjit , Burkhardt Susanne , Kranaster Laura , Sartorius Alexander , Habel Ute , Grözinger Michael , Fischer Andre , Wiltfang Jens , Zilles-Wegner David
Published: September 2023

There is a strong medical need to develop suitable biomarkers to improve the diagnosis and treatment of depression, particularly in predicting response to certain therapeutic approaches such as electroconvulsive therapy (ECT). MicroRNAs are small non-coding RNAs that have the ability to influence the transcriptome as well as proteostasis at the systems level. Here, we investigate the role of circulating microRNAs in depression and response prediction towards ECT. Of the 64 patients with treatment-resistant major depression (MDD) who received ECT treatment, 62.5% showed a response, defined as a reduction of ≥50% in the MADRS total score from baseline. We performed smallRNA sequencing in blood samples that were taken before the first ECT, after the first and the last ECT. The microRNAome was compared between responders and non-responders. Co-expression network analysis identified three significant microRNA modules with reverse correlation between ECT- responders and non-responders, that were amongst other biological processes linked to inflammation. A candidate microRNA, namely miR-223-3p was down-regulated in ECT responders when compared to non-responders at baseline. In line with data suggesting a role of miR-223-3p in inflammatory processes we observed higher expression levels of proinflammatory factors Il-6, Il-1b, Nlrp3 and Tnf-α in ECT responders at baseline when compared to non-responders. ROC analysis of confirmed the diagnostic power of miR-223-3p demarcating ECT-responders from non-responder subjects (AUC = 0.76, p = 0.0031). Our data suggest that miR-223-3p expression and related cytokine levels could serve as predictors of response to ECT in individuals with treatment-resistant depressive disorders.
Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment
Authors: McMoneagle Erin , Zhou Jin , Zhang Shiyao , Huang Weixue , Josiah Sunday Solomon , Ding Ke , Wang Yun , Zhang Jinwei
Published: September 2023

Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures. γ-Aminobutyric acid (GABA) serves as the primary fast inhibitory neurotransmitter in the brain, and GABA binding to the GABAAreceptor (GABAAR) regulates Cl-and bicarbonate (HCO3-) influx or efflux through the channel pore, leading to GABAergic inhibition or excitation, respectively. The neuron-specific K+-Cl-cotransporter 2 (KCC2) is essential for maintaining a low intracellular Cl-concentration, ensuring GABAAR-mediated inhibition. Impaired KCC2 function results in GABAergic excitation associated with epileptic activity. Loss-of-function mutations and altered expression of KCC2 lead to elevated [Cl-]iand compromised synaptic inhibition, contributing to epilepsy pathogenesis in human patients. KCC2 antagonism studies demonstrate the necessity of limiting neuronal hyperexcitability within the brain, as reduced KCC2 functioning leads to seizure activity. Strategies focusing on direct (enhancing KCC2 activation) and indirect KCC2 modulation (altering KCC2 phosphorylation and transcription) have proven effective in attenuating seizure severity and exhibiting anti-convulsant properties. These findings highlight KCC2 as a promising therapeutic target for treating epilepsy. Recent advances in understanding KCC2 regulatory mechanisms, particularly via signaling pathways such as WNK, PKC, BDNF, and its receptor TrkB, have led to the discovery of novel small molecules that modulate KCC2. Inhibiting WNK kinase or utilizing newly discovered KCC2 agonists has demonstrated KCC2 activation and seizure attenuation in animal models. This review discusses the role of KCC2 in epilepsy and evaluates its potential as a drug target for epilepsy treatment by exploring various strategies to regulate KCC2 activity.
Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT
Authors: Kwon Yujin , Kim Jiyoon , Cho Su-Yeon , Kang Yoon Jin , Lee Jongsoo , Kwon Jaeyoung , Rhee Hyungjin , Bauer Sebastian , Kim Hyung-Sik , Lee Esak , Kim Han Sang , Jung Jae Hung , Kim Hoguen , Kim Won Kyu
Published: September 2023

Gastrointestinal stromal tumors (GISTs) frequently show KIT mutations, accompanied by overexpression and aberrant localization of mutant KIT (MT-KIT). As previously established by multiple studies, including ours, we confirmed that MT-KIT initiates downstream signaling in the Golgi complex. Basic leucine zipper nuclear factor 1 (BLZF1) was identified as a novel MT-KIT-binding partner that tethers MT-KIT to the Golgi complex. Sustained activation of activated transcription factor 6 (ATF6), which belongs to the unfolded protein response (UPR) family, alleviates endoplasmic reticulum (ER) stress by upregulating chaperone expression, including heat shock protein 90 (HSP90), which assists in MT-KIT folding. BLZF1 knockdown and ATF6 inhibition suppressed both imatinib-sensitive and -resistant GIST in vitro. ATF6 inhibitors further showed potent antitumor effects in GIST xenografts, and the effect was enhanced with ER stress-inducing drugs. ATF6 activation was frequently observed in 67% of patients with GIST (n = 42), and was significantly associated with poorer relapse-free survival (P = 0.033). Overall, GIST bypasses ER quality control (QC) and ER stress-mediated cell death via UPR activation and uses the QC-free Golgi to initiate signaling.
Intranasal delivery of NGF rescues hearing impairment in aged SAMP8 mice
Authors: Castelli Vanessa , d’Angelo Michele , Zazzeroni Francesca , Vecchiotti Davide , Alesse Edoardo , Capece Daria , Brandolini Laura , Cattani Franca , Aramini Andrea , Allegretti Marcello , Cimini Annamaria
Published: September 2023

Hearing loss impacts the quality of life and affects communication resulting in social isolation and reduced well-being. Despite its impact on society and economy, no therapies for age-related hearing loss are available so far. Loss of mechanosensory hair cells of the cochlea is a common event of hearing loss in humans. Studies performed in birds demonstrating that they can be replaced following the proliferation and transdifferentiation of supporting cells, strongly pointed out on HCs regeneration as the main focus of research aimed at hearing regeneration. Neurotrophins are growth factors involved in neuronal survival, development, differentiation, and plasticity. NGF has been involved in the interplay between auditory receptors and efferent innervation in the cochlea during development. During embryo development, both NGF and its receptors are highly expressed in the inner ears. It has been reported that NGF is implicated in the differentiation of auditory gangliar and hair cells. Thus, it has been proposed that NGF administration can decrease neuronal damage and prevent hearing loss. The main obstacle to the development of hearing impairment therapy is that efficient means of delivery for selected drugs to the cochlea are missing. Herein, in this study NGF was administered by the intranasal route. The first part of the study was focused on a biodistribution study, which showed the effective delivery in the cochlea; while the second part was focused on analyzing the potential therapeutic effect of NGF in senescence-accelerated prone strain 8 mice. Interestingly, intranasal administration of NGF resulted protective in counteracting hearing impairment in SAMP8 mice, ameliorating hearing performances (analyzed by auditory brainstem responses and distortion product otoacoustic emission) and hair cells morphology (analyzed by microscopy analysis). The results obtained were encouraging indicating that the neurotrophin NGF was efficiently delivered to the inner ear and that it was effective in counteracting hearing loss.
Mixed effects of a national protected area network on terrestrial and freshwater biodiversity
Authors: Santangeli Andrea , Weigel Benjamin , Antão Laura H. , Kaarlejärvi Elina , Hällfors Maria , Lehikoinen Aleksi , Lindén Andreas , Salemaa Maija , Tonteri Tiina , Merilä Päivi , Vuorio Kristiina , Ovaskainen Otso , Vanhatalo Jarno , Roslin Tomas , Saastamoinen Marjo
Published: September 2023

Protected areas are considered fundamental to counter biodiversity loss. However, evidence for their effectiveness in averting local extinctions remains scarce and taxonomically biased. We employ a robust counterfactual multi-taxon approach to compare occupancy patterns of 638 species, including birds (150), mammals (23), plants (39) and phytoplankton (426) between protected and unprotected sites across four decades in Finland. We find mixed impacts of protected areas, with only a small proportion of species explicitly benefiting from protection—mainly through slower rates of decline inside protected areas. The benefits of protection are enhanced for larger protected areas and are traceable to when the sites were protected, but are mostly unrelated to species conservation status or traits (size, climatic niche and threat status). Our results suggest that the current protected area network can partly contribute to slow down declines in occupancy rates, but alone will not suffice to halt the biodiversity crisis. Efforts aimed at improving coverage, connectivity and management will be key to enhance the effectiveness of protected areas towards bending the curve of biodiversity loss.
Proteogenomics of different urothelial bladder cancer stages reveals distinct molecular features for papillary cancer and carcinoma in situ
Authors: Yao Zhenmei , Xu Ning , Shang Guoguo , Wang Haixing , Tao Hui , Wang Yunzhi , Qin Zhaoyu , Tan Subei , Feng Jinwen , Zhu Jiajun , Ma Fahan , Tian Sha , Zhang Qiao , Qu Yuanyuan , Hou Jun , Guo Jianming , Zhao Jianyuan , Hou Yingyong , Ding Chen
Published: September 2023

The progression of urothelial bladder cancer (UC) is a complicated multi-step process. We perform a comprehensive multi-omics analysis of 448 samples from 190 UC patients, covering the whole spectrum of disease stages and grades. Proteogenomic integration analysis indicates the mutations of HRAS regulated mTOR signaling to form urothelial papilloma rather than papillary urothelial cancer (PUC). DNA damage is a key signaling pathway in the progression of carcinoma in situ (CIS) and related to APOBEC signature. Glucolipid metabolism increase and lower immune cell infiltration are associated with PUC compared to CIS. Proteomic analysis distinguishes the origins of invasive tumors (PUC-derived and CIS-derived), related to distinct clinical prognosis and molecular features. Additionally, loss of RBPMS, associated with CIS-derived tumors, is validated to increase the activity of AP-1 and promote metastasis. This study reveals the characteristics of two distinct branches (PUC and CIS) of UC progression and may eventually benefit clinical practice.
Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles
Authors: Sitarska Ewa , Almeida Silvia Dias , Beckwith Marianne Sandvold , Stopp Julian , Czuchnowski Jakub , Siggel Marc , Roessner Rita , Tschanz Aline , Ejsing Christer , Schwab Yannick , Kosinski Jan , Sixt Michael , Kreshuk Anna , Erzberger Anna , Diz-Muñoz Alba
Published: September 2023

To navigate through diverse tissues, migrating cells must balance persistent self-propelled motion with adaptive behaviors to circumvent obstacles. We identify a curvature-sensing mechanism underlying obstacle evasion in immune-like cells. Specifically, we propose that actin polymerization at the advancing edge of migrating cells is inhibited by the curvature-sensitive BAR domain protein Snx33 in regions with inward plasma membrane curvature. The genetic perturbation of this machinery reduces the cells’ capacity to evade obstructions combined with faster and more persistent cell migration in obstacle-free environments. Our results show how cells can read out their surface topography and utilize actin and plasma membrane biophysics to interpret their environment, allowing them to adaptively decide if they should move ahead or turn away. On the basis of our findings, we propose that the natural diversity of BAR domain proteins may allow cells to tune their curvature sensing machinery to match the shape characteristics in their environment.
Facile hermetic TEM grid preparation for molecular imaging of hydrated biological samples at room temperature
Authors: Kong Lingli , Liu Jianfang , Zhang Meng , Lu Zhuoyang , Xue Han , Ren Amy , Liu Jiankang , Li Jinping , Ling Wai Li , Ren Gang
Published: September 2023

Although structures of vitrified supramolecular complexes have been determined at near-atomic resolution, elucidating in situ molecular structure in living cells remains a challenge. Here, we report a straightforward liquid cell technique, originally developed for real-time visualization of dynamics at a liquid-gas interface using transmission electron microscopy, to image wet biological samples. Due to the scattering effects from the liquid phase, the micrographs display an amplitude contrast comparable to that observed in negatively stained samples. We succeed in resolving subunits within the protein complex GroEL imaged in a buffer solution at room temperature. Additionally, we capture various stages of virus cell entry, a process for which only sparse structural data exists due to their transient nature. To scrutinize the morphological details further, we used individual particle electron tomography for 3D reconstruction of each virus. These findings showcase this approach potential as an efficient, cost-effective complement to other microscopy technique in addressing biological questions at the molecular level.
De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8
Authors: Roy Anindya , Shi Lei , Chang Ashley , Dong Xianchi , Fernandez Andres , Kraft John C. , Li Jing , Le Viet Q. , Winegar Rebecca Viazzo , Cherf Gerald Maxwell , Slocum Dean , Poulson P. Daniel , Casper Garrett E. , Vallecillo-Zúniga Mary L. , Valdoz Jonard Corpuz , Miranda Marcos C. , Bai Hua , Kipnis Yakov , Olshefsky Audrey , Priya Tanu , Carter Lauren , Ravichandran Rashmi , Chow Cameron M. , Johnson Max R. , Cheng Suna , Smith McKaela , Overed-Sayer Catherine , Finch Donna K. , Lowe David , Bera Asim K. , Matute-Bello Gustavo , Birkland Timothy P. , DiMaio Frank , Raghu Ganesh , Cochran Jennifer R. , Stewart Lance J. , Campbell Melody G. , Van Ry Pam M. , Springer Timothy , Baker David
Published: September 2023

The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.
Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets
Authors: Mihalič Filip , Benz Caroline , Kassa Eszter , Lindqvist Richard , Simonetti Leandro , Inturi Raviteja , Aronsson Hanna , Andersson Eva , Chi Celestine N. , Davey Norman E. , Överby Anna K. , Jemth Per , Ivarsson Ylva
Published: September 2023

The virus life cycle depends on host-virus protein-protein interactions, which often involve a disordered protein region binding to a folded protein domain. Here, we used proteomic peptide phage display (ProP-PD) to identify peptides from the intrinsically disordered regions of the human proteome that bind to folded protein domains encoded by the SARS-CoV-2 genome. Eleven folded domains of SARS-CoV-2 proteins were found to bind 281 peptides from human proteins, and affinities of 31 interactions involving eight SARS-CoV-2 protein domains were determined (KD ∼ 7-300 μM). Key specificity residues of the peptides were established for six of the interactions. Two of the peptides, binding Nsp9 and Nsp16, respectively, inhibited viral replication. Our findings demonstrate how high-throughput peptide binding screens simultaneously identify potential host-virus interactions and peptides with antiviral properties. Furthermore, the high number of low-affinity interactions suggest that overexpression of viral proteins during infection may perturb multiple cellular pathways.
Single neuron responses underlying face recognition in the human midfusiform face-selective cortex
Authors: Quian Quiroga Rodrigo , Boscaglia Marta , Jonas Jacques , Rey Hernan G. , Yan Xiaoqian , Maillard Louis , Colnat-Coulbois Sophie , Koessler Laurent , Rossion Bruno
Published: September 2023

Faces are critical for social interactions and their recognition constitutes one of the most important and challenging functions of the human brain. While neurons responding selectively to faces have been recorded for decades in the monkey brain, face-selective neural activations have been reported with neuroimaging primarily in the human midfusiform gyrus. Yet, the cellular mechanisms producing selective responses to faces in this hominoid neuroanatomical structure remain unknown. Here we report single neuron recordings performed in 5 human subjects (1 male, 4 females) implanted with intracerebral microelectrodes in the face-selective midfusiform gyrus, while they viewed pictures of familiar and unknown faces and places. We observed similar responses to faces and places at the single cell level, but a significantly higher number of neurons responding to faces, thus offering a mechanistic account for the face-selective activations observed in this region. Although individual neurons did not respond preferentially to familiar faces, a population level analysis could consistently determine whether or not the faces (but not the places) were familiar, only about 50 ms after the initial recognition of the stimuli as faces. These results provide insights into the neural mechanisms of face processing in the human brain.
Chiral recognition of neutral guests by chiral naphthotubes with a bis-thiourea endo-functionalized cavity
Authors: Wang Song-Meng , Wang Yan-Fang , Huang Liping , Zheng Li-Shuo , Nian Hao , Zheng Yu-Tao , Yao Huan , Jiang Wei , Wang Xiaoping , Yang Liu-Pan
Published: September 2023

Developing chiral receptors with an endo-functionalized cavity for chiral recognition is of great significance in the field of molecular recognition. This study presents two pairs of chiral naphthotubes containing a bis-thiourea endo-functionalized cavity. Each chiral naphthotube has two homochiral centers which were fixed adjacent to the thiourea groups, causing the skeleton and thiourea groups to twist enantiomerically through chiral transfer. These chiral naphthotubes are highly effective at enantiomerically recognizing various neutral chiral molecules with an enantioselectivity up to 17.0. Furthermore, the mechanism of the chiral recognition has been revealed to be originated from differences in multiple non-covalent interactions. Various factors, such as the shape of cavities, substituents of guests, flexibility of host and binding modes are demonstrated to contribute to creating differences in the non-covalent interactions. Additionally, the driving force behind enantioselectivity is mainly attributed to enthalpic differences, and enthalpy -entropy compensation has also been observed to influence enantioselectivity.
Surface-immobilized cross-linked cationic polyelectrolyte enables CO2 reduction with metal cation-free acidic electrolyte
Authors: Qin Hai-Gang , Du Yun-Fan , Bai Yi-Yang , Li Fu-Zhi , Yue Xian , Wang Hao , Peng Jian-Zhao , Gu Jun
Published: September 2023

Electrochemical CO2 reduction in acidic electrolytes is a promising strategy to achieve high utilization efficiency of CO2. Although alkali cations in acidic electrolytes play a vital role in suppressing hydrogen evolution and promoting CO2 reduction, they also cause precipitation of bicarbonate on the gas diffusion electrode (GDE), flooding of electrolyte through the GDE, and drift of the electrolyte pH. In this work, we realize the electroreduction of CO2 in a metal cation-free acidic electrolyte by covering the catalyst with cross-linked poly-diallyldimethylammonium chloride. This polyelectrolyte provides a high density of cationic sites immobilized on the surface of the catalyst, which suppresses the mass transport of H+ and modulates the interfacial field strength. By adopting this strategy, the Faradaic efficiency (FE) of CO reaches 95 ± 3% with the Ag catalyst and the FE of formic acid reaches 76 ± 3% with the In catalyst in a 1.0 pH electrolyte in a flow cell. More importantly, with the metal cation-free acidic electrolyte the amount of electrolyte flooding through the GDE is decreased to 2.5 ± 0.6% of that with alkali cation-containing acidic electrolyte, and the FE of CO maintains above 80% over 36 h of operation at −200 mA·cm−2.
Genetically encoded discovery of perfluoroaryl macrocycles that bind to albumin and exhibit extended circulation in vivo
Authors: Wong Jeffrey Y. K. , Ekanayake Arunika I. , Kharchenko Serhii , Kirberger Steven E. , Qiu Ryan , Kelich Payam , Sarkar Susmita , Li Jiaqian , Fernandez Kleinberg X. , Alvizo-Paez Edgar R. , Miao Jiayuan , Kalhor-Monfared Shiva , John J. Dwyer , Kang Hongsuk , Choi Hwanho , Nuss John M. , Vederas John C. , Lin Yu-Shan , Macauley Matthew S. , Vukovic Lela , Pomerantz William C. K. , Derda Ratmir
Published: September 2023

Peptide-based therapeutics have gained attention as promising therapeutic modalities, however, their prevalent drawback is poor circulation half-life in vivo. In this paper, we report the selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine SNAr chemistry, with decafluoro-diphenylsulfone (DFS). Testing of the binding of the selected peptides to albumin identified SICRFFC as the lead sequence. We replaced DFS with isosteric pentafluorophenyl sulfide (PFS) and the PFS-SICRFFCGG exhibited KD = 4–6 µM towards human serum albumin. When injected in mice, the concentration of the PFS-SICRFFCGG in plasma was indistinguishable from the reference peptide, SA-21. More importantly, a conjugate of PFS-SICRFFCGG and peptide apelin-17 analogue (N3-PEG6-NMe17A2) showed retention in circulation similar to SA-21; in contrast, apelin-17 analogue was cleared from the circulation after 2 min. The PFS-SICRFFC is the smallest known peptide macrocycle with a significant affinity for human albumin and substantial in vivo circulation half-life. It is a productive starting point for future development of compact macrocycles with extended half-life in vivo.
Detection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas
Authors: Herrgott Grayson A. , Snyder James M. , She Ruicong , Malta Tathiane M. , Sabedot Thais S. , Lee Ian Y. , Pawloski Jacob , Podolsky-Gondim Guilherme G. , Asmaro Karam P. , Zhang Jiaqi , Cannella Cara E. , Nelson Kevin , Thomas Bartow , deCarvalho Ana C. , Hasselbach Laura A. , Tundo Kelly M. , Newaz Rehnuma , Transou Andrea , Morosini Natalia , Francisco Victor , Poisson Laila M. , Chitale Dhananjay , Mukherjee Abir , Mosella Maritza S. , Robin Adam M. , Walbert Tobias , Rosenblum Mark , Mikkelsen Tom , Kalkanis Steven , Tirapelli Daniela P. C. , Weisenberger Daniel J. , Carlotti Carlos G. , Rock Jack , Castro Ana Valeria , Noushmehr Houtan
Published: September 2023

Recurrence of meningiomas is unpredictable by current invasive methods based on surgically removed specimens. Identification of patients likely to recur using noninvasive approaches could inform treatment strategy, whether intervention or monitoring. In this study, we analyze the DNA methylation levels in blood (serum and plasma) and tissue samples from 155 meningioma patients, compared to other central nervous system tumor and non-tumor entities. We discover DNA methylation markers unique to meningiomas and use artificial intelligence to create accurate and universal models for identifying and predicting meningioma recurrence, using either blood or tissue samples. Here we show that liquid biopsy is a potential noninvasive and reliable tool for diagnosing and predicting outcomes in meningioma patients. This approach can improve personalized management strategies for these patients.
Laser-induced nitrogen fixation
Authors: Wang Huize , Seemakurthi Ranga Rohit , Chen Gao-Feng , Strauss Volker , Savateev Oleksandr , Hai Guangtong , Ding Liangxin , López Núria , Wang Haihui , Antonietti Markus
Published: September 2023

For decarbonization of ammonia production in industry, alternative methods by exploiting renewable energy sources have recently been explored. Nonetheless, they still lack yield and efficiency to be industrially relevant. Here, we demonstrate an advanced approach of nitrogen fixation to synthesize ammonia at ambient conditions via laser–induced multiphoton dissociation of lithium oxide. Lithium oxide is dissociated under non–equilibrium multiphoton absorption and high temperatures under focused infrared light, and the generated zero–valent metal spontaneously fixes nitrogen and forms a lithium nitride, which upon subsequent hydrolysis generates ammonia. The highest ammonia yield rate of 30.9 micromoles per second per square centimeter is achieved at 25 °C and 1.0 bar nitrogen. This is two orders of magnitude higher than state–of–the–art ammonia synthesis at ambient conditions. The focused infrared light here is produced by a commercial simple CO2 laser, serving as a demonstration of potentially solar pumped lasers for nitrogen fixation and other high excitation chemistry. We anticipate such laser-involved technology will bring unprecedented opportunities to realize not only local ammonia production but also other new chemistries .