bluuebunny/crossref_metadata_2025 huggingface dataset:
Intake of ultra-processed food, dietary diversity and the risk of nutritional inadequacy among adults in India
Authors: Mediratta Srishti , Ghosh Santu , Mathur Pulkit
Published: October 2023

Objective:

This study assessed diet diversity and consumption of ultra-processed foods and explored its impact on macronutrient intake and risk of micronutrient inadequacy.

Design:

Cross-sectional, non-probability snowball sampling.

Setting:

Nutrient intake was assessed using 24-h dietary recall method and diet diversity through FAO-diet diversity score (DDS). Mann–Whitney U test was used to assess differences in risk of inadequacy across gender. Spearman’s rank correlation assessed associations between energy contributed by ultra-processed food and risk of nutrient inadequacy.

Participants:

A total of 589 adults (20–40 years) belonging to upper-middle and high-income groups.

Results:

The average individual DDS was 4·4 ± 0·6. Most of the participants (>80 %) had intakes less than national recommendations of pulses/eggs/flesh foods, milk/milk products, fruits, vegetables and nuts. Ultra-processed foods contributed to 17 % of total energy intake, 12 % of protein, 17 % of carbohydrate, 29 % of added sugar, 20 % of total fat and 33 % of Na intake. The average risk of nutrient inadequacies for Zn (98 % v. 75 %), folate (67 % v. 22 %) and niacin (83 % v. 44 %) was higher among males than females (P < 0·001). The average risk of nutrient inadequacies for Fe (58 % v. 7 %), vitamin B6 (95 % v. 90 %) and vitamin A (68 % v. 44 %) was higher among females than males (P < 0·001). There was a positive correlation between energy contributed by ultra-processed food and risk of niacin (ρ = 0·136, P = 0·001) and folate (ρ = 0·089, P = 0·049) inadequacy.

Conclusion:

Reformulating ultra-processed food to reduce fat, sugar and salt and increase micronutrients and behaviour change communication strategies that promote dietary diversity will improve micronutrient adequacy and diet quality.
Enhanced De Facto Constraints Imposed by Non-legally Binding Instruments and Interactions with Normative Environment: An Analysis of the Joint Statements for the Conservation and Management of Japanese Eel Stock
Authors: HAGIWARA Kazuki
Published: October 2023

Since 2012, Japan, China, South Korea, and Chinese Taipei have consecutively held informal consultation meetings to discuss the conservation of Japanese eel stock. As a conservation and management measure, these participants adopted the Joint Statement in 2014 to regulate the initial input of Japanese eel seeds into aquaculture ponds. Despite the fact that the input limits were de facto constraints, these measures were implemented as domestic legal regulations in each participant's jurisdiction. This study examines the nature of the de facto constraints imposed by the Joint Statement for conserving and managing Japanese eel stock as a case study of stock regulations. This study further explores the possibilities of strengthening the de facto constraints through interactions with the normative environment; that is, the principle of sustainable development, domestic laws, and the relevant provisions in the United Nations Convention on the Law of the Sea (UNCLOS).
Theorizing Subdisciplinary Exchange: Historical Sociology, Ethnography, and the Case of SSHA
Authors: Mayrl Damon , Wilson Nicholas Hoover , Mahler Matthew , Pacewicz Josh
Published: October 2023

What happens at the point of interchange between scholarly communities? We examine this question by investigating the case of growing ties between historical sociology and ethnography, two social scientific methods that once seemed to have little in common. Drawing on methodological writings by ethnographers and original interviews with practicing historical sociologists, we argue that these ties have been shaped by structural and methodological homologies between the two disciplines. Structurally, ethnography and historical sociology are similarly positioned in sociology more broadly, as enterprises with sometimes-tense relationships with dominant assumptions of the social sciences. Methodologically, both ethnographers and historical sociologists face the challenges of bounding the research process, navigating access to data, analyzing and retaining data while “in the field,” and overcoming cultural distance between themselves and the worlds they are studying. Taken together, these findings extend work in the sociology of science and knowledge and suggest some key conditions for intellectual efflorescence.
A systematic review of endovenous ablation for the treatment of small	saphenous varicose veins
Authors: Tan Junjie , Chen Yanhui , Huang Jianwen , Xu Weiguo
Published: October 2023

Summary: Insufficiency of the small saphenous vein causes 15% of varicose veins in the lower extremities. Endovenous ablation for the treatment of small saphenous vein varices has become a trend, and an increasing number of studies have reported the effects of different types of endovenous ablation in patients with small saphenous varicose veins. The purpose of this systematic review is to summarize the results of existing studies on endovenous ablation for the treatment of small saphenous varicose veins, compare its role and efficacy, and provide insights into the future development of endovenous ablation for treating small saphenous varicose veins. A systematic review of literature published from January 1, 2002 to January 1, 2022 was conducted from PubMed, Embase, and China Academic Journals full-text databases. The pre-determined inclusion criteria were clinical literature of endovenous ablation for treating small saphenous varicose veins. Keywords included “ablation”, “small saphenous vein”, “lesser saphenous vein”, “short saphenous vein”, “xiaoyinjingmai” and “xiaorong”. Of the 506 articles screened, 33 articles were included in this review: 19 articles were related to endovenous laser ablation, five were related to mechanochemical ablation, seven were related to radiofrequency ablation, and two were related to both endovenous laser ablation and radiofrequency ablation. The anatomical success rate of endovenous laser ablation, radiofrequency ablation, and mechanochemical ablation were 94.3%, 96.0%, and 88.1%, respectively, and the heterogeneities were all moderate. Most of the current studies are of a low-quality level of research. Hence, long-term follow-up studies and large-scale randomized controlled trials are required to obtain high-quality evidence. Although the gold standard for the treatment of small saphenous vein insufficiency remains unclear, endovenous ablation is still the recommended method.
Climatology of Large Peak Current Cloud‐to‐Ground Lightning Flashes in China’s Most Populous Areas
Authors: Wang Fei , Zhang Yijun , Chen Luwen , Zhang Yang , Yao Wen , Zheng Dong
Published: October 2023

Using a 10‐year data set of cloud‐to‐ground lightning (CG) flashes, the climatological characteristics of ±CG flashes with a large peak current (>75 kA or <−75 kA) (±LPCCGs) are for the first time obtained in China’s most populous areas in terms of density distribution, seasonal variation, and monthly and diurnal evolution. The results show that the distribution of +LPCCG flashes has evident seasonal variations, while the activity center of −LPCCG flashes always remains in Southwest China. The diurnal evolution of +LPCCG flash percentages in southern China’s Mainland shows an opposite trend to that in the north. Furthermore, the peak current distributions of +LPCCG flashes in most of China’s mainland are found to be distinct from those shown in other regions of the world. Additionally, Southwest China is found to be an important and special area for LPCCG flash activity in China. Not only is it the density center of ±LPCCG flashes, but the peak current distribution of −LPCCG flashes in this region also shows an evidently different pattern from those in other regions. The diurnal evolution of the ‐LPCCG/+LPCCG flash frequencies in Southwest China also shows a different pattern from that in other regions.
Paleo‐Evolution of Martian Subsurface Ice and Its Role in the Polar Physical and Isotopic Layering
Authors: Vos E. , Aharonson O. , Schörghofer N. , Forget F. , Lange L. , Millour E.
Published: October 2023

Mars harbors ice deposits in several forms, on the surface and in the subsurface, which exchange with each other on various timescales. We seek to study the pore ice evolution over millennial time scales and how it contributes to and affects the Polar cap's evolution. We calculate the evolution of SubSurface Ice (SSI) pore filling by coupling two models, the Mars LMD Global Climate Model, which calculates the atmospheric and surface evolution on an annual timescale, and the dynamical version of the Mars Subsurface Ice Model, which calculates the evolution of the SSI on a millennial timescale. The SSI latitudinal boundary fluctuates over more than 25° in one obliquity cycle, overall extending equatorward of latitude ±35° at high obliquity, and receding to about ±60° at low obliquity. In locations where the SSI is stable continuously over orbital cycles, the simulations predict layering caused by a sublimation front at the SSI top boundary. Between 5 and 2.5 Myr ago, the subsurface lost at least ∼95 m of polar equivalent layer ice. The SSI flux routinely reaches ∼1 mm/Mars year. In addition to the direct contribution to the growth of the North Polar Layered Deposits (NPLD), the SSI causes variations in the NPLD accumulation rate due to the changes in the SSI distribution that affect the seasonal energy budget. These variations are comparable to the change in rate due to variations in orbital elements. When running paleo‐climate simulations, particularly to reconstruct the NPLD profile, changes in the SSI distribution should be considered.
Targeting E3 ubiquitin ligases and their adaptors as a therapeutic strategy for metabolic diseases
Authors: Jeong Yelin , Oh Ah-Reum , Jung Young Hoon , Gi HyunJoon , Kim Young Un , Kim KyeongJin
Published: October 2023

Posttranslational modification of proteins via ubiquitination determines their activation, translocation, dysregulation, or degradation. This process targets a large number of cellular proteins, affecting all biological pathways involved in the cell cycle, development, growth, and differentiation. Thus, aberrant regulation of ubiquitination is likely associated with several diseases, including various types of metabolic diseases. Among the ubiquitin enzymes, E3 ubiquitin ligases are regarded as the most influential ubiquitin enzymes due to their ability to selectively bind and recruit target substrates for ubiquitination. Continued research on the regulatory mechanisms of E3 ligases and their adaptors in metabolic diseases will further stimulate the discovery of new targets and accelerate the development of therapeutic options for metabolic diseases. In this review, based on recent discoveries, we summarize new insights into the roles of E3 ubiquitin ligases and their adaptors in the pathogenesis of metabolic diseases by highlighting recent evidence obtained in both human and animal model studies.
Spatial transcriptomics in neuroscience
Authors: Jung Namyoung , Kim Tae-Kyung
Published: October 2023

The brain is one of the most complex living tissue types and is composed of an exceptional diversity of cell types displaying unique functional connectivity. Single-cell RNA sequencing (scRNA-seq) can be used to efficiently map the molecular identities of the various cell types in the brain by providing the transcriptomic profiles of individual cells isolated from the tissue. However, the lack of spatial context in scRNA-seq prevents a comprehensive understanding of how different configurations of cell types give rise to specific functions in individual brain regions and how each distinct cell is connected to form a functional unit. To understand how the various cell types contribute to specific brain functions, it is crucial to correlate the identities of individual cells obtained through scRNA-seq with their spatial information in intact tissue. Spatial transcriptomics (ST) can resolve the complex spatial organization of cell types in the brain and their connectivity. Various ST tools developed during the past decade based on imaging and sequencing technology have permitted the creation of functional atlases of the brain and have pulled the properties of neural circuits into ever-sharper focus. In this review, we present a summary of several ST tools and their applications in neuroscience and discuss the unprecedented insights these tools have made possible.
Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism
Authors: An Yong Jin , Jo Sihyang , Kim Jin-Mo , Kim Han Sun , Kim Hyun Young , Jeon Sang-Min , Han Dawool , Yook Jong In , Kang Keon Wook , Park Sunghyouk
Published: October 2023

Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both in cells and in purified nuclei, 13C3-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In the purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), knockout (KO) of which abrogates incorporation. Heterologous expression of nucleus-localized LDHA reverses the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence on the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism–epigenetics axis controlled by the cell’s own status or the environmental status.
Lipocalin-2: a therapeutic target to overcome neurodegenerative diseases by regulating reactive astrogliosis
Authors: Jung Byung-Kwon , Ryu Kwon-Yul
Published: October 2023

Glial cell activation precedes neuronal cell death during brain aging and the progression of neurodegenerative diseases. Under neuroinflammatory stress conditions, lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin or 24p3, is produced and secreted by activated microglia and reactive astrocytes. Lcn2 expression levels are known to be increased in various cells, including reactive astrocytes, through the activation of the NF-κB signaling pathway. In the central nervous system, as LCN2 exerts neurotoxicity when secreted from reactive astrocytes, many researchers have attempted to identify various strategies to inhibit LCN2 production, secretion, and function to minimize neuroinflammation and neuronal cell death. These strategies include regulation at the transcriptional, posttranscriptional, and posttranslational levels, as well as blocking its functions using neutralizing antibodies or antagonists of its receptor. The suppression of NF-κB signaling is a strategy to inhibit LCN2 production, but it may also affect other cellular activities, raising questions about its effectiveness and feasibility. Recently, LCN2 was found to be a target of the autophagy‒lysosome pathway. Therefore, autophagy activation may be a promising therapeutic strategy to reduce the levels of secreted LCN2 and overcome neurodegenerative diseases. In this review, we focused on research progress on astrocyte-derived LCN2 in the central nervous system.
NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections
Authors: Klabunde Björn , Wesener André , Bertrams Wilhelm , Beinborn Isabell , Paczia Nicole , Surmann Kristin , Blankenburg Sascha , Wilhelm Jochen , Serrania Javier , Knoops Kèvin , Elsayed Eslam M. , Laakmann Katrin , Jung Anna Lena , Kirschbaum Andreas , Hammerschmidt Sven , Alshaar Belal , Gisch Nicolas , Abu Mraheil Mobarak , Becker Anke , Völker Uwe , Vollmeister Evelyn , Benedikter Birke J. , Schmeck Bernd
Published: October 2023

Lower respiratory tract infections caused byStreptococcus pneumoniae(Spn) are a leading cause of death globally. Here we investigate the bronchial epithelial cellular response toSpninfection on a transcriptomic, proteomic and metabolic level. We found the NAD+salvage pathway to be dysregulated upon infection in a cell line model, primary human lung tissue and in vivo in rodents, leading to a reduced production of NAD+. Knockdown of NAD+salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD+treatment ofSpninhibited its growth while growth of other respiratory pathogens improved. Boosting NAD+production increased NAD+levels in immortalized and primary cells and decreased bacterial replication upon infection. NAD+treatment ofSpndysregulated the bacterial metabolism and reduced intrabacterial ATP. Enhancing the bacterial ATP metabolism abolished the antibacterial effect of NAD+. Thus, we identified the NAD+salvage pathway as an antibacterial pathway inSpninfections, predicting an antibacterial mechanism of NAD+.
Global organic and inorganic aerosol hygroscopicity and its effect on radiative forcing
Authors: Pöhlker Mira L. , Pöhlker Christopher , Quaas Johannes , Mülmenstädt Johannes , Pozzer Andrea , Andreae Meinrat O. , Artaxo Paulo , Block Karoline , Coe Hugh , Ervens Barbara , Gallimore Peter , Gaston Cassandra J. , Gunthe Sachin S. , Henning Silvia , Herrmann Hartmut , Krüger Ovid O. , McFiggans Gordon , Poulain Laurent , Raj Subha S. , Reyes-Villegas Ernesto , Royer Haley M. , Walter David , Wang Yuan , Pöschl Ulrich
Published: October 2023

The climate effects of atmospheric aerosol particles serving as cloud condensation nuclei (CCN) depend on chemical composition and hygroscopicity, which are highly variable on spatial and temporal scales. Here we present global CCN measurements, covering diverse environments from pristine to highly polluted conditions. We show that the effective aerosol hygroscopicity,κ, can be derived accurately from the fine aerosol mass fractions of organic particulate matter (ϵorg) and inorganic ions (ϵinorg) through a linear combination,κ = ϵorg ⋅ κorg + ϵinorg ⋅ κinorg. In spite of the chemical complexity of organic matter, its hygroscopicity is well captured and represented by a global average value ofκorg = 0.12 ± 0.02 withκinorg = 0.63 ± 0.01 as the corresponding value for inorganic ions. By showing that the sensitivity of global climate forcing to changes inκorgandκinorgis small, we constrain a critically important aspect of global climate modelling.
Mechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy
Authors: Wang Yingwei , Li Qi , Zhao Jupeng , Chen Jiamin , Wu Dongxue , Zheng Youling , Wu Jiaxin , Liu Jie , Lu Jianlong , Zhang Jianhua , Wu Zheng
Published: October 2023

Current approaches in myocardial infarction treatment are limited by low cellular oxidative stress resistance, reducing the long-term survival of therapeutic cells. Here we develop a liquid-crystal substrate with unique surface properties and mechanical responsiveness to produce size-controllable cardiospheres that undergo pyroptosis to improve cellular bioactivities and resistance to oxidative stress. We perform RNA sequencing and study cell metabolism to reveal increased metabolic levels and improved mitochondrial function in the preconditioned cardiospheres. We test therapeutic outcomes in a rat model of myocardial infarction to show that cardiospheres improve long-term cardiac function, promote angiogenesis and reduce cardiac remodeling during the 3-month observation. Overall, this study presents a promising and effective system for preparing a large quantity of functional cardiospheres, showcasing potential for clinical application.
Efficient magnetic switching in a correlated spin glass
Authors: Krempaský Juraj , Springholz Gunther , D’Souza Sunil Wilfred , Caha Ondřej , Gmitra Martin , Ney Andreas , Vaz C. A. F. , Piamonteze Cinthia , Fanciulli Mauro , Kriegner Dominik , Krieger Jonas A. , Prokscha Thomas , Salman Zaher , Minár Jan , Dil J. Hugo
Published: October 2023

The interplay between spin-orbit interaction and magnetic order is one of the most active research fields in condensed matter physics and drives the search for materials with novel, and tunable, magnetic and spin properties. Here we report on a variety of unique and unexpected observations in thin multiferroic Ge1−xMnxTe films. The ferrimagnetic order parameter in this ferroelectric semiconductor is found to switch direction under magnetostochastic resonance with current pulses many orders of magnitude lower as for typical spin-orbit torque systems. Upon a switching event, the magnetic order spreads coherently and collectively over macroscopic distances through a correlated spin-glass state. Utilizing these observations, we apply a novel methodology to controllably harness this stochastic magnetization dynamics.
A cleaner snow future mitigates Northern Hemisphere snowpack loss from warming
Authors: Hao Dalei , Bisht Gautam , Wang Hailong , Xu Donghui , Huang Huilin , Qian Yun , Leung L. Ruby
Published: October 2023

Light-absorbing particles (LAP) deposited on seasonal snowpack can result in snow darkening, earlier snowmelt, and regional climate change. However, their future evolution and contributions to snowpack change relative to global warming remain unclear. Here, using Earth System Model simulations, we project significantly reduced black carbon deposition by 2081-2100, which reduces the December-May average LAP-induced radiative forcing in snow over the Northern Hemisphere from 1.3 Wm−2 during 1995-2014 to 0.65 (SSP126) and 0.49 (SSP585) Wm−2. We quantify separately the contributions of climate change and LAP evolution on future snowpack and demonstrate that projected LAP changes in snow over the Tibetan Plateau will alleviate future snowpack loss due to climate change by 52.1 ± 8.0% and 8.0 ± 1.1% at the end of the century for the two scenarios, mainly due to reduced black carbon contamination. Our findings highlight a cleaner snow future and its benefits for future water supply from snowmelt especially under the sustainable development pathway of SSP126.
Thin lamellar films with enhanced mechanical properties for durable radiative cooling
Authors: Xiong Lianhu , Wei Yun , Chen Chuanliang , Chen Xin , Fu Qiang , Deng Hua
Published: October 2023

Passive daytime radiative cooling is a promising path to tackle energy, environment and security issues originated from global warming. However, the contradiction between desired high solar reflectivity and necessary applicable performance is a major limitation at this stage. Herein, we demonstrate a “Solvent exchange-Reprotonation” processing strategy to fabricate a lamellar structure integrating aramid nanofibers with core-shell TiO2-coated Mica microplatelets for enhanced strength and durability without compromising optical performance. Such approach enables a slow but complete two-step protonation transition and the formation of three-dimensional dendritic networks with strong fibrillar joints, where overloaded scatterers are stably grasped and anchored in alignment, thereby resulting in a high strength of ~112 MPa as well as excellent environmental durability including ultraviolet aging, high temperature, scratches, etc. Notably, the strong backward scattering excited by multiple core-shell and shell-air interfaces guarantees a balanced reflectivity (~92%) and thickness (~25 μm), which is further revealed by outdoor tests where attainable subambient temperature drops are ~3.35 °C for daytime and ~6.11 °C for nighttime. Consequently, both the cooling capacity and comprehensive outdoor-services performance, greatly push radiative cooling towards real-world applications.
Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15
Authors: Moro Ramona N. , Biswas Uddipta , Kharat Suhas S. , Duzanic Filip D. , Das Prosun , Stavrou Maria , Raso Maria C. , Freire Raimundo , Chaudhuri Arnab Ray , Sharan Shyam K. , Penengo Lorenza
Published: October 2023

DNA replication and repair defects or genotoxic treatments trigger interferon (IFN)-mediated inflammatory responses. However, whether and how IFN signaling in turn impacts the DNA replication process has remained elusive. Here we show that basal levels of the IFN-stimulated gene 15, ISG15, and its conjugation (ISGylation) are essential to protect nascent DNA from degradation. Moreover, IFNβ treatment restores replication fork stability in BRCA1/2-deficient cells, which strictly depends on topoisomerase-1, and rescues lethality of BRCA2-deficient mouse embryonic stem cells. Although IFNβ activates hundreds of genes, these effects are specifically mediated by ISG15 and ISGylation, as their inactivation suppresses the impact of IFNβ on DNA replication. ISG15 depletion significantly reduces cell proliferation rates in human BRCA1-mutated triple-negative, whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, which we propose as an in-built mechanism of drug resistance linked to BRCAness.
Orientation distributions of vacuum-deposited organic emitters revealed by single-molecule microscopy
Authors: Tenopala-Carmona Francisco , Hertel Dirk , Hillebrandt Sabina , Mischok Andreas , Graf Arko , Weitkamp Philipp , Meerholz Klaus , Gather Malte C.
Published: October 2023

The orientation of luminescent molecules in organic light-emitting diodes strongly influences device performance. However, our understanding of the factors controlling emitter orientation is limited as current measurements only provide ensemble-averaged orientation values. Here, we use single-molecule imaging to measure the transition dipole orientation of individual emitter molecules in a state-of-the-art thermally evaporated host and thereby obtain complete orientation distributions of the hyperfluorescence-terminal emitter C545T. We achieve this by realizing ultra-low doping concentrations (10−6 wt%) of C545T and minimising background levels to reliably measure its photoluminescence. This approach yields the orientation distributions of >1000 individual emitter molecules in a system relevant to vacuum-processed devices. Analysis of solution- and vacuum-processed systems reveals that the orientation distributions strongly depend on the nanoscale environment of the emitter. This work opens the door to attaining unprecedented information on the factors that determine emitter orientation in current and future material systems for organic light-emitting devices.
Multifaceted analysis of cross-tissue transcriptomes reveals phenotype–endotype associations in atopic dermatitis
Authors: Sekita Aiko , Kawasaki Hiroshi , Fukushima-Nomura Ayano , Yashiro Kiyoshi , Tanese Keiji , Toshima Susumu , Ashizaki Koichi , Miyai Tomohiro , Yazaki Junshi , Kobayashi Atsuo , Namba Shinichi , Naito Tatsuhiko , Wang Qingbo S. , Kawakami Eiryo , Seita Jun , Ohara Osamu , Sakurada Kazuhiro , Okada Yukinori , Amagai Masayuki , Koseki Haruhiko
Published: October 2023

Atopic dermatitis (AD) is a skin disease that is heterogeneous both in terms of clinical manifestations and molecular profiles. It is increasingly recognized that AD is a systemic rather than a local disease and should be assessed in the context of whole-body pathophysiology. Here we show, via integrated RNA-sequencing of skin tissue and peripheral blood mononuclear cell (PBMC) samples along with clinical data from 115 AD patients and 14 matched healthy controls, that specific clinical presentations associate with matching differential molecular signatures. We establish a regression model based on transcriptome modules identified in weighted gene co-expression network analysis to extract molecular features associated with detailed clinical phenotypes of AD. The two main, qualitatively differential skin manifestations of AD, erythema and papulation are distinguished by differential immunological signatures. We further apply the regression model to a longitudinal dataset of 30 AD patients for personalized monitoring, highlighting patient heterogeneity in disease trajectories. The longitudinal features of blood tests and PBMC transcriptome modules identify three patient clusters which are aligned with clinical severity and reflect treatment history. Our approach thus serves as a framework for effective clinical investigation to gain a holistic view on the pathophysiology of complex human diseases.
Mechanistic insight on water dissociation on pristine low-index TiO2 surfaces from machine learning molecular dynamics simulations
Authors: Zeng Zezhu , Wodaczek Felix , Liu Keyang , Stein Frederick , Hutter Jürg , Chen Ji , Cheng Bingqing
Published: October 2023

Water adsorption and dissociation processes on pristine low-index TiO2 interfaces are important but poorly understood outside the well-studied anatase (101) and rutile (110). To understand these, we construct three sets of machine learning potentials that are simultaneously applicable to various TiO2 surfaces, based on three density-functional-theory approximations. Here we show the water dissociation free energies on seven pristine TiO2 surfaces, and predict that anatase (100), anatase (110), rutile (001), and rutile (011) favor water dissociation, anatase (101) and rutile (100) have mostly molecular adsorption, while the simulations of rutile (110) sensitively depend on the slab thickness and molecular adsorption is preferred with thick slabs. Moreover, using an automated algorithm, we reveal that these surfaces follow different types of atomistic mechanisms for proton transfer and water dissociation: one-step, two-step, or both. These mechanisms can be rationalized based on the arrangements of water molecules on the different surfaces. Our finding thus demonstrates that the different pristine TiO2 surfaces react with water in distinct ways, and cannot be represented using just the low-energy anatase (101) and rutile (110) surfaces.
PIWI-interacting RNA expression regulates pathogenesis in a Caenorhabditis elegans model of Lewy body disease
Authors: Huang Xiaobing , Wang Changliang , Zhang Tianjiao , Li Rongzhen , Chen Liang , Leung Ka Lai , Lakso Merja , Zhou Qinghua , Zhang Hongjie , Wong Garry
Published: October 2023

PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that regulate gene expression, yet their molecular functions in neurobiology are unclear. While investigating neurodegeneration mechanisms using human α-syn(A53T)Tg and AβTg;α-syn(A53T)Tg pan-neuronal overexpressing strains, we unexpectedly observed dysregulation of piRNAs. RNAi screening revealed that knock down of piRNA biogenesis genes improved thrashing behavior; further, a tofu-1 gene deletion ameliorated phenotypic deficits in α-syn(A53T)Tg and AβTg;α-syn(A53T)Tg transgenic strains. piRNA expression was extensively downregulated and H3K9me3 marks were decreased after tofu-1 deletion in α-syn(A53T)Tg and AβTg;α-syn(A53T)Tg strains. Dysregulated piRNAs targeted protein degradation genes suggesting that a decrease of piRNA expression leads to an increase of degradation ability in C. elegans. Finally, we interrogated piRNA expression in brain samples from PD patients. piRNAs were observed to be widely overexpressed at late motor stage. In this work, our results provide evidence that piRNAs are mediators in pathogenesis of Lewy body diseases and suggest a molecular mechanism for neurodegeneration in these and related disorders.
Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation
Authors: Wang Xiaoquan , Wang Youqiao , Cao Anqi , Luo Qinhong , Chen Daoyuan , Zhao Weiqi , Xu Jun , Li Qinkai , Bu Xianzhang , Quan Junmin
Published: October 2023

Cyclic GMP-AMP synthase (cGAS) is an essential sensor of aberrant cytosolic DNA for initiating innate immunity upon invading pathogens and cellular stress, which is considered as a potential drug target for autoimmune and autoinflammatory diseases. Here, we report the discovery of a class of cyclopeptide inhibitors of cGAS identified by an in vitro screening assay from a focused library of cyclic peptides. These cyclopeptides specifically bind to the DNA binding site of cGAS and block the binding of dsDNA with cGAS, subsequently inhibit dsDNA-induced liquid phase condensation and activation of cGAS. The specificity and potency of one optimal lead XQ2B were characterized in cellular assays. Concordantly, XQ2B inhibited herpes simplex virus-1 (HSV-1)-induced antiviral immune responses and enhanced HSV-1 infection in vitro and in vivo. Furthermore, XQ2B significantly suppressed the elevated levels of type I interferon and proinflammatory cytokines in primary macrophages from Trex1-/- mice and systemic inflammation in Trex1-/- mice. XQ2B represents the specific cGAS inhibitor targeting protein-DNA interaction and phase separation and serves as a scaffold for the development of therapies in the treatment of cGAS-dependent inflammatory diseases.
Ecological mechanisms and current systems shape the modular structure of the global oceans’ prokaryotic seascape
Authors: Milke Felix , Meyerjürgens Jens , Simon Meinhard
Published: October 2023

Major biogeographic features of the microbial seascape in the oceans have been established and their underlying ecological mechanisms in the (sub)tropical oceans and the Pacific Ocean identified. However, we still lack a unifying understanding of how prokaryotic communities and biogeographic patterns are affected by large-scale current systems in distinct ocean basins and how they are globally shaped in line with ecological mechanisms. Here we show that prokaryotic communities in the epipelagic Pacific and Atlantic Ocean, in the southern Indian Ocean, and the Mediterranean Sea are composed of modules of co-occurring taxa with similar environmental preferences. The relative partitioning of these modules varies along latitudinal and longitudinal gradients and are related to different hydrographic and biotic conditions. Homogeneous selection and dispersal limitation were identified as the major ecological mechanisms shaping these communities and their free-living (FL) and particle-associated (PA) fractions. Large-scale current systems govern the dispersal of prokaryotic modules leading to the highest diversity near subtropical fronts.
Fitness cost associated with cell phenotypic switching drives population diversification dynamics and controllability
Authors: Henrion Lucas , Martinez Juan Andres , Vandenbroucke Vincent , Delvenne Mathéo , Telek Samuel , Zicler Andrew , Grünberger Alexander , Delvigne Frank
Published: October 2023

Isogenic cell populations can cope with stress conditions by switching to alternative phenotypes. Even if it can lead to increased fitness in a natural context, this feature is typically unwanted for a range of applications (e.g., bioproduction, synthetic biology, and biomedicine) where it tends to make cellular response unpredictable. However, little is known about the diversification profiles that can be adopted by a cell population. Here, we characterize the diversification dynamics for various systems (bacteria and yeast) and for different phenotypes (utilization of alternative carbon sources, general stress response and more complex development patterns). Our results suggest that the diversification dynamics and the fitness cost associated with cell switching are coupled. To quantify the contribution of the switching cost on population dynamics, we design a stochastic model that let us reproduce the dynamics observed experimentally and identify three diversification regimes, i.e., constrained (at low switching cost), dispersed (at medium and high switching cost), and bursty (for very high switching cost). Furthermore, we use a cell-machine interface called Segregostat to demonstrate that different levels of control can be applied to these diversification regimes, enabling applications involving more precise cellular responses.
Generative complex networks within a dynamic memristor with intrinsic variability
Authors: Guo Yunpeng , Duan Wenrui , Liu Xue , Wang Xinxin , Wang Lidan , Duan Shukai , Ma Cheng , Li Huanglong
Published: October 2023

Artificial neural networks (ANNs) have gained considerable momentum in the past decade. Although at first the main task of the ANN paradigm was to tune the connection weights in fixed-architecture networks, there has recently been growing interest in evolving network architectures toward the goal of creating artificial general intelligence. Lagging behind this trend, current ANN hardware struggles for a balance between flexibility and efficiency but cannot achieve both. Here, we report on a novel approach for the on-demand generation of complex networks within a single memristor where multiple virtual nodes are created by time multiplexing and the non-trivial topological features, such as small-worldness, are generated by exploiting device dynamics with intrinsic cycle-to-cycle variability. When used for reservoir computing, memristive complex networks can achieve a noticeable increase in memory capacity a and respectable performance boost compared to conventional reservoirs trivially implemented as fully connected networks. This work expands the functionality of memristors for ANN computing.
Control of metal oxides’ electronic conductivity through visual intercalation chemical reactions
Authors: Zhang Yuanyuan , Zhang Xiaohua , Pang Quanquan , Yan Jianhua
Published: October 2023

Cation intercalation is an effective method to optimize the electronic structures of metal oxides, but tuning intercalation structure and conductivity by manipulating ion movement is difficult. Here, we report a visual topochemical synthesis strategy to control intercalation pathways and structures and realize the rapid synthesis of flexible conductive metal oxide films in one minute at room temperature. Using flexible TiO2 nanofiber films as the prototype, we design three charge-driven models to intercalate preset Li+-ions into the TiO2 lattice slowly (µm/s), rapidly (mm/s), or ultrafast (cm/s). The Li+-intercalation causes real-time color changes of the TiO2 films from white to blue and then black, corresponding to the structures of LixTiO2 and LixTiO2-δ, and the enhanced conductivity from 0 to 1 and 40 S/m. This work realizes large-scale and rapid synthesis of flexible TiO2 nanofiber films with tunable conductivity and is expected to extend the synthesis to other conductive metal oxide films.
Defeating depolarizing fields with artificial flux closure in ultrathin ferroelectrics
Authors: Gradauskaite Elzbieta , Meier Quintin N. , Gray Natascha , Sarott Martin F. , Scharsach Tizian , Campanini Marco , Moran Thomas , Vogel Alexander , Del Cid-Ledezma Karla , Huey Bryan D. , Rossell Marta D. , Fiebig Manfred , Trassin Morgan
Published: October 2023

Material surfaces encompass structural and chemical discontinuities that often lead to the loss of the property of interest in so-called dead layers. It is particularly problematic in nanoscale oxide electronics, where the integration of strongly correlated materials into devices is obstructed by the thickness threshold required for the emergence of their functionality. Here we report the stabilization of ultrathin out-of-plane ferroelectricity in oxide heterostructures through the design of an artificial flux-closure architecture. Inserting an in-plane-polarized ferroelectric epitaxial buffer provides the continuity of polarization at the interface; despite its insulating nature, we observe the emergence of polarization in our out-of-plane-polarized model of ferroelectric BaTiO3 from the very first unit cell. In BiFeO3, the flux-closure approach stabilizes a 251° domain wall. Its unusual chirality is probably associated with the ferroelectric analogue to the Dzyaloshinskii–Moriya interaction. We, thus, see that in an adaptively engineered geometry, the depolarizing-field-screening properties of an insulator can even surpass those of a metal and be a source of functionality. This could be a useful insight on the road towards the next generation of oxide electronics.
Acousto-optic modulation of gigawatt-scale laser pulses in ambient air
Authors: Schrödel Yannick , Hartmann Claas , Zheng Jiaan , Lang Tino , Steudel Max , Rutsch Matthias , Salman Sarper H. , Kellert Martin , Pergament Mikhail , Hahn-Jose Thomas , Suppelt Sven , Dörsam Jan Helge , Harth Anne , Leemans Wim P. , Kärtner Franz X. , Hartl Ingmar , Kupnik Mario , Heyl Christoph M.
Published: October 2023

Control over the intensity, shape, direction and phase of coherent light is essential in numerous fields, from gravitational wave astronomy, quantum metrology and ultrafast sciences to semiconductor fabrication. Modern photonics, however, can involve parameter regimes where the wavelength or high optical powers involved restrict control due to absorption, light-induced damage or optical nonlinearity in solid media. Here we propose to circumvent these constraints using gaseous media tailored by high-intensity ultrasound waves. We demonstrate an implementation of this approach by efficiently deflecting ultrashort laser pulses using ultrasound waves in ambient air, without the use of transmissive solid media. At optical peak powers of 20 GW, exceeding previous limits of solid-based acousto-optic modulation by about three orders of magnitude, we reach a deflection efficiency greater than 50% while preserving excellent beam quality. Our approach is not limited to laser pulse deflection; gas-phase photonic schemes controlled by sonic waves could potentially be useful for realizing a new class of optical elements such as lenses or waveguides, which are effectively invulnerable against damage and can operate in new spectral regions.
Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial
Authors: Galsky Matthew D. , Daneshmand Siamak , Izadmehr Sudeh , Gonzalez-Kozlova Edgar , Chan Kevin G. , Lewis Sara , Achkar Bassam El , Dorff Tanya B. , Cetnar Jeremy Paul , Neil Brock O. , D’Souza Anishka , Mamtani Ronac , Kyriakopoulos Christos , Jun Tomi , Gogerly-Moragoda Mahalya , Brody Rachel , Xie Hui , Nie Kai , Kelly Geoffrey , Horowitz Amir , Kinoshita Yayoi , Ellis Ethan , Nose Yohei , Ioannou Giorgio , Cabal Rafael , Del Valle Diane M. , Haines G. Kenneth , Wang Li , Mouw Kent W. , Samstein Robert M. , Mehrazin Reza , Bhardwaj Nina , Yu Menggang , Zhao Qianqian , Kim-Schulze Seunghee , Sebra Robert , Zhu Jun , Gnjatic Sacha , Sfakianos John , Pal Sumanta K.
Published: October 2023

Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy. Seventy-six patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval (CI): 32%, 55%), and 32 of 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI: 0.91, 1), meeting the co-primary objective. The most common adverse events were fatigue, anemia, neutropenia and nausea. Somatic alterations in pre-specified genes (ATM,RB1,FANCCandERCC2) or increased tumor mutational burden did not improve the positive predictive value of cCR. Exploratory analyses of peripheral blood mass cytometry and soluble protein analytes demonstrated an association between the baseline and on-treatment immune contexture with clinical outcomes. Stringently defined cCR after gemcitabine, cisplatin, plus nivolumab facilitated bladder sparing and warrants further study. ClinicalTrials.gov identifier:NCT03558087.
AZD5582 plus SIV-specific antibodies reduce lymph node viral reservoirs in antiretroviral therapy-suppressed macaques
Authors: Dashti Amir , Sukkestad Sophia , Horner Anna M. , Neja Margaret , Siddiqi Zain , Waller Chevaughn , Goldy Jordan , Monroe Dominique , Lin Alice , Schoof Nils , Singh Vidisha , Mavigner Maud , Lifson Jeffrey D. , Deleage Claire , Tuyishime Marina , Falcinelli Shane D. , King Hannah A. D. , Ke Ruian , Mason Rosemarie D. , Archin Nancie M. , Dunham Richard M. , Safrit Jeffrey T. , Jean Sherrie , Perelson Alan S. , Margolis David M. , Ferrari Guido , Roederer Mario , Silvestri Guido , Chahroudi Ann
Published: October 2023

The main barrier to HIV cure is a persistent reservoir of latently infected CD4+ T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach to target this reservoir involves agents that reactivate latent HIV proviruses followed by direct clearance of cells expressing induced viral antigens by immune effector cells and immunotherapeutics. We previously showed that AZD5582, an antagonist of inhibitor of apoptosis proteins and mimetic of the second mitochondrial-derived activator of caspases (IAPi/SMACm), induces systemic reversal of HIV/SIV latency but with no reduction in size of the viral reservoir. In this study, we investigated the effects of AZD5582 in combination with four SIV Env-specific Rhesus monoclonal antibodies (RhmAbs) ± N-803 (an IL-15 superagonist) in SIV-infected, ART-suppressed rhesus macaques. Here we confirm the efficacy of AZD5582 in inducing SIV reactivation, demonstrate enhancement of latency reversal when AZD5582 is used in combination with N-803 and show a reduction in total and replication-competent SIV-DNA in lymph-node-derived CD4+ T cells in macaques treated with AZD5582 + RhmAbs. Further exploration of this therapeutic approach may contribute to the goal of achieving an HIV cure.
Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial
Authors: Bahlis Nizar J. , Costello Caitlin L. , Raje Noopur S. , Levy Moshe Y. , Dholaria Bhagirathbhai , Solh Melhem , Tomasson Michael H. , Damore Michael A. , Jiang Sibo , Basu Cynthia , Skoura Athanasia , Chan Edward M. , Trudel Suzanne , Jakubowiak Andrzej , Gasparetto Cristina , Chu Michael P. , Dalovisio Andrew , Sebag Michael , Lesokhin Alexander M.
Published: October 2023

Multiple myeloma (MM) is a plasma cell malignancy expressing B cell maturation antigen (BCMA). Elranatamab, a bispecific antibody, engages BCMA on MM and CD3 on T cells. The MagnetisMM-1 trial evaluated its safety, pharmacokinetics and efficacy. Primary endpoints, including the incidence of dose-limiting toxicities as well as objective response rate (ORR) and duration of response (DOR), were met. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Eighty-eight patients with relapsed or refractory MM received elranatamab monotherapy, and 55 patients received elranatamab at efficacious doses. Patients had received a median of five prior regimens; 90.9% were triple-class refractory, 29.1% had high cytogenetic risk and 23.6% received prior BCMA-directed therapy. No dose-limiting toxicities were observed during dose escalation. Adverse events included cytopenias and cytokine release syndrome. Exposure was dose proportional. With a median follow-up of 12.0 months, the ORR was 63.6% and 38.2% of patients achieving complete response or better. For responders, the median DOR was 17.1 months. All 13 patients evaluable for minimal residual disease achieved negativity. Even after prior BCMA-directed therapy, 53.8% achieved response. For all 55 patients, median PFS was 11.8 months, and median OS was 21.2 months. Elranatamab achieved durable responses, manageable safety and promising survival for patients with MM. ClinicalTrials.gov Identifier: NCT03269136.