bluuebunny/crossref_metadata_2025 huggingface dataset:
A dimensionality reduction approach in helicopter level flight performance testing
Authors: Arush I. , Pavel M.D. , Mulder M.
Published: July 2023

Evaluation of the power required in level flight is essential to any new or modified helicopter performance flight-testing effort. The conventional flight-test method is based on an overly simplification of the induced and profile power components required for a helicopter in level flight. This simplistic approach incorporates several drawbacks that not only make execution of flight sorties inefficient and time consuming, but also compromise the level of accuracy achieved. This paper proposes an alternative flight-test method for evaluating the level-flight performance of a conventional helicopter while addressing and rectifying all identified deficiencies of the conventional method. The proposed method, referred to as the corrected-variables screening using dimensionality reduction (CVSDR), uses an original list of 36 corrected variables derived from basic dimensional analysis principles. This list of 36 corrected variables is reduced using tools of dimensionality reduction to keep only the most effective level-flight predictors. The CVSDR method is demonstrated and tested in this paper using flight-test data from a MBB BO-105 helicopter. It is shown that the CVSDR method predicts the power required for level flight about 21% more accurately than the conventional method while reducing the required flight time by an estimate of at least 60%. Unlike the conventional method, the CVSDR is not bounded by the high-speed approximation associated with the induced power estimation, therefore it is also relevant to the low airspeed regime. This low-airspeed relevancy allows the CVSDR method to bridge between the level-flight regime and the hover. Although demonstrated in this paper for a specific type of helicopter, the CVSDR method is applicable for level-flight performance flight testing of any type of conventional helicopter.
Benefit–Cost Analysis of Increased Trade: An Order-of-Magnitude Estimate of the Benefit–Cost Ratio
Authors: Feyrer James , Tyazhelnikov Vladimir , Aleman-Castilla Benjamin , Wong Brad
Published: July 2023

Drawing upon recent studies that empirically estimate both the benefits and costs of trade, this paper addresses a simple and important question: By how much do the benefits of increased global trade outweigh the costs? To the best of our knowledge, this is the first attempt to answer this question at global and World Bank income-grouping levels using empirically estimated relationships from the trade cost literature. Using a structural gravity model, we simulate changes in three primary trade constraints: a 10% reduction in tariff levels, a 10% reduction in effective distance, and a 10% increase in free trade agreement depth. The projection leads to a roughly 5% increase in global trade by value. Our model suggests that increased trade has an incredibly high benefit–cost ratio (BCR) for the developing world with an order-of-magnitude estimate for low- and lower–middle-income countries of 100 and for upper–middle-income countries of 50. However, the BCR for high-income countries is substantially lower, with a value closer to 5. Overall, the results suggest that free trade leads to substantial net benefits globally, generating US$ 700 billion in benefits (0.83% of global GDP) and US$ 100 billion in costs (0.12% of global GDP) in the first year, a differential that grows over time. Sensitivity analyses suggest that our BCRs are on the lower end of a plausible range. The results point to the incredible value of free trade, particularly for developing countries, and reiterate the importance of considering distributional impacts when implementing trade reforms.
How electrostatic forces affect particle behaviour in turbulent channel flows
Authors: Zhang Huan , Cui Yuankai , Zheng Xiaojing
Published: July 2023

In dispersed two-phase flows, particle electrification is a prevalent phenomenon that plays a crucial role in particle transport. However, the influences of electrostatic forces on particle behaviour in wall-bounded turbulent flows, especially in bidisperse cases, is not well understood. In this study, using direct numerical simulations based on a coupled Eulerian–Lagrangian point-particle approach at friction Reynolds number

$Re_\tau =550$

, we demonstrate that when the electrostatic Stokes number is of the order of

$O(10^{-1})$

, electrostatic forces could considerably alter particle behaviour in both monodisperse and bidisperse particle-laden turbulent channel flows. Specifically, the wall-normal profiles of the particle concentration are determined by the competition of turbophoresis, biased sampling and electrostatic effects. The electrostatic forces are found to reduce the concentrations of lighter particles by electrostatic drift directly, whereas they alter those of heavier particles by strengthening turbophoresis indirectly. With increasing electrical charge, the dynamics of the lighter particles remains approximately unchanged, but that of the heavier particles is modulated significantly due to their relatively strong particle–electrostatic interaction. In the near-wall region, electrostatic forces tend to homogenize the distribution of lighter particles in the spanwise direction by inhibiting the formation and destruction of particle clusterings and voids, thereby maintaining the anisotropic streaky clusterings. Furthermore, even though the clustering dynamics remains unchanged, the spatial extents of the clusterings at the channel centreline are suppressed (enhanced) by a factor of two, probably due to the remarkable reduction (increase) of particle concentration in this layer.
Exploring Constraints to Well-Being for Older Adults in Transition Into an Assisted Living Home: A Qualitative Study
Authors: Mueller Kaitlin E. , Van Puymbroeck Marieke , Crowe Brandi M. , Davis Nicole J.
Published: July 2023

Transitions into an assisted living home (ALH) are difficult and may impact the well-being of older adults. A thematic analysis guided by grounded theory was employed to better understand how a transition into an ALH influenced older adults’ overall well-being. Individual, face-to-face interviews were conducted with a convenience sample of 14 participants at an ALH in the rural, southeastern U.S. Two central findings that influenced well-being during the transition process were revealed: loss of independence (sub-themes include loss of physical and mental health and loss of driving) and downsizing in space and possessions. The themes support and broaden the Hierarchical Leisure Constraints Theory, a Modified Constraints to Wellbeing model is proposed, and implications for older adult health care practitioners in ALHs are recommended. Further research is needed on the Modified Constraints to Wellbeing model and how to better describe these constraints to older adults’ well-being when relocating into ALHs.
Negotiating Nationhood: Constitutional Warfare, International Law, and the Birth of Bangladesh
Authors: Farid Cynthia
Published: July 2023

This paper argues the Government in Exile (GIE), the first government of independent Bangladesh, played an important role in framing the founding moment in legal terms. The GIE's constitutional warfare through its adherence to legalism, and subsequent internationalization of the conflict significantly shaped the independence movement of 1971. The GIE was composed of leaders who were lawyers, economists and other intellectuals who sought refuge in neighboring India. The agency of the founders and their allegiance to constitutional principles catalyzed the founding moment, oversaw the transition to an independent state and ultimately led to a swift adoption of a constitution that endures despite much instability. This national struggle of 1971 also played out in the international arena. In the process, lawyers from the so-called Third World articulated, reshaped, and generated new debates about international legal principles such as sovereignty, territoriality, and self-determination (and criterion for legitimacy of exiled governments)—most of which were considered to be well-settled at the time.
Assessing pig farm biosecurity measures for the control of Salmonella on European farms
Authors: Smith Richard P. , May Hannah E. , Burow Elke , Meester Marina , Tobias Tijs J. , Sassu Elena-Lucia , Pavoni Enrico , Di Bartolo Ilaria , Prigge Christopher , Wasyl Dariusz , Zmudzki Jacek , Viltrop Arvo , Nurmoja Imbi , Zoche-Golob Veit , Alborali Giovanni L. , Romantini Romina , Dors Arkadiusz , Krumova-Valcheva Gergana , Koláčková Ivana , Aprea Guiseppe , Daskalov Hristo
Published: July 2023

Salmonella spp. is a common zoonotic pathogen, causing gastrointestinal infections in people. Pigs and pig meat are a major source of infection. Although farm biosecurity is believed to be important for controlling Salmonella transmission, robust evidence is lacking on which measures are most effective. This study enrolled 250 pig farms across nine European countries. From each farm, 20 pooled faecal samples (or similar information) were collected and analysed for Salmonella presence. Based on the proportion of positive results, farms were categorised as at higher or lower Salmonella risk, and associations with variables from a comprehensive questionnaire investigated. Multivariable analysis indicated that farms were less likely to be in the higher-risk category if they had ‘<400 sows’; used rodent baits close to pig enclosures; isolated stay-behind (sick) pigs; did not answer that the hygiene lock/ anteroom was easy to clean; did not have a full perimeter fence; did apply downtime of at least 3 days between farrowing batches; and had fully slatted flooring in all fattener buildings. A principal components analysis assessed the sources of variation between farms, and correlation between variables. The study results suggest simple control measures that could be prioritised on European pig farms to control Salmonella.
Geoscientists Make a Difference
Authors: Lunn Jenny
Published: July 2023

A new special report demonstrates that geoscientists’ knowledge, skills, and competencies can be used to advance every one of the United Nations Sustainable Development Goals.
Impacts of a Cascadia Subduction Zone Earthquake on Water Levels and Wetlands of the Lower Columbia River and Estuary
Authors: Brand M. W. , Diefenderfer H. L. , O’Connor J. E. , Borde A. B. , Jay D. A. , Al‐Bahadily A. , McKeon M. , Talke S. A.
Published: July 2023

Subsidence after a subduction zone earthquake can cause major changes in estuarine bathymetry. Here, we quantify the impacts of earthquake‐induced subsidence on hydrodynamics and habitat distributions in a major system, the lower Columbia River Estuary, using a hydrodynamic and habitat model. Model results indicate that coseismic subsidence increases tidal range, with the smallest changes at the coast and a maximum increase of ∼10% in a region of topographic convergence. All modeled scenarios reduce intertidal habitat by 24%–25% and shifts ∼93% of estuarine wetlands to lower‐elevation habitat bands. Incorporating dynamic effects of tidal change from subsidence yields higher estimates of remaining habitat by multiples of 0–3.7, dependent on the habitat type. The persistent tidal change and chronic habitat disturbance after an earthquake poses strong challenges for estuarine management and wetland restoration planning, particularly when coupled with future sea‐level rise effects.
Robust Relationship Between Midlatitudes CAPE and Moist Static Energy Surplus in Present and Future Simulations
Authors: Wang Ziwei , Moyer Elisabeth J.
Published: July 2023

Convective available potential energy (CAPE), a metric associated with severe weather, is expected to increase with warming, but we have lacked a framework that describes its changes in the populated midlatitudes. In the tropics, theory suggests mean CAPE should rise following the Clausius–Clapeyron (C–C) relationship at ∼6%/K. In the heterogeneous midlatitudes, where the mean change is less relevant, we show that CAPE changes are larger and can be well‐described by a simple framework based on moist static energy surplus, which is robust across climate states. This effect is highly general and holds across both high‐resolution nudged regional simulations and free‐running global climate models. The simplicity of this framework means that complex distributional changes in future CAPE can be well‐captured by a simple scaling of present‐day data using only three parameters.
Isolating and Investigating Updrafts Induced by Wildland Fires Using an Airborne Doppler Lidar During FIREX‐AQ
Authors: Strobach E. J. , Brewer W. A. , Senff C. J. , Baidar S. , McCarty B.
Published: July 2023

Understanding the complex dynamical interactions that occur during the evolution of a wildland fire still remains a challenge within the research community. Processes such as entrainment, the incident wind field, the interaction between neighboring updrafts, among other processes, motivates the need for more intensive measurement campaigns to determine the mechanisms responsible for the processes observed as wildland fire updrafts evolve. A recent opportunity to examine processes associated with wildland fires was made possible with a Doppler lidar (DL) mounted on a Twin Otter aircraft to measure horizontal and vertical winds during the 2019 Fire Influence on Regional‐to‐Global Environments and Air Quality campaign. Using the data collected, a technique was developed to isolate updrafts over designated hotspots with the intention of statistically analyzing the updraft samples as well as assessing specific cases that underscore the complex dynamical interactions generated by wildland fire behavior. Strong evidence in support of statistically derived relationships between the updraft characteristics and downdraft extrema at the flanks of updrafts are shown using methods developed herein. In addition to the influence of entrainment/detrainment on the updraft structure are features such as updraft displacement and interacting updrafts that could only be resolved by a high along‐ and cross‐beam resolution DL. Lastly, it was found that a high degree of symmetry between profiles to the left and right of core updrafts was preserved for most of the cases, which validates some of the assumptions typically used in idealized updraft formulations.
Trends in HOMA-IR values among South Korean adolescents from 2007–2010 to 2019–2020: a sex-, age-, and weight status-specific analysis
Authors: Kim Sujin , Song Kyungchul , Lee Myeongseob , Suh Junghwan , Chae Hyun Wook , Kim Ho-Seong , Kwon Ahreum
Published: July 2023

Background/Objectives

An increase in obesity prevalence may lead to an increase in the HOMA-IR value. This study aimed to investigate changes in age- and sex-specific homeostasis model assessment of insulin resistance (HOMA-IR) values among South Korean adolescents, using data from the Korean National Health and Nutrition Examination Survey (KNHANES) IV, V, and VIII conducted between 2007–2010 and 2019–2020.

Subjects/Methods

Overall, 4621 adolescents aged 10–18 years were evaluated, including 3473 from the 2007–2010 dataset and 1148 from the 2019–2020 dataset. The mean HOMA-IR values and percentile curves were evaluated by age, sex, and weight status.

Results

The mean HOMA-IR values peaked at puberty in both sexes and further increased during puberty in the 2019–2020 dataset (boys 5.21, 95% confidence interval [CI] 4.16–6.26; girls 5.21, 95% CI 3.09–7.33) compared with the 2007–2010 dataset (boys 3.25, 95% CI 3.04–3.47; girls 3.58, 95% CI 3.31–3.85). Both groups (with normal-weight and overweight/obesity) exhibited a peak HOMA-IR value during puberty in both sexes and both datasets, although the group with overweight/obesity had a higher and wider peak age range. While the mean HOMA-IR values did not change in adolescents with normal-weight, they increased during puberty and post-puberty in boys with overweight/obesity.

Conclusions

HOMA-IR values should be interpreted considering sex, weight status, and pubertal stages. In particular, during the pubertal period, insulin resistance (IR) can coexist not only due to weight-related factors but also as a result of the distinct hormonal changes characteristic of puberty. Over the 10-year period, the mean HOMA-IR values increased in the group with overweight/obesity during puberty and post-puberty, highlighting the need for active intervention to prevent metabolic complications in adolescents with overweight/obesity.
Early-life differences in the gut microbiota composition and functionality of infants at elevated likelihood of developing autism spectrum disorder
Authors: Zuffa Simone , Schimmel Patrick , Gonzalez-Santana Ayoze , Belzer Clara , Knol Jan , Bölte Sven , Falck-Ytter Terje , Forssberg Hans , Swann Jonathan , Diaz Heijtz Rochellys
Published: July 2023

Evidence from cross-sectional human studies, and preliminary microbial-based intervention studies, have implicated the microbiota-gut-brain axis in the neurobiology of autism spectrum disorder (ASD). Using a prospective longitudinal study design, we investigated the developmental profile of the fecal microbiota and metabolome in infants with (n = 16) and without (n = 19) a family history of ASD across the first 36 months of life. In addition, the general developmental levels of infants were evaluated using the Mullen Scales of Early Learning (MSEL) test at 5 and 36 months of age, and with ADOS-2 at 36 months of age. At 5 months of age, infants at elevated-likelihood of ASD (EL) harbored less Bifidobacterium and more Clostridium and Klebsiella species compared to the low-likelihood infants (LL). Untargeted metabolic profiling highlighted that LL infants excreted a greater amount of fecal γ-aminobutyric acid (GABA) at 5 months, which progressively declined with age. Similar age-dependent patterns were not observed in the EL group, with GABA being consistently low across all timepoints. Integrated microbiome-metabolome analysis showed a positive correlation between GABA and Bifidobacterium species and negative associations with Clostridium species. In vitro experiments supported these observations demonstrating that bifidobacteria can produce GABA while clostridia can consume it. At the behavioral level, there were no significant differences between the EL and LL groups at 5 months. However, at 36 months of age, the EL group had significantly lower MSEL and ADOS-2 scores compared to the LL group. Taken together, the present results reveal early life alterations in gut microbiota composition and functionality in infants at elevated-likelihood of ASD. These changes occur before any behavioral impairments can be detected, supporting a possible role for the gut microbiota in emerging behavioral variability later in life.
MiR-662 is associated with metastatic relapse in early-stage breast cancer and promotes metastasis by stimulating cancer cell stemness
Authors: Puppo Margherita , Valluru Manoj Kumar , Croset Martine , Ceresa Davide , Iuliani Michele , Khan Ashrin , Wicinski Julien , Charafe-Jauffret Emmanuelle , Ginestier Christophe , Pantano Francesco , Ottewell Penelope Dawn , Clézardin Philippe
Published: July 2023

Background

Breast cancer (BC) metastasis, which often occurs in bone, contributes substantially to mortality. MicroRNAs play a fundamental role in BC metastasis, although microRNA-regulated mechanisms driving metastasis progression remain poorly understood.

Methods

MiRome analysis in serum from BC patients was performed by TaqMan™ low-density array. MiR-662 was overexpressed following MIMIC-transfection or lentivirus transduction. Animal models were used to investigate the role of miR-662 in BC (bone) metastasis. The effect of miR-662-overexpressing BC cell conditioned medium on osteoclastogenesis was investigated. ALDEFLUOR assays were performed to study BC stemness. RNA-sequencing transcriptomic analysis of miR-662-overexpressing BC cells was performed to evaluate gene expression changes.

Results

High levels of hsa-miR-662 (miR-662) in serum from BC patients, at baseline (time of surgery), were associated with future recurrence in bone. At an early-stage of the metastatic disease, miR-662 could mask the presence of BC metastases in bone by inhibiting the differentiation of bone-resorbing osteoclasts. Nonetheless, metastatic miR-662-overexpressing BC cells then progressed as overt osteolytic metastases thanks to increased stem cell-like traits.

Conclusions

MiR-662 is involved in BC metastasis progression, suggesting it may be used as a prognostic marker to identify BC patients at high risk of metastasis.
Dysregulation of a lncRNA within the TNFRSF10A locus activates cell death pathways
Authors: Kaczynski Tadeusz J. , Husami Nadine J. , Au Elizabeth D. , Farkas Michael H.
Published: July 2023

TNFRSF10A (tumor necrosis factor receptor superfamily member 10A)encodes a cell surface receptor protein involved in apoptotic, necroptotic, and inflammatory pathways. Dysregulation ofTNFRSF10Ahas been implicated in sensitization to apoptosis and to the development of multiple diseases, yet little is known of theAC100861.1long noncoding RNA (lncRNA) that lies head-to-head withTNFRSF10A. Given its genomic positioning, we sought to investigate the function ofAC100861.1, focusing on its potential relationship withTNFRSF10Aand the role it may play in death receptor signaling. Using knockdown and overexpression strategies, we probed cell viability and examined transcript and protein-level changes in key genes involved in apoptosis, necroptosis, and inflammation. Decreased cell viability was observed uponTNFRSF10Aoverexpression, regardless of whether the cells were subjected to the chemical stressor tunicamycin. Similarly, overexpression ofAC100861.1led to increased cell death, with a further increase observed under conditions of cellular stress. Knockdown ofTNFRSF10Aincreased cell death only when the cells were stressed, andAC100861.1knockdown exhibited no effect on cell death. Neither knockdown nor overexpression of either of these genes greatly affected the expression of the other. ManipulatingAC100861.1, however, led to marked changes in the expression of genes involved in necroptosis and inflammatory cell-signaling pathways. Additionally, RNA fluorescence in situ hybridization (RNA-FISH) revealed that theAC100861.1transcript is localized primarily to the cytoplasm. Together, these data suggest thatAC100861.1may have a role in regulating necroptotic and inflammatory signaling pathways and that this function is separate from changes inTNFRSF10Aexpression. Given the importance of this genomic locus for cell survival, these data provide insight into the function of a poorly understood lncRNA with potential implications regarding disease pathology and treatment.
Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion
Authors: Minami Yoshito , Hoshino Atsushi , Higuchi Yusuke , Hamaguchi Masahide , Kaneko Yusaku , Kirita Yuhei , Taminishi Shunta , Nishiji Toshiyuki , Taruno Akiyuki , Fukui Michiaki , Arany Zoltan , Matoba Satoaki
Published: July 2023

Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Therapeutic efforts at lipid reduction via increasing cytoplasmic lipolysis unfortunately worsens hepatitis due to toxicity of liberated fatty acid. An alternative approach could be lipid reduction through autophagic disposal, i.e., lipophagy. We engineered a synthetic adaptor protein to induce lipophagy, combining a lipid droplet-targeting signal with optimized LC3-interacting domain. Activating hepatocyte lipophagy in vivo strongly mitigated both steatosis and hepatitis in a diet-induced mouse NASH model. Mechanistically, activated lipophagy promoted the excretion of lipid from hepatocytes, thereby suppressing harmful intracellular accumulation of nonesterified fatty acid. A high-content compound screen identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin in vivo strongly inhibited the transition to steatohepatitis. These data thus identify lipophagy as a promising therapeutic approach to prevent NASH progression.
Functional decomposition of metabolism allows a system-level quantification of fluxes and protein allocation towards specific metabolic functions
Authors: Mori Matteo , Cheng Chuankai , Taylor Brian R. , Okano Hiroyuki , Hwa Terence
Published: July 2023

Quantifying the contribution of individual molecular components to complex cellular processes is a grand challenge in systems biology. Here we establish a general theoretical framework (Functional Decomposition of Metabolism, FDM) to quantify the contribution of every metabolic reaction to metabolic functions, e.g. the synthesis of biomass building blocks. FDM allowed for a detailed quantification of the energy and biosynthesis budget for growing Escherichia coli cells. Surprisingly, the ATP generated during the biosynthesis of building blocks from glucose almost balances the demand from protein synthesis, the largest energy expenditure known for growing cells. This leaves the bulk of the energy generated by fermentation and respiration unaccounted for, thus challenging the common notion that energy is a key growth-limiting resource. Moreover, FDM together with proteomics enables the quantification of enzymes contributing towards each metabolic function, allowing for a first-principle formulation of a coarse-grained model of global protein allocation based on the structure of the metabolic network.
Spatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories
Authors: Fang Jingru , Castillon Guillaume , Phan Sebastien , McArdle Sara , Hariharan Chitra , Adams Aiyana , Ellisman Mark H. , Deniz Ashok A. , Saphire Erica Ollmann
Published: July 2023

Ebola virus (EBOV) infection induces the formation of membrane-less, cytoplasmic compartments termed viral factories, in which multiple viral proteins gather and coordinate viral transcription, replication, and assembly. Key to viral factory function is the recruitment of EBOV polymerase, a multifunctional machine that mediates transcription and replication of the viral RNA genome. We show that intracellularly reconstituted EBOV viral factories are biomolecular condensates, with composition-dependent internal exchange dynamics that likely facilitates viral replication. Within the viral factory, we found the EBOV polymerase clusters into foci. The distance between these foci increases when viral replication is enabled. In addition to the typical droplet-like viral factories, we report the formation of network-like viral factories during EBOV infection. Unlike droplet-like viral factories, network-like factories are inactive for EBOV nucleocapsid assembly. This unique view of EBOV propagation suggests a form-to-function relationship that describes how physical properties and internal structures of biomolecular condensates influence viral biogenesis.
A squarate-pillared titanium oxide quantum sieve towards practical hydrogen isotope separation
Authors: Yan Qingqing , Wang Jing , Zhang Linda , Liu Jiaqi , Wahiduzzaman Mohammad , Yan Nana , Yu Liang , Dupuis Romain , Wang Hao , Maurin Guillaume , Hirscher Michael , Guo Peng , Wang Sujing , Du Jiangfeng
Published: July 2023

Separating deuterium from hydrogen isotope mixtures is of vital importance to develop nuclear energy industry, as well as other isotope-related advanced technologies. As one of the most promising alternatives to conventional techniques for deuterium purification, kinetic quantum sieving using porous materials has shown a great potential to address this challenging objective. From the knowledge gained in this field; it becomes clear that a quantum sieve encompassing a wide range of practical features in addition to its separation performance is highly demanded to approach the industrial level. Here, the rational design of an ultra-microporous squarate pillared titanium oxide hybrid framework has been achieved, of which we report the comprehensive assessment towards practical deuterium separation. The material not only displays a good performance combining high selectivity and volumetric uptake, reversible adsorption-desorption cycles, and facile regeneration in adsorptive sieving of deuterium, but also features a cost-effective green scalable synthesis using chemical feedstock, and a good stability (thermal, chemical, mechanical and radiolytic) under various working conditions. Our findings provide an overall assessment of the material for hydrogen isotope purification and the results represent a step forward towards next generation practical materials for quantum sieving of important gas isotopes.
Reprogramming of the transcriptome after heat stress mediates heat hormesis in Caenorhabditis elegans
Authors: Xu Fan , Li Ruoyao , von Gromoff Erika D. , Drepper Friedel , Knapp Bettina , Warscheid Bettina , Baumeister Ralf , Qi Wenjing
Published: July 2023

Transient stress experiences not only trigger acute stress responses, but can also have long-lasting effects on cellular functions. InCaenorhabditis elegans, a brief exposure to heat shock during early adulthood extends lifespan and improves stress resistance, a phenomenon known as heat hormesis. Here, we investigated the prolonged effect of hormetic heat stress on the transcriptome of worms and found that the canonical heat shock response is followed by a profound transcriptional reprogramming in the post-stress period. This reprogramming relies on the endoribonuclease ENDU-2 but not the heat shock factor 1. ENDU-2 co-localizes with chromatin and interacts with RNA polymerase II, enabling specific regulation of transcription after the stress period. Failure to activate the post-stress response does not affect the resistance of animals to heat shock but eliminates the beneficial effects of hormetic heat stress. In summary, our work discovers that the RNA-binding protein ENDU-2 mediates the long-term impacts of transient heat stress via reprogramming transcriptome after stress exposure.
Structural journey of an insecticidal protein against western corn rootworm
Authors: Marini Guendalina , Poland Brad , Leininger Chris , Lukoyanova Natalya , Spielbauer Dan , Barry Jennifer K. , Altier Dan , Lum Amy , Scolaro Eric , Ortega Claudia Pérez , Yalpani Nasser , Sandahl Gary , Mabry Tim , Klever Jeffrey , Nowatzki Timothy , Zhao Jian-Zhou , Sethi Amit , Kassa Adane , Crane Virginia , Lu Albert L. , Nelson Mark E. , Eswar Narayanan , Topf Maya , Saibil Helen R.
Published: July 2023

The broad adoption of transgenic crops has revolutionized agriculture. However, resistance to insecticidal proteins by agricultural pests poses a continuous challenge to maintaining crop productivity and new proteins are urgently needed to replace those utilized for existing transgenic traits. We identified an insecticidal membrane attack complex/perforin (MACPF) protein, Mpf2Ba1, with strong activity against the devastating coleopteran pest western corn rootworm (WCR) and a novel site of action. Using an integrative structural biology approach, we determined monomeric, pre-pore and pore structures, revealing changes between structural states at high resolution. We discovered an assembly inhibition mechanism, a molecular switch that activates pre-pore oligomerization upon gut fluid incubation and solved the highest resolution MACPF pore structure to-date. Our findings demonstrate not only the utility of Mpf2Ba1 in the development of biotechnology solutions for protecting maize from WCR to promote food security, but also uncover previously unknown mechanistic principles of bacterial MACPF assembly.
Label-free adaptive optics single-molecule localization microscopy for whole zebrafish
Authors: Park Sanghyeon , Jo Yonghyeon , Kang Minsu , Hong Jin Hee , Ko Sangyoon , Kim Suhyun , Park Sangjun , Park Hae Chul , Shim Sang-Hee , Choi Wonshik
Published: July 2023

Specimen-induced aberration has been a major factor limiting the imaging depth of single-molecule localization microscopy (SMLM). Here, we report the application of label-free wavefront sensing adaptive optics to SMLM for deep-tissue super-resolution imaging. The proposed system measures complex tissue aberrations from intrinsic reflectance rather than fluorescence emission and physically corrects the wavefront distortion more than three-fold stronger than the previous limit. This enables us to resolve sub-diffraction morphologies of cilia and oligodendrocytes in whole zebrafish as well as dendritic spines in thick mouse brain tissues at the depth of up to 102 μm with localization number enhancement by up to 37 times and localization precision comparable to aberration-free samples. The proposed approach can expand the application range of SMLM to whole zebrafish that cause the loss of localization number owing to severe tissue aberrations.
Exon-intron boundary inhibits m6A deposition, enabling m6A distribution hallmark, longer mRNA half-life and flexible protein coding
Authors: Luo Zhiyuan , Ma Qilian , Sun Shan , Li Ningning , Wang Hongfeng , Ying Zheng , Ke Shengdong
Published: July 2023

Regional bias of N6-methyladenosine (m6A) mRNA modification avoiding splice site region, calls for an open hypothesis whether exon-intron boundary could affect m6A deposition. By deep learning modeling, we find that exon-intron boundary represses a proportion (12% to 34%) of m6A deposition at adjacent exons (~100 nt to splice site). Experiments validate that m6A signal increases once the host gene does not undergo pre-mRNA splicing to produce the same mRNA. Inhibited m6A sites have higher m6A enhancers and lower m6A silencers locally and show high heterogeneity at different exons genome-widely, with only a small proportion (12% to 15%) of exons showing strong inhibition, enabling more stable mRNAs and flexible protein coding. m6A is majorly responsible for why mRNAs with more exons be more stable. Exon junction complex (EJC) only partially contributes to this exon-intron boundary m6A inhibition in some short internal exons, highlighting additional factors yet to be identified.
ACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis
Authors: Yang Ziqing , Zou Shaomin , Zhang Yijing , Zhang Jieping , Zhang Peng , Xiao Lishi , Xie Yunling , Meng Manqi , Feng Junyan , Kang Liang , Lee Mong-Hong , Fang Lekun
Published: July 2023

Gastric cancer (GC), one of the most common malignant tumors in the world, exhibits a rapid metastasis rate and causes high mortality. Diagnostic markers and potential therapeutic targets for GCs are urgently needed. Here we show that Actin-like protein 6 A (ACTL6A), encoding an SWI/SNF subunit, is highly expressed in GCs. ACTL6A is found to be critical for regulating the glutathione (GSH) metabolism pathway because it upregulates γ-glutamyl-cysteine ligase catalytic subunit (GCLC) expression, thereby reducing reactive oxygen species (ROS) levels and inhibiting ferroptosis, a regulated form of cell death driven by the accumulation of lipid-based ROS. Mechanistic studies show that ACTL6A upregulates GCLC as a cotranscription factor with Nuclear factor (erythroid-derived 2)-like 2 (NRF2) and that the hydrophobic region of ACTL6A plays an important role. Our data highlight the oncogenic role of ACTL6A in GCs and indicate that inhibition of ACTL6A or GCLC could be a potential treatment strategy for GCs.
A unified field theory of topological defects and non-linear local excitations
Authors: Skogvoll Vidar , Rønning Jonas , Salvalaglio Marco , Angheluta Luiza
Published: July 2023

Topological defects and smooth excitations determine the properties of systems showing collective order. We introduce a generic non-singular field theory that comprehensively describes defects and excitations in systems with O(n) broken rotational symmetry. Within this formalism, we explore fast events, such as defect nucleation/annihilation and dynamical phase transitions where the interplay between topological defects and non-linear excitations is particularly important. To highlight its versatility, we apply this formalism in the context of Bose-Einstein condensates, active nematics, and crystal lattices.
End-to-end differentiability and tensor processing unit computing to accelerate materials’ inverse design
Authors: Liu Han , Liu Yuhan , Li Kevin , Zhao Zhangji , Schoenholz Samuel S. , Cubuk Ekin D. , Gupta Puneet , Bauchy Mathieu
Published: July 2023

Numerical simulations have revolutionized material design. However, although simulations excel at mapping an input material to its output property, their direct application to inverse design has traditionally been limited by their high computing cost and lack of differentiability. Here, taking the example of the inverse design of a porous matrix featuring targeted sorption isotherm, we introduce a computational inverse design framework that addresses these challenges, by programming differentiable simulation on TensorFlow platform that leverages automated end-to-end differentiation. Thanks to its differentiability, the simulation is used to directly train a deep generative model, which outputs an optimal porous matrix based on an arbitrary input sorption isotherm curve. Importantly, this inverse design pipeline leverages the power of tensor processing units (TPU)—an emerging family of dedicated chips, which, although they are specialized in deep learning, are flexible enough for intensive scientific simulations. This approach holds promise to accelerate inverse materials design.
Different pieces of the same puzzle: a multifaceted perspective on the complex biological basis of Parkinson’s disease
Authors: Müller-Nedebock Amica C. , Dekker Marieke C. J. , Farrer Matthew J. , Hattori Nobutaka , Lim Shen-Yang , Mellick George D. , Rektorová Irena , Salama Mohamed , Schuh Artur F. S. , Stoessl A. Jon , Sue Carolyn M. , Tan Ai Huey , Vidal Rene L. , Klein Christine , Bardien Soraya
Published: July 2023

The biological basis of the neurodegenerative movement disorder, Parkinson’s disease (PD), is still unclear despite it being ‘discovered’ over 200 years ago in Western Medicine. Based on current PD knowledge, there are widely varying theories as to its pathobiology. The aim of this article was to explore some of these different theories by summarizing the viewpoints of laboratory and clinician scientists in the PD field, on the biological basis of the disease. To achieve this aim, we posed this question to thirteen “PD experts” from six continents (for global representation) and collated their personal opinions into this article. The views were varied, ranging from toxin exposure as a PD trigger, to LRRK2 as a potential root cause, to toxic alpha-synuclein being the most important etiological contributor. Notably, there was also growing recognition that the definition of PD as a single disease should be reconsidered, perhaps each with its own unique pathobiology and treatment regimen.
Two distinct trajectories of clinical and neurodegeneration events in Parkinson’s disease
Authors: Zhou Cheng , Wang Linbo , Cheng Wei , Lv JinChao , Guan Xiaojun , Guo Tao , Wu Jingjing , Zhang Wei , Gao Ting , Liu Xiaocao , Bai Xueqin , Wu Haoting , Cao Zhengye , Gu Luyan , Chen Jingwen , Wen Jiaqi , Huang Peiyu , Xu Xiaojun , Zhang Baorong , Feng Jianfeng , Zhang Minming
Published: July 2023

Increasing evidence suggests that Parkinson’s disease (PD) exhibits disparate spatial and temporal patterns of progression. Here we used a machine-learning technique—Subtype and Stage Inference (SuStaIn) — to uncover PD subtypes with distinct trajectories of clinical and neurodegeneration events. We enrolled 228 PD patients and 119 healthy controls with comprehensive assessments of olfactory, autonomic, cognitive, sleep, and emotional function. The integrity of substantia nigra (SN), locus coeruleus (LC), amygdala, hippocampus, entorhinal cortex, and basal forebrain were assessed using diffusion and neuromelanin-sensitive MRI. SuStaIn model with above clinical and neuroimaging variables as input was conducted to identify PD subtypes. An independent dataset consisting of 153 PD patients and 67 healthy controls was utilized to validate our findings. We identified two distinct PD subtypes: subtype 1 with rapid eye movement sleep behavior disorder (RBD), autonomic dysfunction, and degeneration of the SN and LC as early manifestations, and cognitive impairment and limbic degeneration as advanced manifestations, while subtype 2 with hyposmia, cognitive impairment, and limbic degeneration as early manifestations, followed later by RBD and degeneration of the LC in advanced disease. Similar subtypes were shown in the validation dataset. Moreover, we found that subtype 1 had weaker levodopa response, more GBA mutations, and poorer prognosis than subtype 2. These findings provide new insights into the underlying disease biology and might be useful for personalized treatment for patients based on their subtype.
A jeff = 1/2 Kitaev material on the triangular lattice: the case of NaRuO2
Authors: Razpopov Aleksandar , Kaib David A. S. , Backes Steffen , Balents Leon , Wilson Stephen D. , Ferrari Francesco , Riedl Kira , Valentí Roser
Published: July 2023

Motivated by recent reports of a quantum-disordered ground state in the triangular lattice compound NaRuO2, we derive a jeff = 1/2 magnetic model for this system by means of first-principles calculations. The pseudospin Hamiltonian is dominated by bond-dependent off-diagonal Γ interactions, complemented by a ferromagnetic Heisenberg exchange and a notably antiferromagnetic Kitaev term. In addition to bilinear interactions, we find a sizable four-spin ring exchange contribution with a strongly anisotropic character, which has been so far overlooked when modeling Kitaev materials. The analysis of the magnetic model, based on the minimization of the classical energy and exact diagonalization of the quantum Hamiltonian, points toward the existence of a rather robust easy-plane ferromagnetic order, which cannot be easily destabilized by physically relevant perturbations.
Studying the genetics of participation using footprints left on the ascertained genotypes
Authors: Benonisdottir Stefania , Kong Augustine
Published: July 2023

The trait of participating in a genetic study probably has a genetic component. Identifying this component is difficult as we cannot compare genetic information of participants with nonparticipants directly, the latter being unavailable. Here, we show that alleles that are more common in participants than nonparticipants would be further enriched in genetic segments shared by two related participants. Genome-wide analysis was performed by comparing allele frequencies in shared and not-shared genetic segments of first-degree relative pairs of the UK Biobank. In nonoverlapping samples, a polygenic score constructed from that analysis is significantly associated with educational attainment, body mass index and being invited to a dietary study. The estimated correlation between the genetic components underlying participation in UK Biobank and educational attainment is estimated to be 36.6%—substantial but far from total. Taking participation behaviour into account would improve the analyses of the study data, including those of health traits.
A multi-omics dataset of human transcriptome and proteome stable reference
Authors: Lu Shaohua , Lu Hong , Zheng Tingkai , Yuan Huiming , Du Hongli , Gao Youhe , Liu Yongtao , Pan Xuanzhen , Zhang Wenlu , Fu Shuying , Sun Zhenghua , Jin Jingjie , He Qing-Yu , Chen Yang , Zhang Gong
Published: July 2023

The development of high-throughput omics technology has greatly promoted the development of biomedicine. However, the poor reproducibility of omics techniques limits their application. It is necessary to use standard reference materials of complex RNAs or proteins to test and calibrate the accuracy and reproducibility of omics workflows. The transcriptome and proteome of most cell lines shift during culturing, which limits their applicability as standard samples. In this study, we demonstrated that the human hepatocellular cell line MHCC97H has a very stable transcriptome (r = 0.983~0.997) and proteome (r = 0.966~0.988 for data-dependent acquisition, r = 0.970~0.994 for data-independent acquisition) after 9 subculturing generations, which allows this steady standard sample to be consistently produced on an industrial scale in long term. Moreover, this stability was maintained across labs and platforms. In sum, our study provides omics standard reference material and reference datasets for transcriptomic and proteomics research. This helps to further standardize the workflow and data quality of omics techniques and thus promotes the application of omics technology in precision medicine.
Interface microstructure effects on dynamic failure behavior of layered Cu/Ta microstructures
Authors: Kumar Rajesh , Chen Jie , Mishra Avanish , Dongare Avinash M.
Published: July 2023

Structural metallic materials with interfaces of immiscible materials provide opportunities to design and tailor the microstructures for desired mechanical behavior. Metallic microstructures with plasticity contributors of the FCC and BCC phases show significant promise for damage-tolerant applications due to their enhanced strengths and thermal stability. A fundamental understanding of the dynamic failure behavior is needed to design and tailor these microstructures with desired mechanical responses under extreme environments. This study uses molecular dynamics (MD) simulations to characterize plasticity contributors for various interface microstructures and the damage evolution behavior of FCC/BCC laminate microstructures. This study uses six model Cu/Ta interface systems with different orientation relationships that are as- created, and pre-deformed to understand the modifications in the plasticity contributions and the void nucleation/evolution behavior. The results suggest that pre-existing misfit dislocations and loading orientations (perpendicular to and parallel to the interface) affect the activation of primary and secondary slip systems. The dynamic strengths are observed to correlate with the energy of the interfaces, with the strengths being highest for low-energy interfaces and lowest for high-energy interfaces. However, the presence of pre-deformation of these interface microstructures affects not only the dynamic strength of the microstructures but also the correlation with interface energy.
Deep learning model for distinguishing Mayo endoscopic subscore 0 and 1 in patients with ulcerative colitis
Authors: Kim Ji Eun , Choi Yoon Ho , Lee Yeong Chan , Seong Gyeol , Song Joo Hye , Kim Tae Jun , Kim Eun Ran , Hong Sung Noh , Chang Dong Kyung , Kim Young-Ho , Shin Soo-Yong
Published: July 2023

The aim of this study was to address the issue of differentiating between Mayo endoscopic subscore (MES) 0 and MES 1 using a deep learning model. A dataset of 492 ulcerative colitis (UC) patients who demonstrated MES improvement between January 2018 and December 2019 at Samsung Medical Center was utilized. Specifically, two representative images of the colon and rectum were selected from each patient, resulting in a total of 984 images for analysis. The deep learning model utilized in this study consisted of a convolutional neural network (CNN)-based encoder, with two auxiliary classifiers for the colon and rectum, as well as a final MES classifier that combined image features from both inputs. In the internal test, the model achieved an F1-score of 0.92, surpassing the performance of seven novice classifiers by an average margin of 0.11, and outperforming their consensus by 0.02. The area under the receiver operating characteristic curve (AUROC) was calculated to be 0.97 when considering MES 1 as positive, with an area under the precision-recall curve (AUPRC) of 0.98. In the external test using the Hyperkvasir dataset, the model achieved an F1-score of 0.89, AUROC of 0.86, and AUPRC of 0.97. The results demonstrate that the proposed CNN-based model, which integrates image features from both the colon and rectum, exhibits superior performance in accurately discriminating between MES 0 and MES 1 in patients with UC.