bluuebunny/crossref_metadata_2025 huggingface dataset:
Crystal structure of halofuginone hydrobromide, C16H18BrClN3O3Br
Authors: Kaduk James A. , Gates-Rector Stacy , Blanton Thomas N.
Published: November 2022

The crystal structure of one form of halofuginone hydrobromide has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Halofuginone hydrobromide crystallizes in space group P21 (#4) with a = 8.87398(13), b = 14.25711(20), c = 15.0153(3) Å, β = 91.6867(15)°, V = 1898.87(4) Å3, and Z = 4. The crystal structure consists of alternating layers (parallel to the ab-plane) of planar and nonplanar portions of the cations. N–H⋯Br and O–H⋯Br hydrogen bonds link the protonated piperidine rings and bromide anions into a two-dimensional network parallel to the ab-plane. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).
An evolutionary form design method based on aesthetic dimension selection and NSGA-II
Authors: Wang Lingyu , Zhu Siyu , Qi Jin , Hu Jie
Published: November 2022

In the era of rapid product update and intense competition, aesthetic design has been increasingly important in various fields, as aesthetic feelings of customers largely influence their purchase preferences. However, the quantification of aesthetic feeling is still a very subjective process due to vague evaluations. The determination of form parameters according to aesthetics is difficult hitherto. Aesthetic measure recently arises as a prominent tool for this purpose using formulas derived from aesthetic theory. But as revealed by existing studies, it needs to be customized with deterministic and objective methods to be reliable in practice use. To facilitate this application, this paper proposes an evolutionary form design method, integrating aesthetic dimension selection and parameter optimization. After summarizing initial aesthetic dimensions, aesthetic dimension selection based on expert decision-making and particle swarm optimization (PSO) is carried out. With filtered aesthetic dimensions, design parameters are optimized with NSGA-II (non-dominated sorting genetic algorithm). The quality of pareto solutions obtained to be design schemes is assessed by three criteria to conduct sensitivity analysis of cross and mutation probability and population size. Our experiment using bicycle form design shows that the proposed evolutionary form design method can generate numerous and variant aesthetic design schemes rapidly. This is very useful for both product redesign and innovative new product development.
Overall patterns of eye-specific retino-geniculo-cortical projections to layers III, IV, and VI in primary visual cortex of the greater galago (Otolemur crassicudatus), and correlation with cytochrome oxidase blobs
Authors: Olavarria Jaime F. , Qi Huixin , Takahata Toru , Kaas Jon H.
Published: November 2022

Studies in the greater galago have not provided a comprehensive description of the organization of eye-specific retino-geniculate-cortical projections to the recipient layers in V1. Here we demonstrate the overall patterns of ocular dominance domains in layers III, IV, and VI revealed following a monocular injection of the transneuronal tracer wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP). We also correlate these patterns with the array of cytochrome oxidase (CO) blobs in tangential sections through the unfolded and flattened cortex. In layer IV, we observed for the first time that eye-specific domains form an interconnected pattern of bands 200–250 μm wide arranged such that they do not show orientation bias and do not meet the V1 border at right angles, as is the case in macaques. We also observed distinct WGA-HRP labeled patches in layers III and VI. The patches in layer III, likely corresponding to patches of K lateral geniculate nucleus (LGN) input, align with layer IV ocular dominance columns (ODCs) of the same eye dominance and overlap partially with virtually all CO blobs in both hemispheres, implying that CO blobs receive K LGN input from both eyes. We further found that CO blobs straddle the border between layer IV ODCs, such that the distribution of CO staining is approximately equal over ipsilateral and contralateral ODCs. These results, together with studies showing that a high percentage of cells in CO blobs are monocular, suggest that CO blobs consist of ipsilateral and contralateral subregions that are in register with underlying layer IV ODCs of the same eye dominance. In macaques and humans, CO blobs are centered on ODCs in layer IV. Our finding that CO blobs in galago straddle the border of neighboring layer IV ODCs suggests that this novel feature may represent an alternative way by which visual information is processed by eye-specific modular architecture in mammalian V1.
Iconoclasm – A Geographical Viewpoint
Authors: Biger Gideon
Published: November 2022

Iconoclasm mainly concerns the destruction of icons, based on the Commandment of the Bible ‘Thou shalt not make unto thee any graven image…’ (Exodus 20:4). Iconoclasm can be presented in two different ways. One is that of an ‘inside aspect’, taking place within a given religious system. The other is an ‘outside aspect’, through which a religious system destroys the religious symbols of another religion. Dealing mainly with the ‘outside aspect’, one may find many religious sites which were destroyed or had their functions changed while these were occupied by another religious group. The holy city of Jerusalem, which lived under different religious regimes, can present this phenomenon, as each regime changed the landscape of the city according to its own perspective.
Does idiosyncratic risk matter for climate policy?
Authors: Jaimes Richard
Published: November 2022

This paper studies the implications of distortions in intertemporal margins for the conduct of climate policy. We do so by introducing a framework that combines a standard two-period overlapping generations (OLG) model with a tractable model of household heterogeneity, in which over-accumulation of capital arises from uninsurable idiosyncratic labor income risk. We illustrate that market-based climate policies must be adjusted when the government cannot provide full insurance to households by taxing only capital and is constrained to transfer resources across generations for risk-sharing. In a numerical exercise, we find that idiosyncratic risk leads to an optimal capital income tax rate of 35 per cent and a carbon price 7.5 per cent lower than its first best.
Mind the gap – safely incorporating deep learning models into the actuarial toolkit
Authors: Richman Ronald
Published: November 2022

Deep neural network models have substantial advantages over traditional and machine learning methods that make this class of models particularly promising for adoption by actuaries. Nonetheless, several important aspects of these models have not yet been studied in detail in the actuarial literature: the effect of hyperparameter choice on the accuracy and stability of network predictions, methods for producing uncertainty estimates and the design of deep learning models for explainability. To allow actuaries to incorporate deep learning safely into their toolkits, we review these areas in the context of a deep neural network for forecasting mortality rates.
Riding the (brain) waves! Using neural oscillations to inform bilingualism research
Authors: Rossi Eleonora , Pereira Soares Sergio Miguel , Prystauka Yanina , Nakamura Megan , Rothman Jason
Published: November 2022

The study of the brains’ oscillatory activity has been a standard technique to gain insights into human neurocognition for a relatively long time. However, as a complementary analysis to ERPs, only very recently has it been utilized to study bilingualism and its neural underpinnings. Here, we provide a theoretical and methodological starter for scientists in the (psycho)linguistics and neurocognition of bilingualism field(s) to understand the bases and applications of this analytical tool. Towards this goal, we provide a description of the characteristics of the human neural (and its oscillatory) signal, followed by an in-depth description of various types of EEG oscillatory analyses, supplemented by figures and relevant examples. We then utilize the scant, yet emergent, literature on neural oscillations and bilingualism to highlight the potential of how analyzing neural oscillations can advance our understanding of the (psycho)linguistic and neurocognitive understanding of bilingualism.
Early-stage lung cancer associated with higher frequency of chest x-ray up to three years prior to diagnosis
Authors: Bradley Stephen H. , Kennedy Martyn P.T. , Callister Matthew E.J.
Published: November 2022

Objectives:

Symptom awareness campaigns have contributed to improved early detection of lung cancer. Previous research suggests that this may have been achieved partly by diagnosing lung cancer in those who were not experiencing symptoms of their cancer. This study aimed to explore the relationship between frequency of chest x-ray in the three years prior to diagnosis and stage at diagnosis.

Settings:

Lung cancer service in a UK teaching hospital.

Participants:

Patients diagnosed with lung cancer between 2010 and 2013 were identified. The number of chest x-rays for each patient in the three years prior to diagnosis was recorded. Statistical analysis of chest x-ray frequency comparing patients with early- and late-stage disease was performed.

Results:

One-thousand seven-hundred fifty patients were included – 589 (33.7%) with stage I/II and 1,161 (66.3%) with stage III/IV disease. All patients had at least one chest x-ray in the six months prior to diagnosis. Those with early-stage disease had more chest x-rays in this period (1.32 vs 1.15 radiographs per patient, P = 0.009). In the period 36 months to six months prior to lung cancer diagnosis, this disparity was even greater (1.70 vs 0.92, radiographs per patient, P < 0.001).

Conclusions:

Increased rates of chest x-ray are likely to contribute to earlier detection. Given the known symptom lead time many patients diagnosed through chest x-ray may not have been experiencing symptoms caused by their cancer. The number of chest x-rays performed could reflect patient and/or clinician behaviours in response to symptoms.
The protection of women and girls with disabilities in armed conflict: Adopting a gender-, age- and disability-inclusive approach to select IHL provisions
Authors: La Vecchia Sara
Published: November 2022

The Convention on the Rights of Persons with Disabilities has brought about a major shift in our understanding of and approach to disability, not least in terms of its implications for other frameworks of international law. Yet, considerations with regard to disability in the context of international humanitarian law (IHL) remain the exception, meaning that persons with disabilities in practice often do not benefit from the same degree of protection as others who find themselves in situations of armed conflict. These shortcomings can be further exacerbated by an interplay between impairment and other individual characteristics such as gender and age, resulting in at times exceptional disadvantages faced by women and girls with disabilities. The present article therefore aims to propose ways in which our modern-day understanding of disability may inform the interpretation and application of IHL, as well as to showcase how the interaction between disability and other characteristics such as gender and age will shape said interpretation and application.
Lernen im Skillslab – es lohnt sich, in Übungsräume zu investieren
Authors: Schlegel Claudia
Published: November 2022

Zusammenfassung. Ein sicheres Lernumfeld ermöglicht Studierenden, erworbenes Wissen praktisch umzusetzen und Handlungskompetenzen aufzubauen. Sogenannte Skillslabs bieten sich als Übungsräume dazu an. Sie haben sich in den Pflegeausbildungen etabliert, ihre Wirksamkeit ist wissenschaftlich belegt. Davon profitieren auch Patientinnen und Patienten.
Roles of External Forcing and Internal Variability in Precipitation Changes of a Sub‐Region of the U.S. Mid‐Atlantic During 1979–2019
Authors: Dong Lu , Leung L. Ruby
Published: November 2022

Observations of the seasonal mean precipitation averaged over a sub‐region of the U.S. mid‐Atlantic show significant increases in summer but no changes in winter during 1979–2019. Clarifying the drivers of these observed changes is important for understanding and interpreting future projections of regional precipitation by climate models. This study examines the relative effects of external forcing and internal variability in the observed multi‐decadal changes using the historical and RCP8.5/SSP585 simulations from 37 models in the Coupled Model Intercomparison Project phase 5 (CMIP5), 35 models in CMIP6, as well as large ensemble simulations from 6 models, each including more than 20 members. During 1979–2019, enhanced warming over land relative to ocean due to external forcing induces low pressure anomalies over land that contribute to the wetting summer. While similar wetting also occurs during winter, such effect is offset by the drying associated with the positive phase of the North Atlantic Oscillation (NAO) in recent decades. Internal variability produces large uncertainty in the multi‐decadal precipitation changes simulated by climate models through changes in large‐scale circulation associated with the NAO in winter and the North Atlantic Subtropical High in summer. These multi‐decadal relationships between precipitation and large‐scale circulation under internal variability also manifest on inter‐annual timescale. These relationships highlight enhanced moisture transport from the Gulf of Mexico and North Atlantic in winter and near the mid‐Atlantic coast in summer that modulates precipitation change in the study region.
Changes of Hydraulic Transmissivity Orientation Induced by Tele‐Seismic Waves
Authors: Zhang Yan , Manga Michael , Fu Li‐Yun , Yang Qiu‐Ye , Cui Zhen‐Dong , Huang Yuan
Published: November 2022

Water level monitoring data from 5 deep wells on the North China Platform are used to study how two large earthquakes impact deep aquifers. After the passage of seismic waves from earthquakes, a subset of these wells shows changes in the phase shifts of water level responses to lunar diurnal (O1) and semidiurnal (M2) tides. We fit a model for the tidal responses of hydraulically conductive fractures that intersect the wells to explain the phase and amplitude of responses to both O1 and M2 tides. To explain changes after the earthquakes with this model, the apparent orientation of fractures must change. Because the stresses are small, we propose that changes in tidal response occur when the passage of seismic waves modifies the hydraulic connectivity of a network of fractures by unclogging or clogging flow paths, thus changing the apparent orientation of the fractures controlling tidal responses. The seismic energy density that results in changes appears to decrease as the dominant frequency of seismic waves increases.
Functional response to a microbial synbiotic in the gastrointestinal system of children: a randomized clinical trial
Authors: Tierney Braden T. , Versalovic James , Fasano Alessio , Petrosino Joseph F. , Chumpitazi Bruno P. , Mayer Emeran A. , Boetes Jared , Smits Gerard , Parkar Shanthi G. , Voreades Noah , Kartal Ece , Al-Ghalith Gabriel A. , Pane Marco , Bron Peter A. , Reid Gregor , Dhir Raja , Mason Christopher E.
Published: November 2022

Background

Oral microbial therapy has been studied as an intervention for a range of gastrointestinal disorders. Though research suggests that microbial exposure may affect the gastrointestinal system, motility, and host immunity in a pediatric population, data have been inconsistent, with most prior studies being in neither a randomized nor placebo-controlled setting. The aim of this randomized, placebo-controlled study was to evaluate the efficacy of a synbiotic on increasing weekly bowel movements (WBMs) in constipated children.

Methods

Sixty-four children (3–17 years of age) were randomized to receive a synbiotic (n = 33) comprising mixed-chain length oligosaccharides and nine microbial strains, or placebo (n = 31) for 84 days. Stool microbiota was analyzed on samples collected at baseline and completion. The primary outcome was a change from baseline of WBMs in the treatment group compared to placebo.

Results

Treatment increased (p < 0.05) the number of WBMs in children with low baseline WBMs, despite broadly distinctive baseline microbiome signatures. Sequencing revealed that low baseline microbial richness in the treatment group significantly anticipated improvements in constipation (p = 0.00074).

Conclusions

These findings suggest the potential for (i) multi-species-synbiotic interventions to improve digestive health in a pediatric population and (ii) bioinformatics-based methods to predict response to microbial interventions in children.

Impact

Synbiotic microbial treatment improved the number of spontaneous weekly bowel movements in children compared to placebo.

Intervention induced an increased abundance of bifidobacteria in children, compared to placebo.

All administered probiotic species were enriched in the gut microbiome of the intervention group compared to placebo.

Baseline microbial richness demonstrated potential as a predictive biomarker for response to intervention.
Monkeypox: epidemiology, pathogenesis, treatment and prevention
Authors: Huang Yong , Mu Li , Wang Wei
Published: November 2022

Monkeypox is a zoonotic disease that was once endemic in west and central Africa caused by monkeypox virus. However, cases recently have been confirmed in many nonendemic countries outside of Africa. WHO declared the ongoing monkeypox outbreak to be a public health emergency of international concern on July 23, 2022, in the context of the COVID-19 pandemic. The rapidly increasing number of confirmed cases could pose a threat to the international community. Here, we review the epidemiology of monkeypox, monkeypox virus reservoirs, novel transmission patterns, mutations and mechanisms of viral infection, clinical characteristics, laboratory diagnosis and treatment measures. In addition, strategies for the prevention, such as vaccination of smallpox vaccine, is also included. Current epidemiological data indicate that high frequency of human-to-human transmission could lead to further outbreaks, especially among men who have sex with men. The development of antiviral drugs and vaccines against monkeypox virus is urgently needed, despite some therapeutic effects of currently used drugs in the clinic. We provide useful information to improve the understanding of monkeypox virus and give guidance for the government and relative agency to prevent and control the further spread of monkeypox virus.
Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases
Authors: Reichard Kaaren K. , Tefferi Ayalew , Abdelmagid Maymona , Orazi Attilio , Alexandres Christina , Haack Joanna , Greipp Patricia T.
Published: November 2022

Pure erythroid leukemia (PEL), also known as acute erythroid leukemia (AEL), is recognized as a distinct morphologic entity by both the 2016 and 2022 World Health Organization (WHO) classification system. By contrast, the 2022 International Consensus Classification (ICC) includes PEL under a broader category of “acute myeloid leukemia with mutated TP53”. We identified 41 Mayo Clinic cases of PEL (mean age 66 years, range 27–86; 71% males) and provide a comprehensive account of bone marrow morphology, immunophenotype, cytogenetic and mutation profiles. PEL was primary in 14 cases, therapy-related in 14, secondary in 12, and undetermined in one. All cases expressed biallelic TP53 alterations, including TP53 deletion/single TP53 mutation (68%), two TP53 mutations (29%) or two TP53 deletions (3%); additional mutations were infrequent. Karyotype was complex in all cases and monosomal in 90%. Treatment details were available in 29 patients: hypomethylating agent (HMA) alone (n = 5), HMA + venetoclax (n = 12), intensive chemotherapy (n = 4), supportive care/other (n = 8); no responses or allogeneic stem cell transplants were documented, and all patients died at a median 1.8 months (range 0.2–9.3). The current study highlights a consistent and reproducible set of morphologic and genetic characteristics that identify PEL as a distinct AML variant whose dismal prognosis requires urgent attention.
Programmable self-regulated molecular buffers for precise sustained drug delivery
Authors: Desrosiers Arnaud , Derbali Rabeb Mouna , Hassine Sami , Berdugo Jérémie , Long Valérie , Lauzon Dominic , De Guire Vincent , Fiset Céline , DesGroseillers Luc , Leblond Chain Jeanne , Vallée-Bélisle Alexis
Published: November 2022

Unlike artificial nanosystems, biological systems are ideally engineered to respond to their environment. As such, natural molecular buffers ensure precise and quantitative delivery of specific molecules through self-regulated mechanisms based on Le Chatelier’s principle. Here, we apply this principle to design self-regulated nucleic acid molecular buffers for the chemotherapeutic drug doxorubicin and the antimalarial agent quinine. We show that these aptamer-based buffers can be programmed to maintain any specific desired concentration of free drug both in vitro and in vivo and enable the optimization of the chemical stability, partition coefficient, pharmacokinetics and biodistribution of the drug. These programmable buffers can be built from any polymer and should improve patient therapeutic outcome by enhancing drug activity and minimizing adverse effects and dosage frequency.
Miniaturized electromechanical devices with multi-vibration modes achieved by orderly stacked structure with piezoelectric strain units
Authors: Liu Jinfeng , Gao Xiangyu , Jin Haonan , Ren Kaile , Guo Jingyu , Qiao Liao , Qiu Chaorui , Chen Wei , He Yuhang , Dong Shuxiang , Xu Zhuo , Li Fei
Published: November 2022

Piezoelectric devices based on a variety of vibration modes are widely utilized in high-tech fields to make a conversion between mechanical and electrical energies. The excitation of single or coupled vibration modes of piezoelectric devices is mainly related to the structure and property of piezoelectric materials. However, for the generally used piezoelectric materials, e.g., lead zirconate titanate ceramics, most of piezoelectric coefficients in the piezoelectric matrix are equal to zero, resulting in many piezoelectric vibration modes cannot be excited, which hinders the design of piezoelectric devices. In this work, an orderly stacked structure with piezoelectric strain units is proposed to achieve all nonzero piezoelectric coefficients, and consequently generate artificially coupled multi-vibration modes with ultrahigh strains. As an example, an orderly stacked structure with two piezoelectric strain units stator, corresponding to 31–36 coupled vibration mode, was designed and fabricated. Based on this orderly stacked structure with two piezoelectric strain units stator, we made a miniature ultrasonic motor (5 mmLength × 1.3 mmHeight × 1.06 mmWidth). Due to the ultrahigh strain of the 31–36 coupled vibration mode, the velocity per volume of the motor reached 4.66 s−1 mm−2. Furthermore, its moving resolution is around 3 nm, which is two orders higher than that of other piezoelectric motors. This work sheds a light on optimizing the performance of state-of-the-art electromechanical devices and may inspire new devices based on multi-vibration modes.
FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation
Authors: Warrick Joshua I. , Hu Wenhuo , Yamashita Hironobu , Walter Vonn , Shuman Lauren , Craig Jenna M. , Gellert Lan L. , Castro Mauro A. A. , Robertson A. Gordon , Kuo Fengshen , Ostrovnaya Irina , Sarungbam Judy , Chen Ying-bei , Gopalan Anuradha , Sirintrapun Sahussapont J. , Fine Samson W. , Tickoo Satish K. , Kim Kwanghee , Thomas Jasmine , Karan Nagar , Gao Sizhi Paul , Clinton Timothy N. , Lenis Andrew T. , Chan Timothy A. , Chen Ziyu , Rao Manisha , Hollman Travis J. , Li Yanyun , Socci Nicholas D. , Chavan Shweta , Viale Agnes , Mohibullah Neeman , Bochner Bernard H. , Pietzak Eugene J. , Teo Min Yuen , Iyer Gopa , Rosenberg Jonathan E. , Bajorin Dean F. , Kaag Matthew , Merrill Suzanne B. , Joshi Monika , Adam Rosalyn , Taylor John A. , Clark Peter E. , Raman Jay D. , Reuter Victor E. , Chen Yu , Funt Samuel A. , Solit David B. , DeGraff David J. , Al-Ahmadie Hikmat A.
Published: November 2022

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.
Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity
Authors: Ning Hanhan , Huang Shan , Lei Yang , Zhi Renyong , Yan Han , Jin Jiaxing , Hu Zhenyu , Guo Kaimin , Liu Jinhua , Yang Jie , Liu Zhe , Ba Yi , Gao Xin , Hu Deqing
Published: November 2022

Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients.
Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X
Authors: Leitão Elsa , Schröder Christopher , Parenti Ilaria , Dalle Carine , Rastetter Agnès , Kühnel Theresa , Kuechler Alma , Kaya Sabine , Gérard Bénédicte , Schaefer Elise , Nava Caroline , Drouot Nathalie , Engel Camille , Piard Juliette , Duban-Bedu Bénédicte , Villard Laurent , Stegmann Alexander P. A. , Vanhoutte Els K. , Verdonschot Job A. J. , Kaiser Frank J. , Tran Mau-Them Frédéric , Scala Marcello , Striano Pasquale , Frints Suzanna G. M. , Argilli Emanuela , Sherr Elliott H. , Elder Fikret , Buratti Julien , Keren Boris , Mignot Cyril , Héron Delphine , Mandel Jean-Louis , Gecz Jozef , Kalscheuer Vera M. , Horsthemke Bernhard , Piton Amélie , Depienne Christel
Published: November 2022

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.
L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans
Authors: Kim Juewon , Jo Yunju , Cho Donghyun , Ryu Dongryeol
Published: November 2022

The pathways that impact longevity in the wake of dietary restriction (DR) remain still ill-defined. Most studies have focused on nutrient limitation and perturbations of energy metabolism. We showed that the L-threonine was elevated in Caenorhabditis elegans under DR, and that L-threonine supplementation increased its healthspan. Using metabolic and transcriptomic profiling in worms that were fed with RNAi to induce loss of key candidate mediators. L-threonine supplementation and loss-of-threonine dehydrogenaseincreased the healthspan by attenuating ferroptosis in a ferritin-dependent manner. Transcriptomic analysis showed that FTN-1 encoding ferritin was elevated, implying FTN-1 is an essential mediator of longevity promotion. Organismal ferritin levels were positively correlated with chronological aging and L-threonine supplementation protected against age-associated ferroptosis through the DAF-16 and HSF-1 pathways. Our investigation uncovered the role of a distinct and universal metabolite, L-threonine, in DR-mediated improvement in organismal healthspan, suggesting it could be an effective intervention for preventing senescence progression and age-induced ferroptosis.
Microwave mode cooling and cavity quantum electrodynamics effects at room temperature with optically cooled nitrogen-vacancy center spins
Authors: Zhang Yuan , Wu Qilong , Wu Hao , Yang Xun , Su Shi-Lei , Shan Chongxin , Mølmer Klaus
Published: November 2022

Recent experimental and theoretical studies demonstrated microwave mode cooling and cavity quantum electrodynamics (C-QED) effects at room temperature by using optically cooled nitrogen-vacancy (NV) spins. In this article, we consider improvements of these effects by exploring parameters in recent diamond maser experiments with a high frequency microwave resonator. By accounting for the rich electronic and spin levels, we provide a more complete treatment of optical pumping and dissipation in NV centers, and study the dependence of system performance on laser power. We predict the reduction of microwave photon number down to 261 (equivalent to a temperature of 116 K), about five times lower than the values reported recently. We also predict the laser-power controlled C-QED effects across weak-to-strong coupling regimes, and observe saturation of these effects under strong laser pumping. Our model can be modified straightforwardly to investigate similar effects with other solid-state spins and possible C-QED effects in maser operation.
Deep learning application of the discrimination of bone marrow aspiration cells in patients with myelodysplastic syndromes
Authors: Lee Nuri , Jeong Seri , Park Min-Jeong , Song Wonkeun
Published: November 2022

Myelodysplastic syndromes (MDS) are a group of hematologic neoplasms accompanied by dysplasia of the bone marrow hematopoietic cells with cytopenia. Detecting dysplasia is important in the diagnosis of MDS, but it takes considerable time and effort. Also, since the assessment of dysplasia is subjective and difficult to quantify, a more efficient tool is needed for quality control and standardization of bone marrow aspiration smear interpretation. In this study, we developed and evaluated an algorithm to automatically discriminate hematopoietic cell lineages and detect dysplastic cells in bone marrow aspiration smears using deep learning technology. Bone marrow aspiration images were acquired from 34 patients diagnosed with MDS and from 24 normal bone marrow slides. In total, 8065 cells were classified into eight categories: normal erythrocytes, normal granulocytes, normal megakaryocytes, dysplastic erythrocytes, dysplastic granulocytes, dysplastic megakaryocytes, blasts, and others. The algorithm demonstrated acceptable performance in classifying dysplastic cells, with an AUC of 0.945–0.996 and accuracy of 0.912–0.993. The algorithm developed in this study could be used as an auxiliary tool for diagnosing patients with MDS and is expected to contribute to shortening the time required for MDS bone marrow aspiration diagnosis and standardizing visual reading.
Hydrogen permeation through steel during cathodic polarization of lubricating oils in a modified Devanathan–Stachurski cell
Authors: Boiadjieva-Scherzer Tz. , Mirkova L. , Fafilek G. , Reinbold J. , Kronberger H. , Stache H. , Bodesheim G. , Monev M.
Published: November 2022

In lubricated tribo-contacts, hydrogen ingress in steel is possible due to chemical reactions of lubricant components like base oils or additives, and/or contamination upon service particularly water, and/or corrosion processes, and/or electrostatic fields or current flow. Absorbed by the metal, atomic hydrogen may cause serious deleterious effects on the physical–chemical and mechanical properties, reducing the material’s ability to withstand the design loads. The present research work is focused on analyzing the influence of electric field on lubricating oils in contact with steel surface. In order to evaluate the possibility of atomic hydrogen generation and permeation into the steel under cathodic polarization of lubricating oils the electrochemical permeation technique developed by Devanathan and Stachurski is used. The input cell of a Devanathan–Stachurski set up is appropriately modified by realizing a very close distance between the working electrode (steel membrane) and a Pt counter electrode with the oil between. This significantly increases the sensibility of the set up and allows the application of larger voltage and higher temperature to enable hydrogen generation from lubricating oils. The complex effects of cathodic polarization, temperature, additives and presence of water in model lubricating oils on atomic hydrogen permeation into steel is discussed.
Kainate receptor subunit 1 (GRIK1) risk variants and GRIK1 deficiency were detected in the Indian ADHD probands
Authors: Chatterjee Mahasweta , Saha Sharmistha , Dutta Nilanjana , Sinha Swagata , Mukhopadhyay Kanchan
Published: November 2022

Executive dysfunctions caused by structural and functional abnormalities of the prefrontal cortex were reported in patients with Attention deficit hyperactivity disorder (ADHD). Owing to a higher expression of the glutamate ionotropic receptor kainate type subunit 1 (GluK1), encoded by the GRIK1 gene, in brain regions responsible for learning and memory, we hypothesized that GRIK1 might have a role in ADHD. GRIK1 variants rs363504 and rs363538, affecting the receptor function, were analyzed by case–control and family-based methods to identify the association with ADHD. The impact of these variants on ADHD-associated traits and pharmacological intervention were also analyzed. GRIK1 expression was quantified in the peripheral blood. The probands and their fathers had a higher frequency of rs363504 ‘CC’ and rs363538 ‘CA’ genotypes. Family-based investigation revealed maternal over transmission of rs363504 ‘C’ and rs363538 ‘A’ alleles to the probands. Quantitative trait analysis exhibited an association of rs363504 ‘TT’ and rs363538 ‘AA’ genotypes with higher hyperactivity scores of the probands. In the presence of rs363504 ‘TT’ and rs363538 ‘CC’ genotypes, MPH treatment improved hyperactivity and inattention, respectively. GRIK1 expression was significantly downregulated in the probands. We infer that GRIK1 affects ADHD etiology, warranting further in-depth investigation involving a larger cohort and more functional variants.
Electrodeposition of Ni–Mo alloy coatings from choline chloride and propylene glycol deep eutectic solvent plating bath
Authors: Niciejewska Anna , Ajmal Aleeza , Pawlyta Mirosława , Marczewski Marek , Winiarski Juliusz
Published: November 2022

Ni–Mo alloy coatings were deposited on a copper base material from a non-aqueous plating bath based on a deep eutectic solvent (DES) of choline chloride and propylene glycol in a 1:2 molar ratio containing 0.2 mol dm−3NiCl2· 6H2O and 0.01 mol dm−3(NH4)6Mo7O24·4H2O. Uniform and adherent Ni–Mo deposits with a nodular morphology were obtained at all the deposition potentials investigated (from − 0.5 to − 0.9 V vs. Ag). By shifting the potential from − 0.5 to − 0.9 V, the deposition current density increased from − 0.4 to − 1.5 mA cm−2and the overall surface roughness increased. It was also accompanied by an increase in the Mo content from ~ 7 to ~ 13 wt% in the potential range from − 0.5 to − 0.7 V. A further change in the potential from − 0.8 to − 0.9 V caused a decrease in the Mo content to ~ 10 wt% and a deterioration in the quality of the coating. For the most uniform coating, deposited at − 0.6 V and having a thickness of ca. 660 nm, the crystallite size did not exceed 10 nm. With the content of Ni (89 at.%) and Mo (11 at.%), the selected area electron diffraction (SAED) analysis allowed us to identify the cubic phase Ni3.64Mo0.36. The corrosion resistance of Ni–Mo coatings in 0.05 mol dm−3NaCl solution generally increased during exposure of 18 h, as evidenced by ever higher polarization resistance. Finally, regardless of the applied deposition potential, low corrosion currents (in the range of 0.1–0.3 μA cm−2) have been measured for the coatings. EIS revealed that charge transfer resistances were the highest (57–67 kΩ cm2) for coatings deposited at − 0.5 V, − 0.6 V and − 0.7 V. Further increase in the deposition potential in the negative direction was unfavorable.
Effect of high-pressure D2 and H2 annealing on LFN properties in FD-SOI pTFET
Authors: Shin Hyun-Jin , Eadi Sunil Babu , An Yeong-Jin , Ryu Tae-Gyu , Kim Do-woo , Lee Hi-Deok , Kwon Hyuk-Min
Published: November 2022

Tunneling field-effect transistors (TFETs) are a promising candidate for the next generation of low-power devices, but their performance is very sensitive to traps near the tunneling junction. This study investigated the effects of high-pressure deuterium (D2) annealing and hydrogen (H2) annealing on the electrical performance and low-frequency noise (LFN) of a fully depleted silicon-on-insulator p-type TFET. Without high-pressure annealing, the typical noise power spectral density exhibited two Lorentzian spectra that were affected by fast and slow trap sites. With high-pressure annealing, the interface trap density related to fast trap sites was reduced. The passivation of traps near the tunneling junction indicates that high-pressure H2 and D2 annealing improves the electrical performance and LFN properties, and it may become a significant and necessary step for realizing integrated TFET technology in the future.
Discovery and structural characterization of chicoric acid as a SARS-CoV-2 nucleocapsid protein ligand and RNA binding disruptor
Authors: Mercaldi Gustavo Fernando , Bezerra Eduardo Henrique Salviano , Batista Fernanda Aparecida Heleno , Tonoli Celisa Caldana Costa , Soprano Adriana Santos , Shimizu Jacqueline Farinha , Nagai Alice , da Silva Jaqueline Cristina , Filho Helder Veras Ribeiro , do Nascimento Faria Jéssica , da Cunha Marcos Guilherme , Zeri Ana Carolina Mattos , Nascimento Andrey Fabricio Ziem , Proenca-Modena José Luiz , Bajgelman Marcio Chaim , Rocco Silvana Aparecida , Lopes-de-Oliveira Paulo Sérgio , Cordeiro Artur Torres , Bruder Marjorie , Marques Rafael Elias , Sforça Mauricio Luis , Franchini Kleber Gomes , Benedetti Celso Eduardo , Figueira Ana Carolina Migliorini , Trivella Daniela Barretto Barbosa
Published: November 2022

The nucleocapsid (N) protein plays critical roles in coronavirus genome transcription and packaging, representing a key target for the development of novel antivirals, and for which structural information on ligand binding is scarce. We used a novel fluorescence polarization assay to identify small molecules that disrupt the binding of the N protein to a target RNA derived from the SARS-CoV-2 genome packaging signal. Several phenolic compounds, including L-chicoric acid (CA), were identified as high-affinity N-protein ligands. The binding of CA to the N protein was confirmed by isothermal titration calorimetry, 1H-STD and 15N-HSQC NMR, and by the crystal structure of CA bound to the N protein C-terminal domain (CTD), further revealing a new modulatory site in the SARS-CoV-2 N protein. Moreover, CA reduced SARS-CoV-2 replication in cell cultures. These data thus open venues for the development of new antivirals targeting the N protein, an essential and yet underexplored coronavirus target.
Instantaneous 4D micro-particle image velocimetry (µPIV) via multifocal microscopy (MUM)
Authors: Guastamacchia M. G. R. , Xue R. , Madi K. , Pitkeathly W. T. E. , Lee P. D. , Webb S. E. D. , Cartmell S. H. , Dalgarno P. A.
Published: November 2022

Multifocal microscopy (MUM), a technique to capture multiple fields of view (FOVs) from distinct axial planes simultaneously and on one camera, was used to perform micro-particle image velocimetry (µPIV) to reconstruct velocity and shear stress fields imposed by a liquid flowing around a cell. A diffraction based multifocal relay was used to capture images from three different planes with 630 nm axial spacing from which the axial positions of the flow-tracing particles were calculated using the image sharpness metric. It was shown that MUM can achieve an accuracy on the calculated velocity of around (0.52 ± 0.19) µm/s. Using fixed cells, MUM imaged the flow perturbations at sub-cellular level, which showed characteristics similar to those observed in the literature. Using live cells as an exemplar, MUM observed the effect of changing cell morphology on the local flow during perfusion. Compared to standard confocal laser scanning microscope, MUM offers a clear advantage in acquisition speed for µPIV (over 300 times faster). This is an important characteristic for rapidly evolving biological systems where there is the necessity to monitor in real time entire volumes to correlate the sample responses to the external forces.
Deep learning model to predict Epstein–Barr virus associated gastric cancer in histology
Authors: Jeong Yeojin , Cho Cristina Eunbee , Kim Ji-Eon , Lee Jonghyun , Kim Namkug , Jung Woon Yong , Sung Joohon , Kim Ju Han , Lee Yoo Jin , Jung Jiyoon , Pyo Juyeon , Song Jisun , Park Jihwan , Moon Kyoung Min , Ahn Sangjeong
Published: November 2022

The detection of Epstein–Barr virus (EBV) in gastric cancer patients is crucial for clinical decision making, as it is related with specific treatment responses and prognoses. Despite its importance, the limited medical resources preclude universal EBV testing. Herein, we propose a deep learning-based EBV prediction method from H&E-stained whole-slide images (WSI). Our model was developed using 319 H&E stained WSI (26 EBV positive; TCGA dataset) from the Cancer Genome Atlas, and 108 WSI (8 EBV positive; ISH dataset) from an independent institution. Our deep learning model, EBVNet consists of two sequential components: a tumor classifier and an EBV classifier. We visualized the learned representation by the classifiers using UMAP. We externally validated the model using 60 additional WSI (7 being EBV positive; HGH dataset). We compared the model’s performance with those of four pathologists. EBVNet achieved an AUPRC of 0.65, whereas the four pathologists yielded a mean AUPRC of 0.41. Moreover, EBVNet achieved an negative predictive value, sensitivity, specificity, precision, and F1-score of 0.98, 0.86, 0.92, 0.60, and 0.71, respectively. Our proposed model is expected to contribute to prescreen patients for confirmatory testing, potentially to save test-related cost and labor.
Neuroprotective metabolites via fungal biotransformation of a novel sapogenin, cyclocephagenol
Authors: Küçüksolak Melis , Üner Göklem , Ballar Kırmızıbayrak Petek , Bedir Erdal
Published: November 2022

Cyclocephagenol (1), a novel cycloartane-type sapogenin with tetrahydropyran unit, is only encountered inAstragalusspecies. This rare sapogenin has never been a topic of biological activity or modification studies. The objectives of this study were; (i) to perform microbial transformation studies on cyclocephagenol (1) usingAstragalusendophyte,Alternaria eureka1E1BL1, followed by isolation and structural characterization of the metabolites; (ii) to investigate neuroprotective activities of the metabolites; (iii) to understand structure–activity relationships towards neuroprotection. The microbial transformation of cyclocephagenol (1) usingAlternaria eurekaresulted in the production of twenty-one (2–22) previously undescribed metabolites. Oxidation, monooxygenation, dehydration, methyl migration, epoxidation, and ring expansion reactions were observed on the triterpenoid skeleton. Structures of the compounds were established by 1D-, 2D-NMR, and HR-MS analyses. The neuroprotective activities of metabolites and parent compound (1) were evaluated against H2O2-induced cell injury. The structure–activity relationship (SAR) was established, and the results revealed that1and several other metabolites had potent neuroprotective activity. Further studies revealed that selected compounds reduced the amount of ROS and preserved the integrity of the mitochondrial membrane. This is the first report of microbial transformation of cyclocephagenol (1).
Experience of the COVID-19 pandemic in Wuhan leads to a lasting increase in social distancing
Authors: Barak Darija , Gallo Edoardo , Rong Ke , Tang Ke , Du Wei
Published: November 2022

On 11th Jan 2020, the first COVID-19 related death was confirmed in Wuhan, Hubei. The Chinese government responded to the outbreak with a lockdown that impacted most residents of Hubei province and lasted for almost three months. At the time, the lockdown was the strictest both within China and worldwide. Using an interactive web-based experiment conducted half a year after the lockdown with participants from 11 Chinese provinces, we investigate the behavioral effects of this ‘shock’ event experienced by the population of Hubei. We find that both one’s place of residence and the strictness of lockdown measures in their province are robust predictors of individual social distancing behavior. Further, we observe that informational messages are effective at increasing compliance with social distancing throughout China, whereas fines for noncompliance work better within Hubei province relative to the rest of the country. We also report that residents of Hubei increase their propensity to social distance when exposed to social environments characterized by the presence of a superspreader, while the effect is not present outside of the province. Our results appear to be specific to the context of COVID-19 and are not explained by general differences in risk attitudes and social preferences.