bluuebunny/crossref_metadata_2025 huggingface dataset:
An overview of elastic waveguides with dynamic sub-structures
Authors: Slepyan Leonid , Movchan Alexander B.
Published: October 2022

The dynamic response of elastic waveguides is important for a wide range of applications that involve dispersive waves as well as wave localization. In particular, a case of special interest relates to waveguides subjected to moving loads. In the case where the elongated structure includes a sequence of built-in resonators, the range of resonance regimes may be extended accordingly. The present paper gives an overview of several mathematical formulations that connect Floquet theory to the dynamic response of multi-scale waveguides, which include inertial sub-structures subjected to external forces.

This article is part of the theme issue ‘Wave generation and transmission in multi-scale complex media and structured metamaterials (part 2)’.
Asymptotics of the meta-atom: plane wave scattering by a single Helmholtz resonator
Authors: Smith M. J. A. , Cotterill P. A. , Nigro D. , Parnell W. J. , Abrahams I. D.
Published: October 2022

Using a combination of multipole methods and the method of matched asymptotic expansions, we present a solution procedure for acoustic plane wave scattering by a single Helmholtz resonator in two dimensions. Closed-form representations for the multipole scattering coefficients of the resonator are derived, valid at low frequencies, with three fundamental configurations examined in detail: the thin-walled, moderately thick-walled and extremely thick-walled limits. Additionally, we examine the impact of dissipation for extremely thick-walled resonators, and also numerically evaluate the scattering, absorption and extinction cross-sections (efficiencies) for representative resonators in all three wall thickness regimes. In general, we observe strong enhancement in both the scattered fields and cross-sections at the Helmholtz resonance frequencies. As expected, dissipation is shown to shift the resonance frequency, reduce the amplitude of the field, and reduce the extinction efficiency at the fundamental Helmholtz resonance. Finally, we confirm results in the literature on Willis-like coupling effects for this resonator design, and connect these findings to earlier works by several of the authors on two-dimensional arrays of resonators, deducing that depolarizability effects (off-diagonal terms) for a single resonator do not ensure the existence of Willis coupling effects (bianisotropy) in bulk.

This article is part of the theme issue ‘Wave generation and transmission in multi-scale complex media and structured metamaterials (part 2)’.
Asymptotic analysis of in-plane dynamic problems for elastic media with rigid clusters of small inclusions
Authors: Nieves Michael J. , Movchan Alexander B.
Published: October 2022

We present formal asymptotic approximations of fields representing the in-plane dynamic response of elastic solids containing clusters of closely interacting small rigid inclusions. For finite densely perforated bodies, the asymptotic scheme is developed to approximate the eigenfrequencies and the associated eigenmodes of the elastic medium with clamped boundaries. The asymptotic algorithm is also adapted to address the scattering of in-plane waves in infinite elastic media containing dense clusters. The results are accompanied by numerical simulations that illustrate the accuracy of the asymptotic approach.

This article is part of the theme issue ‘Wave generation and transmission in multi-scale complex media and structured metamaterials (part 2)’.
Dynamic response of multi-scale geophysical systems: waves and practical applications
Authors: Yakovleva Alexandra A. , Movchan Igor B. , Shaygallyamova Zilya I.
Published: October 2022

In this review paper, we discuss the nature of an apparent link between heterogeneities associated with geological anomalies hidden from direct observation, detected when they are analysed remotely from various distances—including borehole conditions as well as aero imaging. Here, the main emphasis is placed on geological and geophysical features represented by spatially distributed signals measured along drilled well or along predefined spatial routes. In the common practice of indirect measurements of parameters of seismically active regions, there exist certain observations on correlations in the vicinity of structural and geological anomalies, repeated patterns in the representation of correlation functions and corresponding classification in multidimensional statistical methods. Underlying natural physical processes, which determine the structure of the primary anomalous environment, are of interest. Physical analogies, based on the mathematical modelling and generalization of empirical data, may suggest that such a process may be linked to wave phenomena on a geological scale. Applications include analysis of anomalies associated with non-potential fields, mapping of geodynamic zones and seismic microzoning; reconstruction of the geostructural vertical section of the mountainous regions.

This article is part of the theme issue 'Wave generation and transmission in multi-scale complex media and structured metamaterials (part 2)'.
Tuning the decay of sound in a viscous metamaterial
Authors: Ibarias M. , Doporto J. , Krokhin A. A. , Arriaga J.
Published: October 2022

Using analytical results for viscous dissipation in phononic crystals, we calculate the decay coefficient of a sound wave propagating at low frequencies through a two-dimensional phononic crystal with a viscous fluid background. It is demonstrated that the effective acoustic viscosity of the phononic crystal may exceed by two to four orders of magnitude the natural hydrodynamic viscosity of the background fluid. Moreover, the decay coefficient exhibits dependence on the direction of propagation; that is, a homogenized phononic crystal behaves like an anisotropic viscous fluid. Strong dependence on the filling fraction of solid scatterers offers the possibility of tuning the dissipative decay length of sound, which is an important characteristic of any acoustic device.

This article is part of the theme issue ‘Wave generation and transmission in multi-scale complex media and structured metamaterials (part 2)’.
Different Associations of Anthropometric Indices with Diabetic Retinopathy and Diabetic Kidney Disease in Chinese Patients with Type 2 Diabetes Mellitus
Authors: Wang Yujie , Pang Xin , Gu Chufeng , Li Chenxin , Li Bo , Zhou Chuandi , Chen Haibing , Zheng Zhi
Published: October 2022

Aims

To investigate the associations of anthropometric indices, including body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), waist circumference (WC) and hip circumference (HC), with diabetic retinopathy (DR) and diabetic kidney disease (DKD) in Chinese patients with type 2 diabetes mellitus (T2DM).

Materials and methods

This cross-sectional study evaluated 5226 participants with T2DM at Shanghai General Hospital between 2005 and 2016. Logistic regression models and restricted cubic spline analysis were used to assess the associations of anthropometric indices with DR and DKD.

Results

A BMI of around 25 kg/m2 was related to a low risk of DR (OR based on the third fifth: 0.752, 95%CI: 0.615-0.920). Besides, HC had an inverse association with DR in men independently of BMI (OR based on the highest fifth: 0.495, 95%CI: 0.350-0.697). In the restricted cubic spline models, BMI, WHtR, WC, and HC showed J-shaped associations with DKD, while WHR showed an S-shaped association with DKD. Compared to the lowest fifth, the odds ratios (OR) based on the highest fifth of BMI, WHR, WHtR, WC and HC for DKD were 1.927 (1.572-2.366), 1.566 (1.277-1.923), 1.91 (1.554-2.351), 1.91 (1.554-2.351) and 1.585 (1.300-1.937) respectively in multivariable models.

Conclusions

A median BMI and a large hip might be related to a low risk of DR, while lower levels of all the anthropometric indices were associated with a lower risk of DKD. Our findings suggested maintain a median BMI, a low WHR, a low WHtR and a large hip for prevention of DR and DKD.
Prioritization of new candidate genes for rare genetic diseases by a disease-aware evaluation of heterogeneous molecular networks
Authors: de la Fuente Lorena , Del Pozo-Valero Marta , Perea-Romero Irene , Blanco-Kelly Fiona , Fernández-Caballero Lidia , Cortón Marta , Ayuso Carmen , Mínguez Pablo
Published: October 2022

Screening for pathogenic variants in the diagnosis of rare genetic diseases can now be performed on all genes thanks to the application of whole exome and genome sequencing (WES, WGS). Yet the repertoire of gene-disease associations is not complete. Several computer-based algorithms and databases integrate distinct gene-gene functional networks to accelerate the discovery of gene-disease associations. We hypothesize that the ability of every type of information to extract relevant insights is disease-dependent. We compiled 33 functional networks classified into 13 knowledge categories (KCs) and observed large variability in their ability to recover genes associated with 91 genetic diseases, as measured using efficiency and exclusivity. We developed GLOWgenes, a network-based algorithm that applies random walk with restart to evaluate KCs ability to recover genes from a given list associated with a phenotype, and modulates the prediction of new candidates accordingly. Comparison with other integration strategies and tools shows that our disease-aware approach can boost the discovery of new gene-disease associations, especially for the less obvious ones. KC contribution also varies if obtained using recently discovered genes. Applied to 15 unsolved WES, GLOWgenes proposed three new genes to be involved in the phenotypes of patients with syndromic inherited retinal dystrophies.
Applying GAN-based data augmentation to improve transcriptome-based prognostication in breast cancer
Authors: Guttà Cristiano , Morhard Christoph , Rehm Markus
Published: October 2022

Established prognostic tests based on limited numbers of transcripts can identify high-risk breast cancer patients yet are approved only for individuals presenting with specific clinical features or disease characteristics. Deep learning algorithms could hold potential for stratifying patient cohorts based on full transcriptome data, yet the development of robust classifiers is hampered by the number of variables in omics datasets typically far exceeding the number of patients. To overcome this hurdle, we propose a classifier based on a data augmentation pipeline consisting of a Wasserstein generative adversarial network (GAN) with gradient penalty and an embedded auxiliary classifier to obtain a trained GAN discriminator (T-GAN-D). Applied to 1244 patients of the METABRIC breast cancer cohort, this classifier outperformed established breast cancer biomarkers in separating low- from high-risk patients (disease specific death, progression or relapse within 10 years from initial diagnosis). Importantly, the T-GAN-D also performed across independent, merged transcriptome datasets (METABRIC and TCGA-BRCA cohorts), and merging data improved overall patient stratification. In conclusion, GAN-based data augmentation therefore allowed generating a robust classifier capable of stratifying low- vs high-risk patients based on full transcriptome data and across independent and heterogeneous breast cancer cohorts.
THE IMPACT OF THE COVID-19 LOCKDOWN ON BIRTH WEIGHT AMONG SINGLETON TERM BIRTHS IN DENMARK
Authors: de Knegt Victoria E. , Hedley Paula L. , Hedermann Gitte , Wilstrup Casper , Bækvad-Hansen Marie , Thagaard Ida N. , Hjalgrim Henrik , Kanters Jørgen , Melbye Mads , Hougaard David M. , Hviid Anders , Krebs Lone , Breindahl Morten , Lausten-Thomsen Ulrik , Christiansen Michael
Published: October 2022

In Denmark, a nationwide COVID-19 lockdown was implemented on March 12, 2020 and eased on April 14, 2020. The COVID-19 lockdown featured reduced prevalence of extremely preterm or extremely low birth weight births. Here we explore the impact of this COVID-19 lockdown on term birth weights in Denmark.

We conducted a nationwide register-based cohort study on 27,870 live singleton infants, born at term (weeks 37-41), between March 12 and April 14, 2015-2020, using data from the Danish Neonatal Screening Biobank. Primary outcomes, corrected for confounders, were birth weight, small-for-gestational-age (SGA), and large-for-gestational-age (LGA), comparing the COVID-19 lockdown to the previous five years. Data were analysed using linear regression to assess associations with birth weight. Multinomial logistic regression was used to assess associations with size-for-gestational-age (xGA) categories.

Adjusted mean birth weight was significantly increased by 16.9 g (95% CI = 4.1 – 31.3) during the lockdown period. A dip in mean birth weight was found in gestational weeks 37 and 38 balanced by an increase in weeks 40 and 41. The 2020 lockdown period was associated with an increased LGA prevalence (aOR 1.13, 95% CI = 1.05 - 1.21). No significant changes in proportions of xGA groups were found between 2015 and 2019.

Conclusion

The nationwide COVID-19 lockdown resulted in a small but significant increase in birth weight and proportion of LGA infants, driven by an increase in birth weight in gestational weeks 40 and 41.

What is known

The COVID-19 lockdown periods have had profound, albeit variable, effects on pregnant women in various countries.

Extremely preterm and stillbirth rates were reduced during COVID-19 lockdown/mitigation periods in Denmark

What is new

During COVID-19 lockdown a moderate, but statistically significant, increase in birth weight was seen.

The proportion of large-for-gestational age pregnancies was statistically significantly elevated in the lockdown period.
Predation, community asynchrony, and metacommunity stability in cyanobacterial mats
Authors: Cissell Ethan C. , McCoy Sophie J.
Published: October 2022

The dynamism of ecological interactions in rapidly changing ecosystems can be understood only by linking community context to population dynamics. Holistic characterization of such mechanisms requires integrating patterns of variability across scales. Here, we integrated observational, experimental, and theoretical approaches to unify local and regional ecological processes driving the dynamics of benthic cyanobacterial mats on coral reefs off the island of Bonaire, Caribbean Netherlands. Community and metacommunity dynamics of mats were tracked for 49 days alongside quantification of macropredation pressure from fishes. We tested the hypothesis that enhanced predation would result in decreased mat persistencein situ. Finally, we constructed a cellular automaton model to predict patterns in mat metacommunity dynamics across different scenarios of top-down and bottom-up control and dispersal. Cyanobacterial mat metacommunities were temporally stable across the study, stabilized by asynchrony in the dynamics of communities. Diverse reef fishes foraged on matsin situand experimental increases in predation pressure decreased the instantaneous mortality rate of mat communities over mat communities experiencing natural levels of predation pressure. Theoretical simulations suggested that dispersal conveys a rescuing effect on mat metacommunity abundance under scenarios of strong trophic control.
Inhibition of the SARS-CoV-2 helicase at single-nucleotide resolution
Authors: Marx Sinduja K. , Mickolajczyk Keith J. , Craig Jonathan M. , Thomas Christopher A. , Pfeffer Akira M. , Abell Sarah J. , Carrasco Jessica D. , Franzi Michaela C. , Huang Jesse R. , Kim Hwanhee C. , Brinkerhoff Henry D. , Kapoor Tarun M. , Gundlach Jens H. , Laszlo Andrew H.
Published: October 2022

The genome of SARS-CoV-2 encodes for a helicase called nsp13 that is essential for viral replication and highly conserved across related viruses, making it an attractive antiviral target. Here we use nanopore tweezers, a high-resolution single-molecule technique, to gain detailed insight into how nsp13 turns ATP-hydrolysis into directed motion along nucleic acid strands. We measured nsp13 both as it translocates along single-stranded DNA or unwinds short DNA duplexes. Our data confirm that nsp13 uses the inchworm mechanism to move along the DNA in single-nucleotide steps, translocating at ~1000 nt/s or unwinding at ~100 bp/s. Nanopore tweezers’ high spatio-temporal resolution enables observation of the fundamental physical steps taken by nsp13 even as it translocates at speeds in excess of 1000 nucleotides per second enabling detailed kinetic analysis of nsp13 motion. As a proof-of-principle for inhibition studies, we observed nsp13’s motion in the presence of the ATPase inhibitor ATPγS. Our data reveals that ATPγS interferes with nsp13’s action by affecting several different kinetic processes. The dominant mechanism of inhibition differs depending on the application of assisting force. These advances demonstrate that nanopore tweezers are a powerful method for studying viral helicase mechanism and inhibition.
Pantr2, a trans-acting lncRNA, modulates the differentiation potential of neural progenitors in vivo
Authors: Augustin Jonathan J , Takayangi Saki , Hoang Thanh , Winer Briana , Blackshaw Seth , Goff Loyal A
Published: October 2022

Ablation of the long non-coding RNA (lncRNA) Pantr2 results in microcephaly in a knockout murine model of corticogenesis, however, the precise mechanisms used are unknown. We present evidence that Pantr2 is a trans-acting lncRNA that regulates gene expression and chromatin accessibility both in vivo and in vitro. We demonstrate that ectopic expression of Pantr2 in a neuroblastoma cell line alters gene expression under differentiating conditions, and that both loss and gain of function of Pantr2 results in changes to cell-cycle dynamics. We show that expression of both the transcription factor Nfix and the cell cycle regulator Rgcc are negatively regulated by Pantr2. Using RNA binding protein motif analysis and existing CLIP-seq data, we annotate potential HuR and QKI binding sites on Pantr2, and demonstrate that HuR does not directly bind Pantr2 using RNA immunoprecipitation assay. Finally, using Gene Ontology enrichment analysis, we identify disruption of both Notch and Wnt signaling following loss of Pantr2 expression, indicating potential Pantr2-dependent regulation of these pathways.
Optimising ddRAD sequencing for population genomic studies with ddgRADer
Authors: Lajmi Aparna , Glinka Felix , Privman Eyal
Published: October 2022

Double-digest Restriction-site Associated DNA sequencing (ddRADseq) is widely used to generate genomic data for non-model organisms in evolutionary and ecological studies. Along with affordable paired-end sequencing, this method makes population genomic analyses more accessible. However, multiple factors should be considered when designing a ddRADseq experiment, which can be challenging for new users. The generated data often suffer from substantial read overlaps and adaptor contamination, severely reducing sequencing efficiency and at times affecting data quality. Here, we analyse diverse datasets from the literature and carry out controlled experiments to understand the effects of enzyme choice and size selection on sequencing efficiency. The empirical data reveal that size selection is imprecise and has limited efficacy. In certain scenarios, a substantial proportion of short fragments pass below the lower size-selection cut-off resulting in low sequencing efficiency. However, enzyme choice can considerably mitigate inadvertent inclusion of these shorter fragments. A simple model based on these experiments is implemented to predict the number of genomic fragments generated after digestion and size selection, number of SNPs genotyped, number of samples that can be multiplexed, and the expected sequencing efficiency. We developed ddgRADer -http://ddgrader.haifa.ac.il/- a user-friendly webtool that aids ddRADseq experimental design while optimising sequencing efficiency. This tool can also be used for single enzyme protocols such as Genotyping-by-Sequencing (GBS). Given user-defined study goals, ddgRADer recommends enzyme pairs and allows users to compare and choose enzymes and size-selection criteria. ddgRADer improves the accessibility and ease of designing ddRADseq experiments and increases the probability of success of the first population genomic study conducted in labs with no prior experience in genomics.
LSD1 acts as an epigenetic barrier against glucocorticoid-induced atrophy and exercise-induced hypertrophy in skeletal muscle
Authors: Araki Hirotaka , Hino Shinjiro , Anan Kotaro , Kuribayashi Kanji , Etoh Kan , Seko Daiki , Takase Ryuta , Kohrogi Kensaku , Hino Yuko , Ono Yusuke , Araki Eiichi , Nakao Mitsuyoshi
Published: October 2022

Skeletal muscle exhibits remarkable plasticity in response to environmental cues, with stress-dependent effects on the fast-twitch and slow-twitch fibers. Although stress-induced gene expression underlies environmental adaptation, it is unclear how transcriptional and epigenetic factors regulate fiber type-specific responses in the muscle. Here, we show that flavin-dependent lysine-specific demethylase 1 (LSD1) differentially controls responses to glucocorticoid and exercise in postnatal skeletal muscle. Using skeletal muscle-specific LSD1 knockout mice andin vitroapproaches, we found that LSD1 loss exacerbated glucocorticoid-induced atrophy in the fast fiber-dominant muscles, with reduced nuclear retention of Foxk1, an anti-autophagic transcription factor. Furthermore, LSD1 depletion enhanced endurance exercise-induced hypertrophy in the slow fiber-dominant muscles, by induced expression of ERRγ, a transcription factor that promotes oxidative metabolism genes. Thus, LSD1 serves as an “epigenetic barrier” that optimizes fiber type-specific responses and muscle mass under the stress conditions. Our results uncover that LSD1 modulators provide emerging therapeutic and preventive strategies against stress-induced myopathies such as sarcopenia, cachexia, and disuse atrophy.

Graphical abstract. LSD1 serves as an “epigenetic barrier” that defines stress sensitivities in the skeletal muscle

LSD1 attenuates glucocorticoid (GC)-induced atrophy in the fast fiber-dominant muscles, in collaboration with Foxk1, an anti-autophagic transcription factor. On the other hand, LSD1 attenuates endurance exercise-induced hypertrophy in the slow fiber-dominant muscles, by inhibiting ERRγ, a transcription factor that promotes oxidative metabolism genes. The loss of LSD1 remarkably sensitized the muscles to GC and endurance exercise.
The START domain potentiates HD-ZIPIII transcriptional activity
Authors: Husbands Aman Y. , Feller Antje , Aggarwal Vasudha , Dresden Courtney E. , Holub Ashton S. , Ha Taekjip , Timmermans Marja C.P.
Published: October 2022

HD-ZIPIII transcription factors (TFs) were repeatedly deployed over 725 million years of evolution to regulate central developmental innovations. The START domain of this pivotal class of developmental regulators was recognized over twenty years ago, but its putative ligands and functional contributions remain unknown. Here, we demonstrate that the START domain promotes HD-ZIPIII TF homodimerization and increases transcriptional potency. Effects on transcriptional output can be ported onto heterologous TFs, consistent with principles of evolution via domain capture. We also show the START domain binds several species of phospholipids, and that mutations in conserved residues predicted to affect either ligand binding, or its downstream readout, abolish HD-ZIPIII DNA-binding competence. Our data present a model in which the START domain potentiates transcriptional activity and uses ligand-induced conformational change to render HD-ZIPIII dimers competent to bind DNA. These findings resolve a long-standing mystery in plant development and highlight the flexible and diverse regulatory potential coded within this widely distributed evolutionary module.
SiRNA Molecules as Potential RNAi Therapeutics to Silence RdRP Region and N-Gene of SARS-CoV-2: An In Silico Approach
Authors: Hasan Mahedi , Tasnim Atiya Tahira , Ashik Arafat Islam , Chowdhury Md Belal , Nishat Zakia Sultana , Fariha Khandaker Atkia , Hossain Tanvir , Ahmed Shamim
Published: October 2022

COVID-19 pandemic keeps pressing onward and effective treatment option against it is still far-off. Since the onslaught in 2020, 13 different variants of SARS-CoV-2 have been surfaced including 05 different variants of concern. Success in faster pandemic handling in the future largely depends on reinforcing therapeutics along with vaccines. As a part of RNAi therapeutics, here we developed a computational approach for predicting siRNAs, which are presumed to be intrinsically active against two crucial mRNAs of SARS-CoV-2, the RNA-dependent RNA polymerase (RdRp), and the nucleocapsid phosphoprotein gene (N gene). Sequence conservancy among the alpha, beta, gamma, and delta variants of SARS-CoV-2 was integrated in the analyses that warrants the potential of these siRNAs against multiple variants. We preliminary found 13 RdRP-targeting and 7 N gene-targeting siRNAs using the siDirect V.2.0. These siRNAs were subsequently filtered through different parameters at optimum condition including macromolecular docking studies. As a result, we selected 4 siRNAs against the RdRP and 3 siRNAs against the N-gene as RNAi candidates. Development of these potential siRNA therapeutics can significantly synergize COVID-19 mitigation by lessening the efforts, furthermore, can lay a rudimentary base for the in silico design of RNAi therapeutics for future emergencies.
Speech and music recruit frequency-specific distributed and overlapping cortical networks
Authors: Rietmolen Noémie te , Mercier Manuel , Trébuchon Agnès , Morillon Benjamin , Schön Daniele
Published: October 2022

To what extent does speech and music processing rely on domain-specific and domain-general neural networks? Using whole-brain intracranial EEG recordings in 18 epilepsy patients listening to natural, continuous speech or music, we investigated the presence of frequency-specific and network-level brain activity. We combined it with a statistical approach in which a clear operational distinction is made betweenshared,preferred,and domain-selectiveneural responses. We show that the majority of focal and network-level neural activity is shared between speech and music processing. Our data also reveal an absence of anatomical regional selectivity. Instead, domain-selective neural responses are restricted to distributed and frequency-specific coherent oscillations, typical of spectral fingerprints. Our work highlights the importance of considering natural stimuli and brain dynamics in their full complexity to map cognitive and brain functions.
The RNA m6A reader YTHDF1 promotes hematopoietic malignancy by maintaining oncogenic translation
Authors: Hong Yun-Guang , Yang Zhigang , Chen Yan , Liu Tian , Zheng Yuyuan , Wu Guo-Cai , Chen Yinhui , Xia Juan , Wen Ruiting , Liu Wenxin , Zhao Yi , Chen Jin , Gao Xiangwei , Chen Zhanghui
Published: October 2022

N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myeloid leukemia (AML), while the detailed mechanism remains elusive. Here we report that YTHDF1, an m6A reader protein, is overexpressed in human AML samples with enrichment in leukemia stem cells (LSCs). Whereas YTHDF1 is dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuates self-renewal and proliferation of patient-derived LSCs, and impedes leukemia establishment in immunodeficient mice. Mechanistically, YTHDF1 promotes the translation of diverse m6A-modified oncogene mRNAs particularlycyclin E2. We applied a structure-based virtual screening of FDA-approved drugs and identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocks the direct binding of YTHDF1 with m6A-modified mRNAs and inhibits YTHDF1-regulated mRNA translation. Moreover, tegaserod inhibits leukemogenesisin vitroand in mice, phenocopying the loss of YTHDF1. Together, our study defines YTHDF1 as an integral regulator of AML progression at the translational level and identifies tegaserod as a potential therapeutic agent for AML by targeting YTHDF1.

Statement of Significance

The RNA m6A reader YTHDF1 is an oncoprotein in AML.

YTHDF1 promotes the translation of m6A-modified oncogene mRNAs.

Tegaserod, an FDA-approved drug for irritable bowel syndrome, inhibits YTHDF1-regulated mRNA translation and leukemogenesis.

Graphical Abstract
Tissue-Specific and Interorgan Metabolic Reprogramming Maintains Tolerance to Sepsis
Authors: Leitner Brooks P. , Lee Won D. , Zhu Wanling , Zhang Xinyi , Gaspar Rafael C. , Li Zongyu , Rabinowitz Joshua D. , Perry Rachel J.
Published: October 2022

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness1. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged for both identification of new metabolic targets, and a deeper understanding of the metabolic fate of glutamine at the systemic and tissue-specific manner2–4. In critically ill patients versus elective surgical controls, skeletal muscle transcriptional metabolic reprogramming is comprised of reduced expression of genes involved in mitochondrial metabolism, electron transport, and glutamate transport, with concomitant increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. To analyze putative interorgan communications during sepsis, we performed systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model, cecal ligation and puncture. In the setting of drastically elevated inflammatory cytokines, we observed >10% body weight loss, >50% reductions in oxygen consumption and carbon dioxide production, and near full suppression of voluntary activity for the 48 hours following sepsis as compared to sham-operated controls. We found increased correlations in the metabolome between liver, kidney, and spleen, with drastic loss of correlations between the heart and quadriceps metabolome and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for skeletal and cardiac muscle during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine’s contribution to TCA anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine’s contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming, rather than global mitochondrial dysfunction, as a mechanistic consequence of sepsis. Using a multi-omic approach, we demonstrate a model by which sepsis-induced proteolysis fuels the liver’s production of anaplerotic substrates and the antioxidant glutathione to sustain tolerance to sepsis.
Chemical potential measurements constrain models of cholesterol-phosphatidylcholine interactions
Authors: Shaw Thomas R. , Wisser Kathleen , Shaffner Taylor A. , Gaffney Anna D. , Machta Benjamin B. , Veatch Sarah L.
Published: October 2022

Bilayer membranes composed of cholesterol and phospholipids exhibit diverse forms of non-ideal mixing. In particular, many previous studies document macroscopic liquid-liquid phase separation as well as nanometer-scale heterogeneity in membranes of phosphatidylcholine (PC) lipids and cholesterol. Here, we present experimental measurements of cholesterol chemical potential (μc) in binary membranes containing dioleoyl PC (DOPC), 1-palmitoyl-2-oleoyl PC (POPC), or dipalmitoyl PC (DPPC), and in ternary membranes of DOPC and DPPC, adapting a calibrated experimental protocol developed to measure μc in cells (Ayuyan and Cohen, Biophys. J. 114:904-918). μc is the thermodynamic quantity that dictates the availability of cholesterol to bind other factors, and notably must be equal between coexisting phases of a phase-separated mixture. It is simply related to concentration under conditions of ideal mixing but is found to be far from ideal for the majority of lipid mixtures investigated. Here we perform experimental measurements of μc, constraining thermodynamic models of membrane interactions. Our measurements are consistent with models involving cholesterol-phospholipid complexes, but only if complexes are more weakly bound than has been assumed in previous reports. Experimental measurements are also well described by regular solution theory and lattice models with pairwise interactions between components. We find that μc can vary by ~1.5 kBT at constant cholesterol mole-fraction implying a more than five-fold change in its availability for binding receptors and other reactions. These findings reinforce that μc depends on membrane composition overall, suggesting avenues for cells to alter the availability of cholesterol without varying cholesterol concentration.

SIGNIFICANCE

The chemical potential of cholesterol (μc) reflects its availability to interact with other molecules. In a complex mixtures this chemical potential can vary dramatically even at fixed cholesterol concentration. In this report, we present measurements of μc in bilayer membranes composed of mixtures of cholesterol with one or two phospholipids. We find that μc in these mixtures depends strongly on the phospholipids that are present, with activity varying by a factor of more than five at fixed cholesterol concentration. This suggests that the availability of cholesterol in biological membranes could be tuned without altering cholesterol concentration directly, by adjusting the concentration of other lipid or protein components.
Osmotic pressure enables high yield assembly of giant vesicles in solutions of physiological ionic strengths
Authors: Cooper Alexis , Girish Vaishnavi , Subramaniam Anand Bala
Published: October 2022

Giant unilamellar vesicles (GUVs) are micrometer scale minimal cellular mimics that are useful for synthetic biology and drug delivery. Unlike assembly in low-salt solutions, assembly of GUVs in solutions with ionic concentrations of 100-150 mM Na/KCl (salty solutions) is challenging. Chemical compounds deposited on the substrate or in the lipid mixture could assist in the assembly of GUVs. Here, we investigate quantitatively the effects of temperature and chemical identity of six assisting polymeric and small molecule compounds on the molar yields of GUVs composed of three different lipid mixtures using high resolution confocal microscopy and large dataset image analysis. All the polymers moderately increased the yields of GUVs either at 22 or 37 degrees Celsius, whereas the small molecule compound was ineffective. Low gelling temperature agarose is the singular compound that consistently produces yields of GUVs of greater than 10 %. We propose a free energy model of budding to explain the effects of polymers in assisting the assembly of GUVs. The osmotic pressure exerted on the membranes by the dissolved polymer balances the increased adhesion between the membranes, thus reducing the free energy for bud formation. Data obtained by modulating the ionic strength and ion valency of the solution shows that the evolution of the yield of GUVs support our model’s prediction. In addition, polymer specific interactions with the substrate and the lipid mixture effects yields. The uncovered mechanistic insight provides a quantitative experimental and theoretical framework to guide future studies. Additionally, this work shows a facile means for obtaining GUVs in solutions of physiological ionic strengths.
Multigenic resistance toXylella fastidiosain wild grapes (Vitissps.) and its implications within a changing climate
Authors: Morales-Cruz Abraham , Aguirre-Liguori Jonas , Massonnet Mélanie , Minio Andrea , Zaccheo Mirella , Cochetel Noe , Walker Andrew , Riaz Summaira , Zhou Yongfeng , Cantu Dario , Gaut Brandon S.
Published: October 2022

Xylella fastidiosais a bacterium that infects crops like grapevines, coffee, almonds, citrus and olives, causing economically devastating damage. There is, however, little understanding of the genes that contribute to resistance, the genomic architecture of resistance, and the potential role of climate in shaping resistance, in part because major crops like grapevines (V. vinifera) are not resistant to the bacterium. Here we studied a wild grapevine species,Vitis arizonica, that segregates for resistance toX. fastidiosa. Using genome-wide association, we identified candidate genes that mediate the host response toX. fastidiosainfection. We uncovered evidence that resistance requires genes from multiple genomic regions, based on data from breeding populations and from additionalVitisspecies. We also inferred that resistance evolved more than once in the wild, suggesting that wildVitisspecies may be a rich source for resistance alleles and mechanisms. Finally, resistance inV. arizonicawas climate dependent, because individuals from low (< 10°C) temperature locations in the wettest quarter were typically susceptible to infection, likely reflecting a lack of pathogen pressure in these climates. Surprisingly, climate was nearly as effective a predictor of resistance phenotypes as some genetic markers. This work underscores that pathogen pressure is likely to increase with climate, but it also provides genetic insight and tools for breeding and transforming resistant crops.
Conformational and oligomeric states of SPOP from small-angle X-ray scattering and molecular dynamics simulations
Authors: Thomasen F. Emil , Cuneo Matthew J. , Mittag Tanja , Lindorff-Larsen Kresten
Published: October 2022

Speckle-type POZ protein (SPOP) is a substrate adaptor in the ubiquitin proteasome system, and plays important roles in cell-cycle control, development, and cancer. SPOP forms linear higher-order oligomers following an isodesmic self-association model. Oligomerization is essential for SPOP’s multivalent interactions with substrates, which facilitate phase separation and localization to biomolecular condensates. Structural characterization of SPOP in its oligomeric state and in solution is, however, challenging due to the inherent conformational and compositional heterogeneity of the oligomeric species. Here, we develop an approach to simultaneously and self-consistently characterize the conformational ensemble and the distribution of oligomeric states of SPOP by combining small-angle X-ray scattering (SAXS) and molecular dynamics simulations. We build initial conformational ensembles of SPOP oligomers using coarse-grained molecular dynamics simulations, and use a Bayesian/maximum entropy approach to refine the ensembles, along with the distribution of oligomeric states, against a concentration series of SAXS experiments. Our results suggest that SPOP oligomers behave as rigid, helical structures in solution, and that a flexible linker region allows SPOP’s substrate binding domains to extend away from the core of the oligomers. Additionally, our results are in good agreement with previous characterization of the isodesmic self-association of SPOP. In the future, the approach presented here can be extended to other systems to simultaneously characterize structural heterogeneity and self-assembly.
High-throughput microgel biofabrication via air-assisted co-axial jetting for cell encapsulation, 3D bioprinting, and scaffolding applications
Authors: Pal Vaibhav , Singh Yogendra Pratap , Gupta Deepak , Alioglu Mecit Altan , Nagamine Momoka , Kim Myoung Hwan , Ozbolat Ibrahim T.
Published: October 2022

Microgels have recently received widespread attention for their applications in a wide array of domains such as tissue engineering, regenerative medicine, and cell and tissue transplantation because of their properties like injectability, modularity, porosity, and the ability to be customized in terms of size, form, and mechanical properties. However, it is still challenging to mass produce microgels with diverse sizes and tunable properties. Herein, we developed an air-assisted co-axial device (ACAD) for continuous production of microgels in a high-throughput manner. To test its robustness, microgels of multiple hydrogels and their combination, including alginate (Alg), gelatin methacrylate (GelMA) and Alg-GelMA, were formed at a maximum production rate of 65,000 microgels per sec while retaining circularity and a size range of 50-500 μm based on varying air pressure levels. The ACAD platform allowed single and multiple cell encapsulation with around 75% efficiency. These microgels illustrated appealing rheological properties such as yield stress, viscosity, and shear modulus for bioprinting applications. Specifically, Alg microgels have the potential to be used as a sacrificial support bath while GelMA microgels have potential for direct extrusion both on their own or when loaded in a bulk GelMA hydrogel. Generated microgels showed high cell viability (>90%) and proliferation over 7 days with their increased interactions with cells, particularly for GelMA microgels. The developed strategy provides a facile and rapid approach without any complex or expensive consumables and accessories for scalable high-throughput microgel production for cell therapy, tissue regeneration and 3D bioprinting applications.
N-terminal Domain Influences Steroid Activation of the Atlantic Sea Lamprey Corticoid Receptor
Authors: Katsu Yoshinao , Lin Xiaozhi , Ji Ruigeng , Chen Ze , Kamisaka Yui , Bamba Koto , Baker Michael E.
Published: October 2022

Lampreys are jawless fish that evolved about 550 million years ago at the base of the vertebrate line. Modern lampreys contain a corticoid receptor (CR), the common ancestor of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), which first appear in cartilaginous fish, such as sharks. Until recently, 344 amino acids at the amino terminus of adult lamprey CR were not present in the lamprey CR sequence in GenBank. A search of the recently sequenced lamprey germline genome identified two CR sequences, CR1 and CR2, containing the 344 previously un-identified amino acids. CR1 also contains a novel four amino acid insertion in the DNA-binding domain (DBD). We studied corticosteroid and progesterone activation of CR1 and CR2 and found their strongest response was to 11-deoxycorticosterone and 11-deoxycortisol, the two circulating corticosteroids in lamprey. Based on steroid specificity, both CRs are close to elephant shark MR and distant from elephant shark GR. HEK293 cells that were transfected with full-length CR1 or CR2 and the MMTV promoter have about 3-fold higher steroid-mediated activation compared to HEK293 cells transfected with these CRs and the TAT3 promoter. Deletion of the amino-terminal domain (NTD) of lamprey CR1 and CR2 to form truncated CRs decreased transcriptional activation by about 70% in HEK293 cells that were transfected with MMTV, but increased transcription by about 6-fold in cells transfected with TAT3. This indicated that the promoter has an important effect on NTD regulation of transcriptional activation of the CR by steroids. Our results also indicate that the entire lamprey CR sequence is needed for an accurate determination of steroid-mediated transcription.
The protozoan commensal Tritrichomonas musculis is a natural adjuvant for mucosal IgA
Authors: Cao Eric Yixiao , Burrows Kyle , Chiaranunt Pailin , Popovic Ana , Zhou Xueyang , Xie Cong , Thakur Ayushi , Britton Graham , Spindler Matthew , Ngai Louis , Tai Siu Ling , Dasoveanu Dragos Cristian , Nguyen Albert , Faith Jeremiah J. , Parkinson John , Gommerman Jennifer L. , Mortha Arthur
Published: October 2022

Immunoglobulin(Ig) A antibodies are the most abundant antibodies supporting mucosal immune homeostasis and host-microbiota interactions. Driven by gut commensal microbes, IgA-secreting plasma cells (PC) differentiate through T cell-dependent (Td) or T cell independent (Ti) mechanisms. While commensal bacteria within the microbiota are known for their ability to promote IgA, the role of non-bacterial commensal microbes on the induction of IgA remains elusive. Here, we demonstrate that permanent colonization with the protozoan commensal Tritrichomonas musculis (T.mu) promotes T-cell dependent, IgA class-switch recombination and intestinal accumulation of IgA-secreting PC. T.mu colonization specifically drives the expansion of T follicular helper cells and a unique ICOS+ non-Tfh cell population, accompanied by an increase in germinal center B cells. Blockade of ICOS:ICOSL co-stimulation or MHCII-expression on B cells are central for the induction of IgA following colonization by T.mu, implicating a previously underappreciated mode of IgA induction following protozoan commensal colonization. Finally, the commensal T.mu further improves the induction of IgA-secreting plasma cells and their peripheral dissemination, even against non-protozoan, orally ingested antigens, identifying T.mu as natural adjuvant for IgA. Collectively, these findings propose a previously unknown, protozoa-driven mode of IgA induction that supports intestinal immune homeostasis even against non-microbial antigens.
Tumor Spheroids Layered in an Imageable Cancer Environment (T-SLICE): a novelin vitroplatform to study tumor biology
Authors: Pugh-Toole Morgan , Dawe Nicholas , Smith Andrew , Boudreau Jeanette E. , Leung Brendan M.
Published: October 2022

Cancer treatment is shifting towards precise medicine informed by tumor genetics and structural features. In recent years, it has become increasingly recognized that patient tumors—even those of the same tissue origin—can differ substantially between patients and respond differently to treatment. Given this, it is necessary to design therapies that target the heterogeneity of tumors. When investigating novel therapeutics in the laboratory, conventional cell culture models do not adequately recapitulate this heterogeneity and therefore may not accurately represent drug responses. Recent advances in miniaturized organ-on-a-chip models have been able to generate more complex microenvironments forin vitrostudies. However, many of these models do not resemble the scale of clinically relevant tumors and pose a high barrier to use because they are technically complex. To facilitate mechanistic studies of the tumor microenvironment (TME), we designed T-SLICE, a chip made using commercially available elastomers and designed to fit in a standard 6-well plate. This simple 3-D tumor model incorporates microfluidic principles into a fully customizable TME, wherein cells drive the formation of biochemical gradients akin to those observed within a real tumor. In T-SLICE, spheroids are seeded atop a monolayer of fibroblasts situated between two closely spaced coverslips (300-700 µm). The restrictive gap height limits the permeation of oxygen (O2) and hinders the removal of carbon dioxide (CO2) and metabolic waste, which leads to the generation of tumor-like hypoxic gradients. We demonstrate that T-SLICE establishes cell-driven oxygen gradients leading to the formation of a hypoxic core, with further impacts on cellular viability, mitochondrial membrane potential (MMP), and proliferation. T-SLICE cultures can be imaged live or fixed and stained for immunohistochemistry (IHC). These features of T-SLICE make it an accessible and faithful model of a tumor’s heterogeneity and open the possibility for more faithful testing of novel therapeutics in the context of a realistic TME.