Miracle-dz/UniFAR-FTUs huggingface dataset:
Evolution of Methyltransferase-Like (METTL) Proteins in Metazoa: A Complex Gene Family Involved in Epitranscriptomic Regulation and Other Epigenetic Processes

Abstract The methyltransferase-like (METTL) proteins constitute a family of seven-beta-strand methyltransferases with S-adenosyl methionine-binding domains that modify DNA, RNA, and proteins. Methylation by METTL proteins contributes to the epigenetic, and in the case of RNA modifications, epitranscriptomic regulation of a variety of biological processes. Despite their functional importance, most investigations of the substrates and functions of METTLs within metazoans have been restricted to model vertebrate taxa. In the present work, we explore the evolutionary mechanisms driving the diversification and functional differentiation of 33 individual METTL proteins across Metazoa. Our results show that METTLs are nearly ubiquitous across the animal kingdom, with most having arisen early in metazoan evolution (i.e., occur in basal metazoan phyla). Individual METTL lineages each originated from single independent ancestors, constituting monophyletic clades, which suggests that each METTL was subject to strong selective constraints driving its structural and/or functional specialization. Interestingly, a similar process did not extend to the differentiation of nucleoside-modifying and protein-modifying METTLs (i.e., each METTL type did not form a unique monophyletic clade). The members of these two types of METTLs also exhibited differences in their rates of evolution. Overall, we provide evidence that the long-term evolution of METTL family members was driven by strong purifying selection, which in combination with adaptive selection episodes, led to the functional specialization of individual METTL lineages. This work contributes useful information regarding the evolution of a gene family that fulfills a variety of epigenetic functions, and can have profound influences on molecular processes and phenotypic traits.
Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma

Significance The collection of large amounts of whole-genome sequencing data allowed for identification of mutational signatures, which are characteristic combinations of substitutions in the context of neighboring bases. The clinical significance of these mutational signatures is still largely unknown. In neuroblastoma, we showed that high levels of cytosine > adenine (C > A) substitutions are associated with poor survival. We identified that these high levels of C > A substitutions result from defects in 8-oxo-guanine repair, specifically from copy number loss of the DNA glycosylases MUTYH and OGG1. The high frequency of C > A substitutions in neuroblastoma contributes to the increased adaptive capacity of these tumors. Thereby, we link basic molecular genetic mutation patterns to clinically significant tumor evolution processes. Neuroblastomas are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole-genome sequencing data analysis revealed a high frequency of somatic cytosine > adenine (C > A) substitutions in primary neuroblastoma tumors, which was associated with poor survival. We showed that increased levels of C > A substitutions correlate with copy number loss (CNL) of OGG1 or MUTYH. Both genes encode DNA glycosylases that recognize 8-oxo-guanine (8-oxoG) lesions as a first step of 8-oxoG repair. Tumor organoid models with CNL of OGG1 or MUTYH show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of MUTYH and OGG1 in neuroblastoma cells. Whole-genome sequencing of single-cell OGG1 and MUTYH knockout clones identified an increased accumulation of C > A substitutions. Mutational signature analysis of these OGG1 and MUTYH knockout clones revealed enrichment for C > A signatures 18 and 36, respectively. Clustering analysis showed that the knockout clones group together with tumors containing OGG1 or MUTYH CNL. In conclusion, we demonstrate that defects in 8-oxoG repair cause accumulation of C > A substitutions in neuroblastoma, which contributes to mutagenesis and tumor evolution.
Combination of Manifold Learning and Deep Learning Algorithms for Mid-Term Electrical Load Forecasting

Mid-term load forecasting (MTLF) is of great significance for power system planning, operation, and power trading. However, the mid-term electrical load is affected by the coupling of multiple factors and demonstrates complex characteristics, which leads to low prediction accuracy in MTLF. Furthermore, MTLF is faced with the “curse of dimensionality” problem due to a large number of variables. This article proposes an MTLF method based on manifold learning, which can extract the underlying factors of load variations to help improve the accuracy of MTLF and significantly reduce the calculation. Unlike linear dimensionality reduction methods, manifold learning has better nonlinear feature extraction ability and is more suitable for load data with nonlinear characteristics. Furthermore, long short-term memory (LSTM) neural networks are used to establish forecasting models in the low-dimensional space obtained by manifold learning. The proposed MTLF method is tested on independent system operator (ISO) New England datasets, and load forecasting in 24, 168, and 720 h ahead is carried out. The numerical results validate that the proposed method has higher prediction accuracy than many mature methods in the mid-term time scale.
A voltage-pulse-modulated giant magnetoresistance switch with four flexible sensing ranges

This article introduces an innovative technique for achieving a giant magnetoresistance (GMR) switch with an adjustable sensing field range. A spin-valve (SV) patterned into a strip shape is grown on a specific (110)-cut Pb(Mg1/3Nb2/3)0.7Ti0. 3O3 (PMN-PT) substrate. In the process of depositing films, a magnetic easy axis of the free layer in the SV is produced along the [001] direction (the x-axis) of the PMN-PT. This PMN-PT can produce a nonvolatile strain by using a positive voltage pulse. Accordingly, the magnetic moment of the free layer can be modulated to the y-axis by the strain-mediated magnetoelectric coupling effect produced in the SV/PMN-PT heterostructure. Furthermore, a negative voltage pulse can release the strain and revert the magnetic moment to the initial [001] direction. The effective field along the [1-10] direction produced by the nonvolatile strain can modulate the easy axis of the free layer, changing it from the x-axis to the y-axis. Therefore, large and small switching fields are achieved in a bipolar GMR switch. Furthermore, by applying positive and negative voltage pulses at appropriate moments, two asymmetrical switching field ranges are obtained. Thus, a GMR switch with four adjustable switching field ranges can be obtained. The proposed modulating model is flexible and can meet the requirements of specific and different application systems. The proposed design reveals a great potential for the application to the internet of things and the development of low-power and high-efficient magnetoresistive sensors.
Elucidating the mechanism by which synthetic helper peptides sensitize Pseudomonas aeruginosa to multiple antibiotics

The emergence and rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to the global healthcare. There is an urgent need for new antibacterial substances or new treatment strategies to deal with the infections by MDR bacterial pathogens, especially the Gram-negative pathogens. In this study, we show that a number of synthetic cationic peptides display strong synergistic antimicrobial effects with multiple antibiotics against the Gram-negative pathogen Pseudomonas aeruginosa. We found that an all-D amino acid containing peptide called D-11 increases membrane permeability by attaching to LPS and membrane phospholipids, thereby facilitating the uptake of antibiotics. Subsequently, the peptide can dissipate the proton motive force (PMF) (reducing ATP production and inhibiting the activity of efflux pumps), impairs the respiration chain, promotes the production of reactive oxygen species (ROS) in bacterial cells and induces intracellular antibiotics accumulation, ultimately resulting in cell death. By using a P. aeruginosa abscess infection model, we demonstrate enhanced therapeutic efficacies of the combination of D-11 with various antibiotics. In addition, we found that the combination of D-11 and azithromycin enhanced the inhibition of biofilm formation and the elimination of established biofilms. Our study provides a realistic treatment option for combining close-to-nature synthetic peptide adjuvants with existing antibiotics to combat infections caused by P. aeruginosa.
Diversity begets diversity during community assembly until ecological limits impose a diversity ceiling

Microbial communities are hugely diverse, but we do not yet understand how species invasions and extinctions drive and limit their diversity. On the one hand, the ecological limits hypothesis posits that diversity is primarily limited by environmental resources. On the other hand, the diversity‐begets‐diversity hypothesis posits that such limits can be easily lifted when new ecological niches are created by biotic interactions. To find out which hypothesis better explains the assembly of microbial communities, we used metabolic modelling. We represent each microbial species by a metabolic network that harbours thousands of biochemical reactions. Together, these reactions determine which carbon and energy sources a species can use, and which metabolic by‐products—potential nutrients for other species—it can excrete in a given environment. We assemble communities by modelling thousands of species invasions in a chemostat‐like environment. We find that early during the assembly process, diversity begets diversity. By‐product excretion transforms a simple environment into one that can sustain dozens of species. During later assembly stages, the creation of new niches slows down, existing niches become filled, successful invasions become rare, and species diversity plateaus. Thus, ecological limitations dominate the late assembly process. We conclude that each hypothesis captures a different stage of the assembly process. Species interactions can raise a community's diversity ceiling dramatically, but only within limits imposed by the environment.
Entero-pancreatic hormone secretion, gastric emptying and glucose absorption after frequently sampled meal tests.

CONTEXT Entero-pancreatic hormone secretion has been reported during the pre-absorptive cephalic and gastric meal phases, but never with a blood sampling frequency providing a temporal resolution that allows close scrutiny and correlations with gastric emptying and glucose-absorption. OBJECTIVE We hypothesized that entero-pancreatic hormone secretion after nutrient ingestion would be rapid and correlate with gastric emptying and glucose absorption. DESIGN AND SETTING Two visits in a clinical research facility. PARTICIPANTS Ten healthy young men. INTERVENTIONS A 75g glucose drink (OG) and a liquid mixed meal (LMM) were ingested (t 0-2 min) on separate days. Acetaminophen and 3-O-methyl-D-glucopyranose (3-OMG) were added to the drinks to evaluate gastric emptying and glucose absorption, respectively. Arterialized venous blood was sampled (t -30,-20,-18,-16,-14,-12,-10,-8,-6,-4,-2, 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30 min). MAIN OUTCOME MEASURES Plasma glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), gastrin, cholecystokinin (CCK), glucagon, pancreatic polypeptide (PP), 3-OMG and glucose. Serum insulin, C-peptide and acetaminophen. RESULTS Acetaminophen increased 8min after OG(p<0.001) and LMM(p<0.05). 3-OMG; 8min after LMM(p<0.0001), 10min after OG(p=0.04). PP; 4min after LMM(p<0.03). Gastrin; 6min after LMM(p<0.003) and OG(p<0.003). CCK; 6min after LMM(p=0.0001). GIP; 8min after OG(p<0.05) and LMM(p<0.03). Glucose; 8min after OG(p<0.001), 12min after LMM(p<0.02). GLP-1; 12min after OG(p<0.01), 10min after LMM (p<0.01). Insulin; 12min after LMM(p=0.02) and OG(p=0.002). C-peptide; 12min after OG(p=0.002) and LMM(p=0.04). CONCLUSIONS Early postprandial hormone responses show characteristic differences with regards to timing and amplitude, but also great individual differences. This should be considered when interpreting mean responses and designing study protocols. CLINICALTRIALS.GOV NUMBER NCT03543423.
Histotripsy Ablation in Preclinical Animal Models of Cancer and Spontaneous Tumors in Veterinary Patients: A Review

New therapeutic strategies are direly needed in the fight against cancer. Over the last decade, several tumor ablation strategies have emerged as stand-alone or combination therapies. Histotripsy is the first completely noninvasive, nonthermal, and nonionizing tumor ablation method. Histotripsy can produce consistent and rapid ablations, even near critical structures. Additional benefits include real-time image guidance, high precision, and the ability to treat tumors of any predetermined size and shape. Unfortunately, the lack of clinically and physiologically relevant preclinical cancer models is often a significant limitation with all focal tumor ablation strategies. The majority of studies testing histotripsy for cancer treatment have focused on small animal models, which have been critical in moving this field forward and will continue to be essential for providing mechanistic insight. While these small animal models have notable translational value, there are significant limitations in terms of scale and anatomical relevance. To address these limitations, a diverse range of large animal models and spontaneous tumor studies in veterinary patients have emerged to complement existing rodent models. These models and veterinary patients are excellent at providing realistic avenues for developing and testing histotripsy devices and techniques designed for future use in human patients. Here, we provide a review of animal models used in preclinical histotripsy studies and compare histotripsy ablation in these models using a series of original case reports across a broad spectrum of preclinical animal models and spontaneous tumors in veterinary patients.
High resolution stereolithography fabrication of perfusable scaffolds to enable long-term meso-scale hepatic culture for disease modeling

Microphysiological systems (MPS), comprising human cell cultured in formats that capture features of the three-dimensional (3D) microenvironments of native human organs under microperfusion, are promising tools for biomedical research. Here we report the development of a mesoscale physiological system (MePS) enabling the long-term 3D perfused culture of primary human hepatocytes at scales of over 106 cells per MPS. A central feature of the MePS, which employs a commercially-available multiwell bioreactor for perfusion, is a novel scaffold comprising a dense network of nano- and micro-porous polymer channels, designed to provide appropriate convective and diffusive mass transfer of oxygen and other nutrients while maintaining physiological values of shear stress. The scaffold design is realized by a high resolution stereolithography fabrication process employing a novel resin. This new culture system sustains mesoscopic hepatic tissue-like cultures with greater hepatic functionality (assessed by albumin and urea synthesis, and CYP3A4 activity) and lower inflammation markers compared to comparable cultures on the commercial polystyrene scaffold. To illustrate applications to disease modeling, we established an insulin-resistant phenotype by exposing liver cells to hyperglycemic and hyperinsulinemic media. Future applications of the MePS include the co-culture of hepatocytes with resident immune cells and the integration with multiple organs to model complex liver-associated diseases
Criss‐crossing autism spectrum disorder and adult neurogenesis

Autism spectrum disorder (ASD) comprises a group of multifactorial neurodevelopmental disorders primarily characterized by deficits in social interaction and repetitive behavior. Although the onset is typically in early childhood, ASD poses a lifelong challenge for both patients and caretakers. Adult neurogenesis (AN) is the process by which new functional neurons are created from neural stem cells existing in the post‐natal brain. The entire event is based on a sequence of cellular processes, such as proliferation, specification of cell fate, maturation, and ultimately, synaptic integration into the existing neural circuits. Hence, AN is implicated in structural and functional brain plasticity throughout life. Accumulating evidence shows that impaired AN may underlie some of the abnormal behavioral phenotypes seen in ASD. In this review, we approach the interconnections between the molecular pathways related to AN and ASD. We also discuss existing therapeutic approaches targeting such pathways both in preclinical and clinical studies. A deeper understanding of how ASD and AN reciprocally affect one another could reveal important converging pathways leading to the emergence of psychiatric disorders.
The role of digital health technology in rural cancer care delivery: A systematic review.

PURPOSE Rural residents face higher cancer incidence rates and mortality rates, disparities that could be mitigated with health technology interventions, yet a digital divide is also apparent. This paper systematically and critically examines existing literature to understand how digital technologies have been used to support rural oncology care. METHODS PubMed, CINAHL Complete, PsycINFO, and Embase were searched using Medical Subject Headings terms and keywords. Studies were eligible if they presented empirical data investigating the use of technology in rural oncology and were published in English in a peer-reviewed journal within the last decade. The Mixed Methods Appraisal Tool was used to assess methodological quality. FINDINGS Digital health has been less extensively utilized in rural oncology compared with the general cancer population and other chronic diseases. We identified 54 studies that used technology in rural cancer care delivery, a comparatively small number, representing a significant gap in the literature. Studies were classified into 4 categories: Telemedicine (n = 32), phone calls (n = 11), Internet (n = 9), and mobile phone (n = 2). Of the 54 articles, 12 were RCTs, 17 were quasi-experimental, 3 were descriptive, 12 were mixed methods, and 10 were qualitative. Most of the studies involved patients only (n = 31) and were not specific to a cancer type (n = 41). CONCLUSIONS Further implementation and expansion of telemedicine and phone-based strategies in rural cancer care delivery are warranted. Rural cancer survivors value digital approaches to their care. However, social and behavioral determinants of health and access to technology must be considered.
Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer’s disease: an adrenergic approach

Alzheimer’s disease (AD), as the most common neurodegenerative disease in elder population, is pathologically characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles composed of highly-phosphorylated tau protein and consequently progressive neurodegeneration. However, both Aβ and tau fails to cover the whole pathological process of AD, and most of the Aβ- or tau-based therapeutic strategies are all failed. Increasing lines of evidence from both clinical and preclinical studies have indicated that age-related cerebrovascular dysfunctions, including the changes in cerebrovascular microstructure, blood-brain barrier integrity, cerebrovascular reactivity and cerebral blood flow, accompany or even precede the development of AD-like pathologies. These findings may raise the possibility that cerebrovascular changes are likely pathogenic contributors to the onset and progression of AD. In this review, we provide an appraisal of the cerebrovascular alterations in AD and the relationship to cognitive impairment and AD pathologies. Moreover, the adrenergic mechanisms leading to cerebrovascular and AD pathologies were further discussed. The contributions of early cerebrovascular factors, especially through adrenergic mechanisms, should be considered and treasured in the diagnostic, preventative, and therapeutic approaches to address AD.
Efficient Ion Sieving in Covalent Organic Framework Membranes with Sub‐2‐Nanometer Channels

Membranes of sub‐2‐nanometer channels show high ion transport rates, but it remains a great challenge to design such membranes with desirable ion selectivities for ion separation applications. Here, covalent organic framework (COF) membranes with a channel size of ≈1.4 nm and abundant hydrogen bonding sites, exhibiting efficient ion sieving properties are demonstrated. The COF membranes have high monovalent cation permeation rates of 0.1–0.2 mol m−2 h−1 and extremely low multivalent cation permeabilities, leading to high monovalent over divalent ion selectivities for K+/Mg2+ of ≈765, Na+/Mg2+ of ≈680, and Li+/Mg2+ of ≈217. Experimental measurements and theoretical simulations reveal that the hydrogen bonding interaction between hydrated cations and the COF channel wall governs the high selectivity, and divalent cations transport through the channel needs to overcome higher energy barriers than monovalent cations. These findings provide an effective strategy for developing sub‐2‐nanometer sized membranes with specific interaction sites for high‐efficiency ionic separation.
Discussion on “Causal mediation of semicompeting risks” by Yen‐Tsung Huang

We thank the editor for the opportunity to discuss the article by Huang on Causal mediation of semicompeting risks. Huang draws attention to the important task of defining a scientifically meaningful causal estimand in time-toevent settings. Huang claims to propose an approach to “casting the semi-competing risks problem in the framework of causal mediation modeling,” further claiming an “advantage in causal interpretation over existing methods. ” Although we agree that defining meaningful estimands is crucial, we question both of these claims. We structure our arguments as follows. First, we question whether there is utility in categorizing problems as “semi-competing risks” when a causal effect is the analytic goal (Young et al., 2020). Second, we review well-established concerns over the interpretation of the class of causal effects Huang considers for studying causal mechanisms, which are cross-world parameters related to natural (pure) effects (Robins and Greenland, 1992). We also question the interpretation of these effects within the motivating subject-matter example. Finally, we review recently proposed alternative effect definitions for studying causal mechanisms, the interventionist (separable) effects (Robins and Richardson, 2011; Didelez, 2019; Stensrud et al., 2020c, 2020a; Robins et al., 2020; Martinussen and Stensrud, 2020), which overcome historical concerns related to natural effects and other cross-world estimands, and we consider their possible applicability to Huang’s subject matter example.