Miracle-dz/UniFAR-FTUs huggingface dataset:
Messenger RNA modifications: Form, distribution, and function

RNA contains more than 100 distinct modifications that promote the functions of stable noncoding RNAs in translation and splicing. Recent technical advances have revealed widespread and sparse modification of messenger RNAs with N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ). Here we discuss the rapidly evolving understanding of the location, regulation, and function of these dynamic mRNA marks, collectively termed the epitranscriptome. We highlight differences among modifications and between species that could instruct ongoing efforts to understand how specific mRNA target sites are selected and how their modification is regulated. Diverse molecular consequences of individual m6A modifications are beginning to be revealed, but the effects of m5C and Ψ remain largely unknown. Future work linking molecular effects to organismal phenotypes will broaden our understanding of mRNA modifications as cell and developmental regulators.
Climate-driven regime shift of a temperate marine ecosystem

No turning back? Ecosystems over time have endured much disturbance, yet they tend to remain intact, a characteristic we call resilience. Though many systems have been lost and destroyed, for systems that remain physically intact, there is debate as to whether changing temperatures will result in shifts or collapses. Wernburg et al. show that extreme warming of a temperate kelp forest off Australia resulted not only in its collapse, but also in a shift in community composition that brought about an increase in herbivorous tropical fishes that prevent the reestablishment of kelp. Thus, many systems may not be resilient to the rapid climate change that we face. Science, this issue p. 169 Rapid warming tropicalizes a temperate kelp forest. Ecosystem reconfigurations arising from climate-driven changes in species distributions are expected to have profound ecological, social, and economic implications. Here we reveal a rapid climate-driven regime shift of Australian temperate reef communities, which lost their defining kelp forests and became dominated by persistent seaweed turfs. After decades of ocean warming, extreme marine heat waves forced a 100-kilometer range contraction of extensive kelp forests and saw temperate species replaced by seaweeds, invertebrates, corals, and fishes characteristic of subtropical and tropical waters. This community-wide tropicalization fundamentally altered key ecological processes, suppressing the recovery of kelp forests.
Durable coexistence of donor and recipient strains after fecal microbiota transplantation

Persistence of fecal transplants Fecal microbiota transplantation is a successful way of treating the distressing symptoms of irritable bowel disease or Clostridium difficile infection. The procedure is done by administering a concentrate of colonic bacteria from a healthy donor. Li et al. used metagenomic data to look at single-nucleotide variants after transplants in humans. Donor and recipient strains coexisted for at least 3 months. Some donor strains replaced related strains of the same species, but totally novel species from a donor were unlikely to thrive in a recipient. Rational design of personalized fecal transplant “cocktails” will therefore rely on resolution beyond the species level. Science, this issue p. 586 The mystery of the success of clinical microbial transplant therapy is beginning to be decoded. Fecal microbiota transplantation (FMT) has shown efficacy in treating recurrent Clostridium difficile infection and is increasingly being applied to other gastrointestinal disorders, yet the fate of native and introduced microbial strains remains largely unknown. To quantify the extent of donor microbiota colonization, we monitored strain populations in fecal samples from a recent FMT study on metabolic syndrome patients using single-nucleotide variants in metagenomes. We found extensive coexistence of donor and recipient strains, persisting 3 months after treatment. Colonization success was greater for conspecific strains than for new species, the latter falling within fluctuation levels observed in healthy individuals over a similar time frame. Furthermore, same-donor recipients displayed varying degrees of microbiota transfer, indicating individual patterns of microbiome resistance and donor-recipient compatibilities.
Blind adaptive equalization of mismatch errors in a time-interleaved A/D converter system

To significantly increase the sampling rate of an A/D converter (ADC), a time-interleaved ADC system is a good option. The drawback of a time-interleaved ADC system is that the ADCs are not exactly identical due to errors in the manufacturing process. This means that time, gain, and offset mismatch errors are introduced in the ADC system. These errors cause distortion in the sampled signal. In this paper, we present a method for estimation and compensation of the mismatch errors. The estimation method requires no knowledge about the input signal except that it should be bandlimited to the Nyquist frequency for the complete ADC system. This means that the errors can be estimated while the ADC is running. The method is also adaptive to slow changes in the mismatch errors. The estimation method has been validated with simulations and measurements from a time-interleaved ADC system.
Factors Associated with Trauma Symptoms Among Runaway/Homeless Adolescents

ABSTRACT Runaway/homeless youth often suffer from exposure to chronic family distress and confront numerous traumatic events that may produce symptoms of PTSD. This study evaluated runaway/homeless youth's PTSD symptoms and associated factors. Data were collected at youth emergency shelters. Ninety-eight percent of participants had elevated PTSD symptom scores. Although use of inhalants and LSD was associated with PTSD symptoms, only depression, anxiety, and dissociation, mother's ecstasy or LSD use, youth's worry about family relationships, and poor family communication predicted higher PTSD scores. Runaway/homeless youth entering emergency shelters services must be evaluated concerning trauma and associated comorbid symptoms.
Certificate management in OPC UA applications: An evaluation of different trust models

OPC Unified Architecture (OPC UA) provides a powerful and inherent security model. These mechanisms rely on software certificates. In an automation system where OPC UA is applied, a strategy must be defined how to manage these certificates, i.e. an organised way of distribution, validation and revocation needs to be found. In general, there exist different concepts of how to achieve this goal. Moreover, there are various, in some cases platform dependent frameworks available which assist the developer in implementing a suitable concept. The aim of this paper is to give an overview of these concepts and frameworks and discuss their positive and negative aspects depending on the structure of different environments in which OPC UA applications shall be embedded.
Cross-species comparisons of host genetic associations with the microbiome

Recent studies in human populations and mouse models reveal notable congruences in gut microbial taxa whose abundances are partly regulated by host genotype. Host genes associating with these taxa are related to diet sensing, metabolism, and immunity. These broad patterns are further validated in similar studies of nonmammalian microbiomes. The next generation of genome-wide association studies will expand the size of the data sets and refine the microbial phenotypes to fully capture these intriguing signatures of host-microbiome coevolution.
Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals

Denisovan DNA retained in Melanesians Modern humans carry remnants of DNA from interbreeding events with archaic lineages, such as Neandertals. However, people from Oceania also retain genes from a second ancient lineage, the Denisovans. Vernot et al. surveyed archaic genomic sequences in a worldwide sample of modern humans, including 35 individuals from the Melanesian Islands. All non-African genomes surveyed contained Neandertal DNA, but a significant Denisovan component was found only in the Melanesians. Reconstruction of this genetic history suggests that Neandertals bred with modern humans multiple times, but Denosivans only once, in ancestors of modern-day Melanesians. Science, this issue p. 235 Neandertal and Denisovan DNA live on in modern day Melanesians. Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.34 gigabases and 303 megabases of the Neandertal and Denisovan genome, respectively. We use these maps of archaic sequences to show that Neandertal admixture occurred multiple times in different non-African populations, characterize genomic regions that are significantly depleted of archaic sequences, and identify signatures of adaptive introgression.
Continuous-time active-RC filter model for computer-aided design and optimization

A general circuit model is presented for integrator-based continuous-time active-RC filters, consisting of inverting amplifiers and a passive feedback network. The structure is analyzed using a matrix description and the explicit transfer-function formula is given for the general case. Extensions of the model are given that take into account finite dc gain and bandwidth of operational amplifiers, as well as other nonideal effects. Noise analysis of the active-RC filters is performed in a general setting. The matrix-based approach is formulated especially for the efficient use in computer-aided analysis and design of active-RC filters. As illustrations, a few application examples of the proposed approach are given.
The radical mechanism of biological methane synthesis by methyl-coenzyme M reductase

A radical route to making methane Microorganisms are the main drivers of Earth's methane cycle. The enzyme ultimately responsible for biological methane production has an ambiguous mechanism because it involves difficult-to-isolate reaction intermediates. Wongnate et al. used stopped-flow and rapid freeze-quench experiments to trap a methyl radical in the active site of methyl-coenzyme M reductase (see the Perspective by Lawton and Rosenzweig). Spectroscopy demonstrated that cofactor F430 contained Ni(II), consistent with computational results. The final step of methanogenesis thus proceeds through Ni(II)-thiolate and methyl radical intermediates rather than an organometallic methyl-Ni(III) mechanism. Science, this issue p. 953;, see also p. 892 The final step of methanogenesis proceeds via Ni(II)-thiolate and methyl radical intermediates. Methyl-coenzyme M reductase, the rate-limiting enzyme in methanogenesis and anaerobic methane oxidation, is responsible for the biological production of more than 1 billion tons of methane per year. The mechanism of methane synthesis is thought to involve either methyl-nickel(III) or methyl radical/Ni(II)-thiolate intermediates. We employed transient kinetic, spectroscopic, and computational approaches to study the reaction between the active Ni(I) enzyme and substrates. Consistent with the methyl radical–based mechanism, there was no evidence for a methyl-Ni(III) species; furthermore, magnetic circular dichroism spectroscopy identified the Ni(II)-thiolate intermediate. Temperature-dependent transient kinetics also closely matched density functional theory predictions of the methyl radical mechanism. Identifying the key intermediate in methanogenesis provides fundamental insights to develop better catalysts for producing and activating an important fuel and potent greenhouse gas.
Efficient fault simulation through dynamic binary translation for dependability analysis of embedded software

Fault injection is fundamental to evaluate the dependability of embedded software. Analyzing the interaction between the software and hardware components when hardware faults occur is efficient, but it is only possible once physical prototypes are available. On the other hand, fault injection on Hardware Description Language (HDL) models is a common practice that can significantly improve the verification phases, but HDL simulation speed constitutes a bottleneck of the design flow. In such a context, executing software on a virtual CPU providing fault-injection capabilities allows engineers to anticipate Embedded Software (ESW) dependability analysis at an earlier design stage. Thus, we present a non-intrusive approach that offers high speed for simulating hardware faults affecting CPU behaviors. This is obtained through dynamic translation of ESW binary code. In this work, hardware fault models (i.e., stuck-at, transient and delay faults) have been abstracted to an instruction-accurate CPU emulator without losing quality for ESW dependability analysis. Experimental results proves both the efficiency and effectiveness of the proposed approach.
Infecção pelo vírus da hepatite c em pacientes em hemodiálise: prevalência e fatores de risco

ABSTRACT – Context - Chronic renal disease patients on hemodialysis are at increased risk of infection by hepatitis C virus (HCV). High prevalence rates have been reported from dialysis units worldwide. Recent studies have shown an inverse relation between HCV infection and life expectancy of patients on hemodialysis and those undergoing renal transplant. Objectives - Assess the prevalence of and risk factors for HCV infection in patients undergoing hemodialysis. Methods - A cross-sectional study was undertaken from January to December, 2007. During this period, 236 patients were tested for anti-HCV antibodies with third generation ELISA. Those who tested positive further underwent qualitative PCR testing for HCV-RNA. A subject was considered HCV-infected if both tests (anti-HCV and HCV-RNA) were positive. Monthly serum ALT and the mean for the 12-month period were obtained from 195 patients. Two hundred eight (88.1%) patients answered a standardized questionnaire aiming to identify risk factors for HCV infection.
Network of epistatic interactions within a yeast snoRNA

Epistasis and mutational fitness landscape A fitness landscape of a gene defines the molecular potential of evolution. This can help us understand the current state of evolution as well as predict unrealized potential. Using deep sequencing to examine mutations in nonessential genes that affect the growth of yeast strains, two studies have generated fitness landscapes and measured the effect of epistatic interactions (see the Perspective by He and Liu). Li et al. generated a library of mutants in a transfer RNA gene, including all single and many double and multiple mutants. The RNA secondary structure was generally predictive of bases under selection. Similarly, Puchta et al. assessed a small nucleolar RNA gene for the fitness effects of individual mutations, which correlated with evolutionary conservation and structural stability. Both studies suggest that epistasis—the combined functional effect—for double substitutions is more often negative than positive. Science, this issue pp. 837 and 840; see also p. 769 Fitness estimates across mutations in a small nucleolar RNA gene predict the spatial structure of RNAs. Epistatic interactions play a fundamental role in molecular evolution, but little is known about the spatial distribution of these interactions within genes. To systematically survey a model landscape of intragenic epistasis, we quantified the fitness of ~60,000 Saccharomyces cerevisiae strains expressing randomly mutated variants of the 333-nucleotide-long U3 small nucleolar RNA (snoRNA). The fitness effects of individual mutations were correlated with evolutionary conservation and structural stability. Many mutations had small individual effects but had large effects in the context of additional mutations, which indicated negative epistasis. Clusters of negative interactions were explained by local thermodynamic threshold effects, whereas positive interactions were enriched among large-effect sites and between base-paired nucleotides. We conclude that high-throughput mapping of intragenic epistasis can identify key structural and functional features of macromolecules.
Biochemical properties, pharmacokinetics and pharmacological response of tiotropium in chronic obstructive pulmonary disease patients

Background: Chronic obstructive pulmonary disease (COPD) is a progressive disease with increasing incidence and mortality. Tiotropium is an inhaled long-acting anti-cholinergic for the maintenance treatment of COPD. Objective: To review biochemical and pharmacokinetic data on tiotropium and discuss in the context of tiotropium's efficacy and safety in COPD. Methods: Review of previously done pharmacokinetic studies performed by the manufacturer of tiotropium. Data obtained through peer-reviewed publications and regulatory websites. Results/conclusions: The long duration of action with tiotropium is owing to prolonged, competitive binding to M3 muscarinic receptors. Tiotropium is poorly absorbed following inhalation, which largely limits side effects. Metabolism of absorbed drug is minimal and excretion is largely through the kidneys. Tiotropium is efficacious and well tolerated by patients with COPD.
C9orf72 is required for proper macrophage and microglial function in mice

Linking neurodegeneration and immune cells The expansion of a repetitive DNA sequence in the C9orf72 gene is the major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Although the expansion decreases C9orf72 expression, most research has focused on the toxic RNA and protein products it creates in neurons. O'Rourke et al. found that C9orf72 unexpectedly plays a key role in innate immune cells. Loss of C9orf72 in mice led to macrophage and microglial dysfunction and age-related neuroinflammation. This raises the possibility of a “dual-effect” disease mechanism, in which toxic byproducts in neurons are combined with microglial dysfunction from decreased C9orf72 expression, together promoting neurodegeneration. Science, this issue p. 1324 Loss of C9orf72 disrupts microglial function and may contribute to neurodegeneration in C9orf72 expansion patients. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and the loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue. Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.
Connecting slow earthquakes to huge earthquakes

Slow earthquakes are characterized by a wide spectrum of fault slip behaviors and seismic radiation patterns that differ from those of traditional earthquakes. However, slow earthquakes and huge megathrust earthquakes can have common slip mechanisms and are located in neighboring regions of the seismogenic zone. The frequent occurrence of slow earthquakes may help to reveal the physics underlying megathrust events as useful analogs. Slow earthquakes may function as stress meters because of their high sensitivity to stress changes in the seismogenic zone. Episodic stress transfer to megathrust source faults leads to an increased probability of triggering huge earthquakes if the adjacent locked region is critically loaded. Careful and precise monitoring of slow earthquakes may provide new information on the likelihood of impending huge earthquakes.
Homogeneously dispersed multimetal oxygen-evolving catalysts

Modulating metal oxides The more difficult step in fuel cells and water electrolysis is the oxygen evolution reaction. The search for earth-abundant materials to replace noble metals for this reaction often turns to oxides of three-dimensional metals such as iron. Zhang et al. show that the applied voltages needed to drive this reaction are reduced for iron-cobalt oxides by the addition of tungsten. The addition of tungsten favorably modulates the electronic structure of the oxyhydroxide. A key development is to keep the metals well mixed and avoid the formation of separate phases. Science, this issue p. 333 The addition of tungsten to iron cobalt oxides lowers the overpotential required for the evolution of oxygen from water. Earth-abundant first-row (3d) transition metal–based catalysts have been developed for the oxygen-evolution reaction (OER); however, they operate at overpotentials substantially above thermodynamic requirements. Density functional theory suggested that non-3d high-valency metals such as tungsten can modulate 3d metal oxides, providing near-optimal adsorption energies for OER intermediates. We developed a room-temperature synthesis to produce gelled oxyhydroxides materials with an atomically homogeneous metal distribution. These gelled FeCoW oxyhydroxides exhibit the lowest overpotential (191 millivolts) reported at 10 milliamperes per square centimeter in alkaline electrolyte. The catalyst shows no evidence of degradation after more than 500 hours of operation. X-ray absorption and computational studies reveal a synergistic interplay between tungsten, iron, and cobalt in producing a favorable local coordination environment and electronic structure that enhance the energetics for OER.
Aging, alopecia, and stem cells

Intrinsic epigenetic status and extrinsic environmental factors affect hair follicle stem cells [Also see Research Article by Matsumura et al. and Report by Wang et al.] Many tissues turn over during adult life, and declines in this process are associated with the progression of aging. Whether renewal is continual (as in the intestinal villi) or episodic (as in hair follicles), it is mainly attributed to somatic stem cells. One fundamental question is whether a decline of tissue renewal reflects the lifelong accumulation of external insults or the internal progression of a clock within stem cells? On pages 613 and 575 of this issue, Wang et al. (1) and Matsumura et al. (2), respectively, gain insight into this phenomenon by examining hair follicle growth and aging.