Miracle-dz/UniFAR-FTUs huggingface dataset:
Accurate and sensitive quantification of protein-DNA binding affinity

Significance One-tenth of human genes produce proteins called transcription factors (TFs) that bind to our genome and read the local DNA sequence. They work together to regulate the degree to which each gene is expressed. The affinity with which DNA is bound by a particular TF can vary more than a thousand-fold with different DNA sequences. This study presents the first computational method able to quantify the sequence-affinity relationship almost perfectly over the full affinity range. It achieves this by analyzing data from experiments that use massively parallel DNA sequencing to comprehensively probe protein–DNA interactions. Strikingly, it can accurately predict the effect in vivo of DNA mutations on gene expression levels in fly embryos even for very-low-affinity binding sites. Transcription factors (TFs) control gene expression by binding to genomic DNA in a sequence-specific manner. Mutations in TF binding sites are increasingly found to be associated with human disease, yet we currently lack robust methods to predict these sites. Here, we developed a versatile maximum likelihood framework named No Read Left Behind (NRLB) that infers a biophysical model of protein-DNA recognition across the full affinity range from a library of in vitro selected DNA binding sites. NRLB predicts human Max homodimer binding in near-perfect agreement with existing low-throughput measurements. It can capture the specificity of the p53 tetramer and distinguish multiple binding modes within a single sample. Additionally, we confirm that newly identified low-affinity enhancer binding sites are functional in vivo, and that their contribution to gene expression matches their predicted affinity. Our results establish a powerful paradigm for identifying protein binding sites and interpreting gene regulatory sequences in eukaryotic genomes.
The Relationship of Phylogeny to Community Structure: The Cactus Yeast Community

Species abundances are important properties of ecological communities. Theoretical debate has arisen over whether communities are governed by assembly rules. Some ecologists have suggested that community organization depends on the phylogenetic relatedness of its interacting members. This postulate has not been adequately tested primarily because molecular phylogenies for entire communities are rare. We use the molecular phylogeny and species abundances from the well‐studied yeasts that live in decaying cactus tissue (i.e., cactus yeast community) to demonstrate that community structure is indeed linked to genetic relatedness but that the relationship is different for the same yeasts found in hosts of two subfamilies of the Cactaceae. In the Opuntia cacti, the genetically related and unrelated yeasts have equivalent probability of being similar in abundance. Conversely, in the columnar cacti, the abundant yeast species tend to be genetically distant from one another, whereas the rare species tend to be closely related. The distinctive biochemical differences between the Opuntia and columnar cacti habitats suggest that conditions imposed by the environment modify the relationship between phylogenetic relatedness and species abundances in the cactus yeast community.
Microbiota promote secretory cell determination in the intestinal epithelium by modulating host Notch signaling

ABSTRACT Resident microbes promote many aspects of host development, although the mechanisms by which microbiota influence host tissues remain unclear. We showed previously that the microbiota is required for allocation of appropriate numbers of secretory cells in the zebrafish intestinal epithelium. Because Notch signaling is crucial for secretory fate determination, we conducted epistasis experiments to establish whether the microbiota modulates host Notch signaling. We also investigated whether innate immune signaling transduces microbiota cues via the Myd88 adaptor protein. We provide the first evidence that microbiota-induced, Myd88-dependent signaling inhibits host Notch signaling in the intestinal epithelium, thereby promoting secretory cell fate determination. These results connect microbiota activity via innate immune signaling to the Notch pathway, which also plays crucial roles in intestinal homeostasis throughout life and when impaired can result in chronic inflammation and cancer. Highlighted Article: Investigations in gnotobiotic zebrafish reveal that resident intestinal microbes determine intestinal secretory cell fate by modulating host Notch signaling, a highly conserved pathway involved in myriad host cell fate decisions.
A Deep Learning-Based Formula Detection Method for PDF Documents

In practice, PDF files may be generated by different tools and their character information quality could be different. As a result, the approaches to detecting formulae from PDF documents usually have much different performance on different PDF files. To address this problem, in this paper we combine and refine the Convolutional Neural Network (CNN) and Recurrent Neural Network (RNN) model to detect formulae according to both their character and vision features. Based on the characteristic of PDF documents, we propose a series of strategies to train and optimize deep networks, such as the implicit class down-sampling strategy which can reduce the unbalancedness between formulae and other page elements (e.g., text paragraphs, tables, figures, etc.). The region proposal method is also redesigned to generate moderate formula candidates through combining the bottom-up and top-down layout analysis. The experimental results show that the combination of CNN and RNN can increase the robustness of our proposed detection method. Furthermore, the proposed method outperforms the existing formula detection methods on both a ground-truth dataset and a larger self-built dataset, which would be released and available for research purposes.
Effect of Dietary Oxalate on the Gut Microbiota of the Mammalian Herbivore Neotoma albigula

ABSTRACT Diet is one of the primary drivers that sculpts the form and function of the mammalian gut microbiota. However, the enormous taxonomic and metabolic diversity held within the gut microbiota makes it difficult to isolate specific diet-microbe interactions. The objective of the current study was to elucidate interactions between the gut microbiota of the mammalian herbivore Neotoma albigula and dietary oxalate, a plant secondary compound (PSC) degraded exclusively by the gut microbiota. We quantified oxalate degradation in N. albigula fed increasing amounts of oxalate over time and tracked the response of the fecal microbiota using high-throughput sequencing. The amount of oxalate degraded in vivo was linearly correlated with the amount of oxalate consumed. The addition of dietary oxalate was found to impact microbial species diversity by increasing the representation of certain taxa, some of which are known to be capable of degrading oxalate (e.g., Oxalobacter spp.). Furthermore, the relative abundances of 117 operational taxonomic units (OTU) exhibited a significant correlation with oxalate consumption. The results of this study indicate that dietary oxalate induces complex interactions within the gut microbiota that include an increase in the relative abundance of a community of bacteria that may contribute either directly or indirectly to oxalate degradation in mammalian herbivores.
Neuropsychiatric Effects of Subthalamic Nucleus Deep Brain Stimulation in Parkinson Disease in China: A Prospectively Controlled Study

Background: The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on motor symptoms receive much attention, but neuropsychiatric outcomes require further study in China. Aim: To investigate the influence of STN-DBS on neuropsychiatric outcomes in patients with PD and the predictive factors in China. Methods: We compared 6-month clinical and neuropsychiatric data between 21 PD patients selected for STN-DBS group and 21 PD patients who only received dopatherapy with Mann-Whitney test or independent t test. Main outcome measures included motor symptoms, orientation and attention, memory, verbal fluency, language and visuospatial ability, disease stage, activity of daily life (ADL), anxiety, depression and drug complications. The correlations between baseline data and clinical outcomes were calculated by linear regression. Results: Motor abilities (p=0.000), ADL (p=0.047), depression (p=0.009), anxiety (p=0.003) and dopaminergic dosage (p=0.000) outcomes were markedly superior in the DBS group versus control group. No significant changes occurred in global cognition or specific cognitive domains. We also detected negative correlations between motor symptoms and ADL (p=0.002), suggesting recovery in motor symptoms can help predict ADL improvement. Conclusion: STN-DBS is a preferable solution to advanced PD in China considering its beneficial effects in motor abilities, ADL, anxiety, depression, dopaminergic medication dosage and cognitive function. ADL improvement can be attributed to recovery in motor symptoms.
Abnormal Golgi pH Homeostasis in Cancer Cells Impairs Apical Targeting of Carcinoembryonic Antigen by Inhibiting Its Glycosyl-Phosphatidylinositol Anchor-Mediated Association with Lipid Rafts.

AIMS Carcinoembryonic antigen (CEACAM5, CEA) is a known tumor marker for colorectal cancer that localizes in a polarized manner to the apical surface in normal colon epithelial cells whereas in cancer cells it is present at both the apical and basolateral surfaces of the cells. Since the Golgi apparatus sorts and transports most proteins to these cell surface domains, we set out here to investigate whether any of the factors commonly associated with tumorigenesis, including hypoxia, generation of reactive oxygen species (ROS), altered redox homeostasis, or an altered Golgi pH, are responsible for mistargeting of CEA to the basolateral surface in cancer cells. RESULTS Using polarized nontumorigenic Madin-Darby canine kidney (MDCK) cells and CaCo-2 colorectal cancer cells as targets, we show that apical delivery of CEA is not affected by hypoxia, ROS, nor changes in the Golgi redox state. Instead, we find that an elevated Golgi pH induces basolateral targeting of CEA and increases its TX-100 solubility, indicating impaired association of CEA with lipid rafts. Moreover, disruption of lipid rafts by methyl-β-cyclodextrin induced accumulation of the CEA protein at the basolateral surface in MDCK cells. Experiments with the glycosylphosphatidylinositol (GPI)-anchorless CEA mutant and CEA-specific GPI-anchored enhanced green fluorescent protein (EGFP-GPI) fusion protein revealed that the GPI-anchor was critical for the pH-dependent apical delivery of the CEA in MDCK cells. Innovation and Conclusion: The findings indicate that an abnormal Golgi pH homeostasis in cancer cells is an important factor that causes mistargeting of CEA to the basolateral surface of cancer cells via inhibiting its GPI-anchor-mediated association with lipid rafts.
Pallidal Deep Brain Stimulation in Patients With Chorea‐Acanthocytosis

Chorea‐acanthocytosis (ChAc) is an autosomal recessive hereditary disorder caused by the mutation of gene VPS13A. Deep brain stimulation of ChAc has made substantial progress in the recent decades. However, the reports were scattered across centers and performed by different neurosurgeons. Here, we report a case series consisting of six patients diagnosed with ChAc, receiving bilateral high‐frequency stimulation of globus pallidus internus (GPi) in a single center.
Impact of Short-Term Training Camp on Aortic Blood Pressure in Collegiate Endurance Runners

To investigate the influence of short-term vigorous endurance training on aortic blood pressure (BP), pulse wave analysis was performed in 36 highly trained elite collegiate endurance runners before and after a 7-day intense training camp. Subjects participated three training sessions per day, which mainly consisted of long distance running and sprint training to reach the daily target distance of 26 km. After the camp, they were divided into two groups based on whether the target training was achieved. Aortic systolic BP, pulse pressure, and tension-time index (TTI, a surrogate index of the myocardial oxygen demand) were significantly elevated after the camp in the accomplished group but not in the unaccomplished group, whereas the brachial BP remained unchanged in both groups. The average daily training distance was significantly correlated with the changes in aortic systolic BP (r = 0.608, p = 0.0002), pulse pressure (r = 0.415, p = 0.016), and TTI (r = 0.438, p = 0.011). These results suggest that aortic BP is affected by a short-term vigorous training camp even in highly trained elite endurance athletes presumably due to a greater training volume compared to usual.
Vaccinia Virus in Blood Samples of Humans, Domestic and Wild Mammals in Brazil

Outbreaks of Vaccinia virus (VACV) affecting cattle and humans have been reported in Brazil in the last 15 years, but the origin of outbreaks remains unknown. Although VACV DNA have been already detected in mice (Mus musculus), opossums (Didelphis albiventris) and dogs during VACV zoonotic outbreaks, no transmission to cattle or humans from any of these were reported during Brazilian outbreaks. In this work, we assessed the PCR positivity to VACV in blood samples of cows and other domestic mammals, wild rodents and other wild mammals, and humans from areas with or without VACV infection reports. Our results show the detection of VACV DNA in blood samples of cows, horse and opossums, raising important questions about VACV spread.
Exploring the perceived health benefits of singing in a choir: an international cross-sectional mixed-methods study

Aim: This mixed-methods exploratory study investigates the perceived health benefits of singing in a choir from an international sample of choristers. Method: An online questionnaire including demographic information, 28 quantitative statements and two qualitative questions relating to the perceived health benefits of singing in a choir was distributed via email and social media over a period of 4 months to a sample of 1,779 choristers. Basic descriptives and comparisons between subgroups of the sample are presented along with thematic analysis of qualitative comments. Results: Basic descriptives suggest an overwhelmingly positive response. Females scored significantly higher than males on physical benefits, social benefits and emotional benefits. Professional singers reported significantly more physical, social and spiritual benefits than amateur singers. Bias may be present in these findings as the results were entirely self-reported by people who already sing in choirs. Qualitative thematic analysis identified six key themes which may counter this bias by providing deeper understanding of the perceived benefits for choir singers. These include social connection, physical and physiological benefits (specifically respiratory health), cognitive stimulation, mental health, enjoyment and transcendence. Conclusion: Choral singing elicits a positive response in the chorister across a plethora of domains. This research confirms previous findings on the health benefits of singing but offers evidence from the largest sample of singers to date. However, results are based on self-perceptions of choristers, and findings are, therefore, limited. Results may be used as a base on which to develop further research in this area. It also provides confirmatory evidence to support choral singing as a means of improving wellbeing in many populations, including but not limited to workplaces, schools, nursing homes, communities and churches.
The Luteovirus P4 Movement Protein Is a Suppressor of Systemic RNA Silencing

The plant viral family Luteoviridae is divided into three genera: Luteovirus, Polerovirus and Enamovirus. Without assistance from another virus, members of the family are confined to the cells of the host plant’s vascular system. The first open reading frame (ORF) of poleroviruses and enamoviruses encodes P0 proteins which act as silencing suppressor proteins (VSRs) against the plant’s viral defense-mediating RNA silencing machinery. Luteoviruses, such as barley yellow dwarf virus-PAV (BYDV-PAV), however, have no P0 to carry out the VSR role, so we investigated whether other proteins or RNAs encoded by BYDV-PAV confer protection against the plant’s silencing machinery. Deep-sequencing of small RNAs from plants infected with BYDV-PAV revealed that the virus is subjected to RNA silencing in the phloem tissues and there was no evidence of protection afforded by a possible decoy effect of the highly abundant subgenomic RNA3. However, analysis of VSR activity among the BYDV-PAV ORFs revealed systemic silencing suppression by the P4 movement protein, and a similar, but weaker, activity by P6. The closely related BYDV-PAS P4, but not the polerovirus potato leafroll virus P4, also displayed systemic VSR activity. Both luteovirus and the polerovirus P4 proteins also showed transient, weak local silencing suppression. This suggests that systemic silencing suppression is the principal mechanism by which the luteoviruses BYDV-PAV and BYDV-PAS minimize the effects of the plant’s anti-viral defense.
Differences in trunk and thigh muscle strength, endurance and thickness between elite sailors and non-sailors

Abstract Dinghy sailors lean their upper body over the windward side of the boat (‘hiking’) to keep the boat’s balance and maximise its speed. Sustaining the hiking position is essential for competitive performance and this study examined sport-specific differences of muscles relevant for hiking in elite sailors. Knee extensor muscle strength as well as trunk muscle strength, muscle endurance and muscle thickness were assessed in elite dinghy sailors (n = 15) and compared to matched, non-sailing controls (n = 15). Isometric extensor strength was significantly higher in sailors at 60° (+14%) but not at 20° knee flexion. Sailors showed significantly higher trunk flexor (but not extensor) strength under isometric (+18%) and eccentric (+11%) conditions, which was associated to greater muscle thickness (rectus abdominis +40%; external oblique +26%) and higher endurance for ventral (+66%) and lateral (+61%) muscle chains compared to non-sailors. Greater muscles thickness and the particular biomechanical requirements to maintain the hiking position may drive the increases in isometric and eccentric muscle strength as well as ventral and lateral trunk endurance. The current findings identified sport-specific muscle function differences and provide performance benchmarks for muscle strength and endurance in elite sailors.
Methodological advances, opportunities, and challenges in AAC research

Abstract Since its inception in 1985, the AAC journal has been publishing scientific articles related to the field of augmentative and alternative communication (AAC) that (a) report research concerning assessment, treatment, rehabilitation, and education of people who use or have the potential to use AAC systems and (b) cover theory, technology, and systems development relevant to AAC. The journal has maintained a consistent focus on the science and practice of AAC while also advancing in varied and impressive ways. Among the many developments apparent in AAC over the years, methodological advancements emerge as pivotal within the evolution of the science of AAC. This report examines the state of the science in behavioral AAC research with specific regard to changes and opportunities in research methodology. Illustrations from articles published in Volume 1 (1985) and Volume 32 (2016) of AAC are used in this paper to frame commentary on (a) contextual consideration in conducting AAC research, (b) types of research design, (c) considerations of procedural rigor, and (d) future methodological directions and resources. If the AAC field is to meet the goal of ensuring that all individuals with complex communication needs achieve their full potential, meaningful questions must be posed to address key problems, and rigorous scientific methods must be employed to answer these questions.
Points to Consider in Designing and Conducting Juvenile Toxicology Studies

In support of a clinical trial in the pediatric population, available nonclinical and clinical data provide input on the study design and safety monitoring considerations. When the existing data are lacking to support the safety of the planned pediatric clinical trial, a juvenile animal toxicity study is likely required. Usually a single relevant species, preferably a rodent, is chosen as the species of choice, while a nonrodent species can be appropriate when scientifically justified. Juvenile toxicology studies, in general, are complicated both conceptually and logistically. Development in young animals is a continuous process with different organs maturing at different rates and time. Structural and functional maturational differences have been shown to affect drug safety. Key points to consider in conducting a juvenile toxicology study include a comparative development of the organ systems, differences in the pharmacokinetics/absorption, distribution, metabolism, excretion (PK/ADME) profiles of the drug between young animal and child, and logistical requirement in the juvenile study design. The purpose of this publication is to note pertinent points to consider when designing and conducting juvenile toxicology studies and to aid in future modifications and enhancements of these studies to enable a superior predictability of safety of medicines in the pediatric population.
Comparison of Four Comamonas Catabolic Plasmids Reveals the Evolution of pBHB To Catabolize Haloaromatics

ABSTRACT Comamonas plasmids play important roles in shaping the phenotypes of their hosts and the adaptation of these hosts to changing environments, and understanding the evolutionary strategy of these plasmids is thus of great concern. In this study, the sequence of the 119-kb 3,5-dibromo-4-hydroxybenzonitrile-catabolizing plasmid pBHB from Comamonas sp. strain 7D-2 was studied and compared with those of three other Comamonas haloaromatic catabolic plasmids. Incompatibility group determination based on a phylogenetic analysis of 24 backbone gene proteins, as well as TrfA, revealed that these four plasmids all belong to the IncP-1β subgroup. Comparison of the four plasmids revealed a conserved backbone region and diverse genetic-load regions. The four plasmids share a core genome consisting of 40 genes (>50% similarities) and contain 12 to 50 unique genes each, most of which are xenobiotic-catabolic genes. Two functional reductive dehalogenase gene clusters are specifically located on pBHB, showing distinctive evolution of pBHB for haloaromatics. The higher catabolic ability of the bhbA2B2 cluster than the bhbAB cluster may be due to the transcription levels and the character of the dehalogenase gene itself rather than that of its extracytoplasmic binding receptor gene. The plasmid pBHB is riddled with transposons and insertion sequence (IS) elements, and ISs play important roles in the evolution of pBHB. The analysis of the origin of the bhb genes on pBHB suggested that these accessory genes evolved independently. Our work provides insights into the evolutionary strategies of Comamonas plasmids, especially into the adaptation mechanism employed by pBHB for haloaromatics.