Miracle-dz/UniFAR-FTUs huggingface dataset:
SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Significance Spinal muscular atrophy is the leading monogenic cause of infant mortality and is caused by homozygous loss of the survival of motor neuron 1 (SMN1) gene. We investigated global transcriptome changes in the spinal cord of inducible SMA mice. SMN depletion caused widespread retention of introns with weak splice sites or belonging to the minor (U12) class. In addition, DNA double strand breaks accumulated in the spinal cord of SMA mice and in human SMA cell culture models. DNA damage was partially rescued by suppressing the formation of R-loops, which accumulated over retained introns. We propose that instead of single gene effects, pervasive splicing defects caused by severe SMN deficiency trigger a global DNA damage and stress response, thus compromising motor neuron survival. Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death.
Mechanocatalytic Depolymerization of Cellulose With Perfluorinated Sulfonic Acid Ionomers

Here, we investigated that the mechanocatalytic depolymerization of cellulose in the presence of Aquivion, a sulfonated perfluorinated ionomer. Under optimized conditions, yields of water soluble sugars of 90–97% were obtained using Aquivion PW98 and PW66, respectively, as a solid acid catalyst. The detailed characterization of the water soluble fraction revealed (i) the selective formation of oligosaccharides with a DP up to 11 and (ii) that depolymerization and reversion reactions concomitantly occurred during the mechanocatalytic process, although the first largely predominated. More importantly, we discussed on the critical role of water contained in Aquivion and cellulose on the efficiency of the mechanocatalytic process.
Detecting faulty empty cells in spreadsheets

Spreadsheets play an important role in various business tasks, such as financial reports and data analysis. In spreadsheets, empty cells are widely used for different purposes, e.g., separating different tables, or default value "0". However, a user may delete a formula unintentionally, and leave a cell empty. Such ad-hoc modification may introduce a faulty empty cell that should have a formula. We observe that the context of an empty cell can help determine whether the empty cell is faulty. For example, is the empty cell next to a cell array in which all cells share the same semantics? Does the empty cell have headers similar to other non-empty cells'? In this paper, we propose EmptyCheck, to detect faulty empty cells in spreadsheets. By analyzing the context of an empty cell, EmptyCheck validates whether the cell belong to a cell array. If yes, the empty cell is faulty since it does not contain a formula. We evaluate EmptyCheck on 100 randomly sampled EUSES spreadsheets. The experimental result shows that EmptyCheck can detect faulty empty cells with high precision (75.00%) and recall (87.04%). Existing techniques can detect only 4.26% of the true faulty empty cells that EmptyCheck detects.
Specificity of Phosphorylation Responses to Mitogen Activated Protein (MAP) Kinase Pathway Inhibitors in Melanoma Cells*

The BRAF-MKK1/2-ERK1/2 pathway is constitutively activated in response to oncogenic mutations of BRAF in many cancer types, including melanoma. Although small molecules that inhibit oncogenic BRAF and MAP kinase kinase (MKK)1/2 have been successful in clinical settings, resistance invariably develops. High affinity inhibitors of ERK1/2 have been shown in preclinical studies to bypass the resistance of melanoma and colon cancer cells to BRAF and MKK1/2 inhibitors, and are thus promising additions to current treatment protocols. But still unknown is how molecular responses to ERK1/2 inhibitors compare with inhibitors currently in clinical use. Here, we employ quantitative phosphoproteomics to evaluate changes in phosphorylation in response to the ERK inhibitors, SCH772984 and GDC0994, and compare these to the clinically used MKK1/2 inhibitor, trametinib. Combined with previous studies measuring phosphoproteomic responses to the MKK1/2 inhibitor, selumetinib, and the BRAF inhibitor, vemurafenib, the outcomes reveal key insights into pathway organization, phosphorylation specificity and off-target effects of these inhibitors. The results demonstrate linearity in signaling from BRAF to MKK1/2 and from MKK1/2 to ERK1/2. They identify likely targets of direct phosphorylation by ERK1/2, as well as inhibitor off-targets, including an off-target regulation of the p38α mitogen activated protein kinase (MAPK) pathway by the MKK1/2 inhibitor, trametinib, at concentrations used in the literature but higher than in vivo drug concentrations. In addition, several known phosphorylation targets of ERK1/2 are insensitive to MKK or ERK inhibitors, revealing variability in canonical pathway responses between different cell systems. By comparing multiple inhibitors targeted to multiple tiers of protein kinases in the MAPK pathway, we gain insight into regulation and new targets of the oncogenic BRAF driver pathway in cancer cells, and a useful approach for evaluating the specificity of drugs and drug candidates.
Growth, Body Chemical Composition, and Tissue Deposition Rates of Nursery Pigs Fed Crystalline or Protein- Bound Lysine1

ABSTRACT A 4-wk experiment was conducted to compare the effect of feeding crystalline lysine relative to the lysine from soybean meal (SBM) on growth performance, body chemical composition, and tissue deposition rates in nursery pigs. Thirty-six pigs were used [18 barrows and 18 gilts, 15 d old; initial BW (mean ± SEM) = 6.11 ± 0.11 kg]. Six pigs (3 barrows and 3 gilts) were killed at the beginning of the experiment and the remaining pigs were killed at the end of the experiment to determine body chemical composition and deposition rates of protein, fat, water, ash, and amino acids. Pigs were blocked by sex and BW (3 blocks of barrows and 3 blocks of gilts) and randomly allotted to 1 of 5 dietary treatments. Pigs were individually penned in 2 nursery facilities, and each treatment was replicated 6 times. The dietary treatments consisted of a corn-SBM basal diet (1.05% lysine) and diets containing either 1.15 or 1.25% total lysine, which were achieved by adding lysine (0.10 or 0.20%) from either SBM or L-lysine hydrochloride (crystalline lysine) to the basal diet. Pigs were given ad libitum access to feed during a 28-d period. Blood samples were collected on the last day of the experiment, and plasma was analyzed for urea concentration. Average daily gain, ADFI, and G:F were similar among dietary treatments (P > 0.50). Pigs fed diets supplemented with lysine from SBM had greater (P 0.10). Body fat concentration and fat deposition were similar (P > 0.25; P > 0.10) in pigs fed diets supplemented with crystalline lysine or lysine from SBM, respectively. Ash concentration was greatest (P
The effect of strain rate on detwinning and superelastic behavior of NiTi shape memory alloys

The effect of strain rate on the superelastic and detwinning behavior of shape memory alloys was studied in a series of experiments. The strain rate was tested in a range from 10 -4 to 10 -2 /s. To ensure a stable and uniform temperature throughout the testing process, fine wire samples were used, and all tests were conducted in a liquid environment. Under these conditions, test results showed that the strain rate had no influence on the superelastic behavior and martensite detwinning of the NiTi alloys. In the superelastic deformation process, the austenite=martensite transformation produced rather high latent heat as part of the transformation process within the specimen. As the strain rate increased, and as conditions became more adiabatic, a significant temperature change due to the release and absorption of latent heat occurred. The temperature rises upon loading and drops upon unloading. This phenomenon manifests itself, as the diameter of the specimens becomes progressively larger, or as test conditions become more adiabatic.
Elemental ratio measurements of organic compounds using aerosol mass spectrometry: characterization, improved calibration, and implications

Abstract. Elemental compositions of organic aerosol (OA) particles provide useful constraints on OA sources, chemical evolution, and effects. The Aerodyne high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) is widely used to measure OA elemental composition. This study evaluates AMS measurements of atomic oxygen-to-carbon (O : C), hydrogen-to-carbon (H : C), and organic mass-to-organic carbon (OM : OC) ratios, and of carbon oxidation state ( OS C) for a vastly expanded laboratory data set of multifunctional oxidized OA standards. For the expanded standard data set, the method introduced by Aiken et al. (2008), which uses experimentally measured ion intensities at all ions to determine elemental ratios (referred to here as "Aiken-Explicit"), reproduces known O : C and H : C ratio values within 20% (average absolute value of relative errors) and 12%, respectively. The more commonly used method, which uses empirically estimated H2O+ and CO+ ion intensities to avoid gas phase air interferences at these ions (referred to here as "Aiken-Ambient"), reproduces O : C and H : C of multifunctional oxidized species within 28 and 14% of known values. The values from the latter method are systematically biased low, however, with larger biases observed for alcohols and simple diacids. A detailed examination of the H2O+, CO+, and CO2+ fragments in the high-resolution mass spectra of the standard compounds indicates that the Aiken-Ambient method underestimates the CO+ and especially H2O+ produced from many oxidized species. Combined AMS–vacuum ultraviolet (VUV) ionization measurements indicate that these ions are produced by dehydration and decarboxylation on the AMS vaporizer (usually operated at 600 °C). Thermal decomposition is observed to be efficient at vaporizer temperatures down to 200 °C. These results are used together to develop an "Improved-Ambient" elemental analysis method for AMS spectra measured in air. The Improved-Ambient method uses specific ion fragments as markers to correct for molecular functionality-dependent systematic biases and reproduces known O : C (H : C) ratios of individual oxidized standards within 28% (13%) of the known molecular values. The error in Improved-Ambient O : C (H : C) values is smaller for theoretical standard mixtures of the oxidized organic standards, which are more representative of the complex mix of species present in ambient OA. For ambient OA, the Improved-Ambient method produces O : C (H : C) values that are 27% (11%) larger than previously published Aiken-Ambient values; a corresponding increase of 9% is observed for OM : OC values. These results imply that ambient OA has a higher relative oxygen content than previously estimated. The OS C values calculated for ambient OA by the two methods agree well, however (average relative difference of 0.06 OS C units). This indicates that OS C is a more robust metric of oxidation than O : C, likely since OS C is not affected by hydration or dehydration, either in the atmosphere or during analysis.
Explaining ‘I Can’t Draw’: Parallels between the Structure and Development of Language and Drawing

Both drawing and language are fundamental and unique to humans as a species. Just as language is a representational system that uses systematic sounds (or manual/bodily signs) to express concepts, drawing is a means of graphically expressing concepts. Yet, unlike language, we consider it normal for people not to learn to draw, and consider those who do to be exceptional. Why do we consider drawing to be so different from language? This paper argues that the structure and development of drawing is indeed analogous to that of language. Because drawings express concepts in the visual-graphic modality using patterned schemas stored in a graphic lexicon that combine using ‘syntactic’ rules, development thus requires acquiring a vocabulary of these schemas from the environment. Without sufficient practice and exposure to an external system, a basic system persists despite arguably impoverished developmental conditions. Such a drawing system is parallel to the resilient systems of language that appear when children are not exposed to a linguistic system within a critical developmental period. Overall, this approach draws equivalence between drawing and the cognitive attributes of other domains of human expression.
Large Visual Stimuli Induce Two Distinct Gamma Oscillations in Primate Visual Cortex

Recent studies have shown the existence of two gamma rhythms in the hippocampus subserving different functions but, to date, primate studies in primary visual cortex have reported a single gamma rhythm. Here, we show that large visual stimuli induce a slow gamma (25–45 Hz) in area V1 of two awake adult female bonnet monkeys and in the EEG of 15 human subjects (7 males and 8 females), in addition to the traditionally known fast gamma (45–70 Hz). The two rhythms had different tuning characteristics for stimulus orientation, contrast, drift speed, and size. Further, fast gamma had short latency, strongly entrained spikes and was coherent over short distances, reflecting short-range processing, whereas slow gamma appeared to reflect long-range processing. Together, two gamma rhythms can potentially provide better coding or communication mechanisms and a more comprehensive biomarker for diagnosis of mental disorders. SIGNIFICANCE STATEMENT Gamma rhythm has been associated with high-level cognitive functions such as attention and feature binding and has been reported to be abnormal in brain disorders such as autism and schizophrenia. Unlike previous studies that have shown a single gamma rhythm in the primate visual cortex, we found that large visual gratings induce two distinct gamma oscillations in both monkey LFP and human EEG. These rhythms, termed slow (25–45 Hz) and fast (45–70 Hz), exhibited distinct tuning preferences, latencies, and coherence profiles, potentially reflecting processing at two different ranges. Multiple gamma oscillations in visual cortex may provide a richer representation of external visual stimuli and could be used for developing brain–machine interfacing applications and screening tests for neuropsychiatric disorders.
MoVEMo: A Structured Approach for Engineering Reward Functions

Reinforcement learning (RL) is a machine learning technique that has been increasingly used in robotic systems. In reinforcement learning, instead of manually pre-program what action to take at each step, we convey the goal a software agent in terms of reward functions. The agent tries different actions in order to maximize a numerical value, i.e. the reward. A misspecified reward function can cause problems such as reward hacking, where the agent finds out ways that maximize the reward without achieving the intended goal. As RL agents become more general and autonomous, the design of reward functions that elicit the desired behaviour in the agent becomes more important and cumbersome. In this paper, we present a technique to formally express reward functions in a structured way; this stimulates a proper reward function design and as well enables the formal verification of it. We start by defining the reward function using state machines. In this way, we can statically check that the reward function satisfies certain properties, e.g., high-level requirements of the function to learn. Later we automatically generate a runtime monitor — which runs in parallel with the learning agent — that provides the rewards according to the definition of the state machine and based on the behaviour of the agent. We use the UPPAAL model checker to design the reward model and verify the TCTL properties that model high-level requirements of the reward function and LARVA to monitor and enforce the reward model to the RL agent at runtime.
Microalbuminuria and Macroalbuminuria in Type 2 Diabetes

Chronic renal insufficiency is reported twice as frequently in persons with diabetes.3 A study done in Nepal found that about 18% of the patients admitted for hemodialysis were diabetic.4 It has been shown that the risk of developing DN in type 2 diabetes is 30–40%. 5 Albuminuria in type 2 diabetic patients is the predominant renal risk marker for nephropathy6 and cardiovascular complications.7 Reduction in albuminuria is associated with a proportional effect on renal protection.6 Therefore, early detection of microalbuminuria in type 2 diabetes is important.
Characteristics of Refractive Errors in a Population of Adults in the Central Region of Poland

Background: To investigate the distribution of refractive errors and their characteristics in older adults from a Polish population. Methods: The study design was a cross-sectional study. A total of 1107 men and women were interviewed and underwent detailed ophthalmic examinations, 998 subjects underwent refraction. Myopia was defined as spherical equivalent (SER) refraction ≤−0.5 dioptres (D) and hyperopia was defined as SER ≥+0.5 dioptres (D). Results: Among those who were refracted the distribution of myopia and hyperopia was 24.1% (95% CI 21.4–26.7) and 37.5% (95% CI 34.5–40.5), respectively. Myopia decreased from 28.7% in subjects aged 35–59 years to 19.3% in those aged 60 years or older and hyperopia increased from 21.8% at 35–59 years of age to 53.3% in subjects aged ≥60 years. Multiple regression analysis showed decreasing age (OR 0.98, 95% CI 0.96–1.00), female gender (OR 1.87, 95% CI 1.18–2.95) and presence of cataract (OR 2.40, 95% CI 1.24–4.63) were independent risk factors associated with myopia. Conclusions: The distribution of refractive errors found in our study is similar to those reported in other Caucasian populations and differs from Asian populations. Myopia was positively associated with younger age, female gender and presence of cataract.
Impact of the Cincinnati Aligning Forces for Quality Multi-Payer Patient Centered Medical Home Pilot on Health Care Quality, Utilization, and Costs

To evaluate the potential for a patient-centered medical home initiative to reduce utilization and cost while improving quality, we examined a natural experiment involving 11 primary care practices in Cincinnati, Ohio, that participated in the Aligning Forces for Quality Multi-Payer Patient Centered Medical Home pilot. Our research design involved difference-in-difference analyses, comparing changes in utilization, costs, and quality between patients attributed to pilot practices compared with those attributed to a matched comparison cohort after 2 years of active engagement by the practices. The Cincinnati pilot was associated with a reduction of ambulatory care–sensitive emergency department visits of approximately 0.7 per 1,000 member months or approximately 22.6% (p = .01). While there was a reduction in total costs of care of $7,679 per 1,000 member months, the difference did not reach statistical significance. After 2 years of the pilot, lipid testing in diabetics had increased by 2.7 percentage points (a 3.3% improvement; p < .0001). Patient-centered medical homes have the potential to improve the quality of care and reduce emergency department use but expectations for cost control in a relatively short time horizon and absent other changes may be unrealistic.
Cell Lysis and Detoxification of Cyanotoxins Using a Novel Combination of Microbubble Generation and Plasma Microreactor Technology for Ozonation

There has been a steady rise in the incidences of algal blooms globally, and worryingly, there is increasing evidence that changes in the global climate are leading to a shift toward cyanobacterial blooms. Many cyanobacterial genera are harmful, producing several potent toxins, including microcystins, for which there are over 90 described analogues. There are a wide range of negative effects associated with these toxins including gastroenteritis, cytotoxicity, hepatotoxicity and neurotoxicity. Although a variety of oxidation based treatment methods have been described, ozonation and advanced oxidation are acknowledged as most effective as they readily oxidise microcystins to non-toxic degradation products. However, most ozonation technologies have challenges for scale up including high costs and sub-optimum efficiencies, hence, a low cost and scalable ozonation technology is needed. Here we designed a low temperature plasma dielectric barrier discharge (DBD) reactor with an incorporated fluidic oscillator for microbubble delivery of ozone. Both technologies have the potential to drastically reduce the costs of ozonation at scale. Mass spectrometry analysis revealed very rapid (<2 min) destruction of two pure microcystins (MC-LR and MC-RR), together with removal of by-products even at low flow rate 1 L min−1 where bubble size was 0.56–0.6 mm and the ozone concentration within the liquid was 20 ppm. Toxicity levels were calculated through protein phosphatase inhibition assays and indicated loss of toxicity as well as confirming the by-products were also non-toxic. Finally, treatment of whole Microcystis aeruginosa cells showed that even at these very low ozone levels, cells can be killed and toxins (MC-LR and Desmethyl MC-LR) removed. Little change was observed in the first 20 min of treatment followed by rapid increase in extracellular toxins, indicating cell lysis, with most significant release at the higher 3 L min−1 flow rate compared to 1 L min−1. This lab-scale investigation demonstrates the potential of the novel plasma micro reactor with applications for in situ treatment of harmful algal blooms and cyanotoxins.
Increasing persistent navigation capabilities for underwater vehicles with augmented terrain-based navigation

Accurate and energy-efficient navigation and localization methods for autonomous underwater vehicles continues to be an active area of research. As interesting as they are important, ocean processes are spatiotemporally dynamic and their study requires vehicles that can maneuver and sample intelligently while underwater for extended durations. In this paper, we present a new technique for augmenting terrain-based navigation with physical water data to enhance the utility of traditional methods for navigation and localization. We examine the construct of this augmentation method over a range of deployment regions, e.g., ocean and freshwater lake. Data from field trials are presented and analyzed for multiple deployments of an autonomous underwater vehicle.