Miracle-dz/UniFAR-FTUs huggingface dataset:
Pulmonary alveolar type I cell population consists of two distinct subtypes that differ in cell fate

Significance Pulmonary alveolar type I (AT1) cells are essential for the gas-exchange function of lungs. AT1 cells retain their cellular plasticity during injury-induced alveolar regeneration. However, we know very little about the developmental heterogeneity of the AT1 cell population. Our study identified a robust genetic marker of postnatal AT1 cells, insulin-like growth factor-binding protein 2 (Igfbp2). We use this marker to demonstrate that the postnatal AT1 cell population actually consists of two AT1 cell subtypes (Hopx+Igfbp2+ and Hopx+Igfbp2− AT1 cells) with distinct cell fates during alveolar regeneration. The large majority of adult AT1 cells expresses Igfbp2 and cannot transdifferentiate into AT2 cells during post pneumonectomy formation of new alveoli. Therefore, Hopx+Igfbp2+ AT1 cells represent the terminally differentiated population of AT1 cells. Pulmonary alveolar type I (AT1) cells cover more than 95% of alveolar surface and are essential for the air–blood barrier function of lungs. AT1 cells have been shown to retain developmental plasticity during alveolar regeneration. However, the development and heterogeneity of AT1 cells remain largely unknown. Here, we conducted a single-cell RNA-seq analysis to characterize postnatal AT1 cell development and identified insulin-like growth factor-binding protein 2 (Igfbp2) as a genetic marker specifically expressed in postnatal AT1 cells. The portion of AT1 cells expressing Igfbp2 increases during alveologenesis and in post pneumonectomy (PNX) newly formed alveoli. We found that the adult AT1 cell population contains both Hopx+Igfbp2+ and Hopx+Igfbp2− AT1 cells, which have distinct cell fates during alveolar regeneration. Using an Igfbp2-CreER mouse model, we demonstrate that Hopx+Igfbp2+ AT1 cells represent terminally differentiated AT1 cells that are not able to transdifferentiate into AT2 cells during post-PNX alveolar regeneration. Our study provides tools and insights that will guide future investigations into the molecular and cellular mechanism or mechanisms underlying AT1 cell fate during lung development and regeneration.
CYFRA 21-1 predicts the efficacy of nivolumab in patients with advanced lung adenocarcinoma

CYFRA 21-1 is a prognostic marker for non–small cell lung cancer. The serum CYFRA 21-1 level is also known as an adjunct for the diagnosis of lung squamous cell carcinoma. This study aimed to examine whether CYFRA 21-1 has predictive implications for nivolumab therapy in patients with advanced lung adenocarcinoma. Of the 79 patients who were treated with nivolumab therapy at the Shizuoka Cancer Center between December 2015 and September 2016, we retrospectively reviewed the data of 50 patients. The patient characteristics were as follows: age <70/≥70 years: 43 (86%)/7; male/female: 31 (62.0%)/19; Eastern Cooperative Oncology Group performance status 0–1/2: 43 (86%)/7; smoking status: no/yes: 18 (36%)/32; epidermal growth factor receptor mutation status negative/positive: 36 (72%)/14; CYFRA 21-1 ≥2.2/<2.2 ng/mL: 28 (56%)/22; carcinoembryonic antigen ≥5/<5 ng/mL: 29 (58%)/21; and number of prior regimens 2–3/≥4: 16 (32%)/34. With a median follow-up of 263.5 (range, 64–352) days, the median progression-free survival was 70 days. The clinical variables investigated using univariate analysis were as follows: age (p = 0.423), carcinoembryonic antigen (p = 0.888), epidermal growth factor receptor mutation status (p = 0.105), performance status (p = 0.968), sex (p = 0.210), number of prior regimens (p = 0.146), CYFRA 21-1 (p = 0.026), and smoking status (p = 0.041). A multivariate analysis identified a serum CYFRA 21-1 level ≥2.2 ng/mL as an independent predictor of a favorable outcome (hazard ratio, 0.44; 95% confidence interval, 0.23–0.85; p = 0.015; median progression-free survival, 155 vs 51.5 days). In conclusion, CYFRA 21-1 might be an independent predictor of outcome for patients with advanced lung adenocarcinoma treated with nivolumab.
Biogenesis of a Mitochondrial Outer Membrane Protein in Trypanosoma brucei

The mitochondrial outer membrane (OM) contains single and multiple membrane-spanning proteins that need to contain signals that ensure correct targeting and insertion into the OM. The biogenesis of such proteins has so far essentially only been studied in yeast and related organisms. Here we show that POMP10, an OM protein of the early diverging protozoan Trypanosoma brucei, is signal-anchored. Transgenic cells expressing variants of POMP10 fused to GFP demonstrate that the N-terminal membrane-spanning domain flanked by a few positively charged or neutral residues is both necessary and sufficient for mitochondrial targeting. Carbonate extraction experiments indicate that although the presence of neutral instead of positively charged residues did not interfere with POMP10 localization, it weakened its interaction with the OM. Expression of GFP-tagged POMP10 in inducible RNAi cell lines shows that its mitochondrial localization depends on pATOM36 but does not require Sam50 or ATOM40, the trypanosomal analogue of the Tom40 import pore. pATOM36 is a kinetoplastid-specific OM protein that has previously been implicated in the assembly of OM proteins and in mitochondrial DNA inheritance. In summary, our results show that although the features of the targeting signal in signal-anchored proteins are widely conserved, the protein machinery that mediates their biogenesis is not.
On Spanning Trees in Catacondensed Molecules

Abstract Among all catacondensed benzenoid molecules the unbranched systems possess the largest number of spanning trees. Some other relations for the spanning-tree count of catacondensed benzenoids are also reported. The results obtained continue to hold for catacondensed molecules composed of rings the size of which differ from six. The propositions reported do, however, depend for their validity on there being rings of only one size in the catacondensed system under study.
Mroh1, a lysosomal regulator localized by WASH-generated actin

ABSTRACT The steps leading to constitutive exocytosis are poorly understood. In Dictyostelium WASH complex mutants, exocytosis is blocked, so cells that take up fluorescent dextran from the medium retain it and remain fluorescent. Here, we establish a FACS-based method to select cells that retain fluorescent dextran, allowing identification of mutants with disrupted exocytosis. Screening a pool of random mutants identified members of the WASH complex, as expected, and multiple mutants in the conserved HEAT-repeat-containing protein Mroh1. In mroh1 mutants, endosomes develop normally until the stage where lysosomes neutralize to postlysosomes, but thereafter the WASH complex is recycled inefficiently, and subsequent exocytosis is substantially delayed. Mroh1 protein localizes to lysosomes in mammalian and Dictyostelium cells. In Dictyostelium, it accumulates on lysosomes as they mature and is removed, together with the WASH complex, shortly before the postlysosomes are exocytosed. WASH-generated F-actin is required for correct subcellular localization; in WASH complex mutants, and immediately after latrunculin treatment, Mroh1 relocalizes from the cytoplasm to small vesicles. Thus, Mroh1 is involved in a late and hitherto undefined actin-dependent step in exocytosis. Highlighted Article: An unusual FACS-based screen using Dictyostelium identifies Mroh1 – a conserved protein with HEAT repeats – as a WASH and F-actin target that is important for constitutive exocytosis of lysosomes.
Inhibition of Cellular Protein Secretion by Norwalk Virus Nonstructural Protein p22 Requires a Mimic of an Endoplasmic Reticulum Export Signal

Protein trafficking between the endoplasmic reticulum (ER) and Golgi apparatus is central to cellular homeostasis. ER export signals are utilized by a subset of proteins to rapidly exit the ER by direct uptake into COPII vesicles for transport to the Golgi. Norwalk virus nonstructural protein p22 contains a YXΦESDG motif that mimics a di-acidic ER export signal in both sequence and function. However, unlike normal ER export signals, the ER export signal mimic of p22 is necessary for apparent inhibition of normal COPII vesicle trafficking, which leads to Golgi disassembly and antagonism of Golgi-dependent cellular protein secretion. This is the first reported function for p22. Disassembly of the Golgi apparatus was also observed in cells replicating Norwalk virus, which may contribute to pathogenesis by interfering with cellular processes that are dependent on an intact secretory pathway. These results indicate that the ER export signal mimic is critical to the antagonistic function of p22, shown herein to be a novel antagonist of ER/Golgi trafficking. This unique and well-conserved human norovirus motif is therefore an appealing target for antiviral drug development.
Modeling the effects of thiamethoxam on Midwestern farm ponds and emergent wetlands

Potential toxic effects of thiamethoxam on nontarget organisms and the community structure of a generic Midwestern farm pond and emergent wetland were assessed using 2 versions of the comprehensive aquatic system model: CASMGFP, a generic farm pond model, and CASMGWL, a generic wetland model. The CASMGFP and CASMGWL are integrated bioenergetics‐based and habitat quality models that describe the daily biomass values of selected producer and consumer populations representative of generalized Midwestern farm ponds and emergent wetlands. The CASMGFP demonstrated the ability to reproduce values of population biomass reported for Midwestern (and other) pond ecosystems; the CASMGWL provided a similar modeling capability for Midwestern emergent wetlands. Lethal and sublethal effects of thiamethoxam were modeled as extrapolations of laboratory toxicity assays using the CASMGFP and the CASMGWL. Time series of daily environmental concentrations of thiamethoxam constructed for 6 regional pesticide applications across the United States failed to produce any calculated impacts on modeled population biomass or changes in community structure of modeled trophic guilds in the CASMGFP or the CASMGWL. However, evaluation of systematically increased daily concentrations demonstrated the ability of both models to simulate direct and indirect toxic effects of this pesticide. The present model study suggests that process‐based food web/ecosystem models can be used to characterize the potential ecological effects of thiamethoxam on generalized farm pond and emergent wetland ecosystems. Environ Toxicol Chem 2018;37:738–754. © 2017 SETAC
Factors increasing the risk of inactivity among administrative, technical, and manual workers in Warszawa public institutions.

OBJECTIVES The research aims to assess the level of physical activity among administrative, technical, and manual workers employed in Warszawa public institutions and to analyze the factors that increase the risk of failing to meet World Health Organization (WHO) recommendations. MATERIAL AND METHODS The study comprised 373 employees of randomly selected institutions. A short version of International Physical Activity Questionnaire (IPAQ) was applied. The correlation between the mean values of duration, days, MET-min/week of efforts, gender, and type of work was analyzed using the Tukey's honest significant difference (HSD) test, while the correlation between the level of physical activity and the socio-demographic characteristics was assessed with the Chi2 test. The strength of the relationship between socio-demographic characteristics and fulfilment of WHO standards was expressed by the odds ratio (OR) and 95% confidence interval (95% CI). The significance level was p = 0.05. RESULTS High levels of physical activity were declared by 41.8% of the manual workers, 14.7% of the administration staff, and 7.3% of the technicians; 19%, 31.5% and 54.5%, respectively, reported low levels of physical activity. Factors determining the fulfilment of the WHO recommendations include: the nature of work (p = 0.003), education (p = 0.004), and income (p = 0.003). The risk of being inactive nearly doubles in the case of administration staff (31.5%) and increases more than 4 times in the case of technicians (54.5%). Respondents with secondary school education (31.6%) are exposed to a 3-fold higher risk of inactivity, while in respondents with higher education (37.2%), the level of the risk is 4-fold higher. Compared to those in the highest income group (23.4%), people who earn less (34.1%) are inactive almost twice as often. CONCLUSIONS Urgent intervention is necessary in all studied groups: increased energy expenditure for recreation and locomotion, educational offers of employers to promote healthy lifestyle, management of leisure time budget, and strategies for changing behavior.
Gene co-expression network analysis for identifying modules and functionally enriched pathways in SCA2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the ATXN2 gene. The repeat resides in an encoded region of the gene resulting in polyglutamine (polyQ) expansion which has been assumed to result in gain of function, predominantly, for the ATXN2 protein. We evaluated temporal cerebellar expression profiles by RNA sequencing of ATXN2Q127 mice versus wild-type (WT) littermates. ATXN2Q127 mice are characterized by a progressive motor phenotype onset, and have progressive cerebellar molecular and neurophysiological (Purkinje cell firing frequency) phenotypes. Our analysis revealed previously uncharacterized early and progressive abnormal patterning of cerebellar gene expression. Weighted Gene Coexpression Network Analysis revealed four gene modules that were significantly correlated with disease status, composed primarily of genes associated with GTPase signaling, calcium signaling and cell death. Of these genes, few overlapped with differentially expressed cerebellar genes that we identified in Atxn2-/- knockout mice versus WT littermates, suggesting that loss-of-function is not a significant component of disease pathology. We conclude that SCA2 is a disease characterized by gain of function for ATXN2.
Decision making in animal breeding programs and their consequences for animal production Tomadas de decisão em programas de melhoramento animal e suas consequências para produção animal

Animal breeding technologies have advanced radically over the last 40 years and changed the way in which animals are farmed worldwide. While advances have been made, these methods have not always lived up to their promise or have led to the appearance of other unpredicted results. This has been caused by various factors such as ignorance of the correlated effects of selection or superestimation of the value of the technology. Also a dependence on technological advances often ignores important factors such as genotype x environment interaction, avoidance of inbreeding or maintenance of variation. This paper looks at some of these advances and their impact on farming practices.
The High-Dimensional Geometry of Binary Neural Networks

Recent research has shown that one can train a neural network with binary weights and activations at train time by augmenting the weights with a high-precision continuous latent variable that accumulates small changes from stochastic gradient descent. However, there is a dearth of theoretical analysis to explain why we can effectively capture the features in our data with binary weights and activations. Our main result is that the neural networks with binary weights and activations trained using the method of Courbariaux, Hubara et al. (2016) work because of the high-dimensional geometry of binary vectors. In particular, the ideal continuous vectors that extract out features in the intermediate representations of these BNNs are well-approximated by binary vectors in the sense that dot products are approximately preserved. Compared to previous research that demonstrated the viability of such BNNs, our work explains why these BNNs work in terms of the HD geometry. Our theory serves as a foundation for understanding not only BNNs but a variety of methods that seek to compress traditional neural networks. Furthermore, a better understanding of multilayer binary neural networks serves as a starting point for generalizing BNNs to other neural network architectures such as recurrent neural networks.
New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy

Abstract CACNA1D encodes the pore-forming α1-subunit of Cav1.3, an L-type voltage-gated Ca2+-channel. Despite the recent discovery of two de novo missense gain-of-function mutations in Cav1.3 in two individuals with autism spectrum disorder (ASD) and intellectual disability CACNA1D has not been considered a prominent ASD-risk gene in large scale genetic analyses, since such studies primarily focus on likely-disruptive genetic variants. Here we report the discovery and characterization of a third de novo missense mutation in CACNA1D (V401L) in a patient with ASD and epilepsy. For the functional characterization we introduced mutation V401L into two major C-terminal long and short Cav1.3 splice variants, expressed wild-type or mutant channel complexes in tsA-201 cells and performed whole-cell patch-clamp recordings. Mutation V401L, localized within the channel’s activation gate, significantly enhanced current densities, shifted voltage dependence of activation and inactivation to more negative voltages and reduced channel inactivation in both Cav1.3 splice variants. Altogether, these gating changes are expected to result in enhanced Ca2+-influx through the channel, thus representing a strong gain-of-function phenotype. Additionally, we also found that mutant channels retained full sensitivity towards the clinically available Ca2+ -channel blocker isradipine. Our findings strengthen the evidence for CACNA1D as a novel candidate autism risk gene and encourage experimental therapy with available channel-blockers for this mutation. The additional presence of seizures and neurological abnormalities in our patient define a novel phenotype partially overlapping with symptoms in two individuals with PASNA (congenital primary aldosteronism, seizures and neurological abnormalities) caused by similar Cav1.3 gain-of-function mutations.
Durable top-k search in document archives

We propose and study a new ranking problem in versioned databases. Consider a database of versioned objects which have different valid instances along a history (e.g., documents in a web archive). Durable top-k search finds the set of objects that are consistently in the top-k results of a query (e.g., a keyword query) throughout a given time interval (e.g., from June 2008 to May 2009). Existing work on temporal top-k queries mainly focuses on finding the most representative top-k elements within a time interval. Such methods are not readily applicable to durable top-k queries. To address this need, we propose two techniques that compute the durable top-k result. The first is adapted from the classic top-k rank aggregation algorithm NRA. The second technique is based on a shared execution paradigm and is more efficient than the first approach. In addition, we propose a special indexing technique for archived data. The index, coupled with a space partitioning technique, improves performance even further. We use data from Wikipedia and the Internet Archive to demonstrate the efficiency and effectiveness of our solutions.
Investigation of the rheological properties of elastomeric polymer-modified bitumen using warm-mix asphalt additives

In recent years, warm-mix asphalt (WMA) is extensively used in the hot-mix asphalt industry for reducing energy requirements and emissions by lowering mixing and compaction temperatures of bitumen. In addition, the use of polymer-modified bitumen (PMB) has become a very important part of pavement construction due to its superior performance, including less ageing, enhanced rutting resistance and lower fatigue cracking properties. This paper presents an experimental evaluation of elastomeric PMB involving WMA additives. In scope of the study, base bitumen has been modified with three different concentrations of styrene–butadiene–styrene (SBS) copolymer. The prepared PMB samples have been mixed with organic and chemical types WMA additives. Following the determination of the conventional properties as well as the rheological properties of the samples using dynamic shear rheometer, rutting behaviour of bitumen samples has been evaluated by zero shear viscosity test. The results of conventional bitumen tests showed a decrease in temperature susceptibility in PMB involving WMA additives. Based on the rheological test results, it was observed that the utilisation of organic WMA additive into PMB improves rutting performance of the modified bitumen especially in the 4% concentration of SBS copolymer.
Hexim1, an RNA-controlled protein hub

ABSTRACT Hexim1 acts as a tumor suppressor and is involved in the regulation of innate immunity. It was initially described as a non-coding RNA-dependent regulator of transcription. Here, we detail how 7SK RNA binds to Hexim1 and turns it into an inhibitor of the positive transcription elongation factor (P-TEFb). In addition to its action on P-TEFb, it plays a role in a variety of different mechanisms: it controls the stability of transcription factor components and assists binding of transcription factors to their targets.
Accurate Heart Rate Monitoring During Physical Exercises Using PPG

Objective: The challenging task of heart rate (HR) estimation from the photoplethysmographic (PPG) signal, during intensive physical exercises, is tackled in this paper. Methods: The study presents a detailed analysis of a novel algorithm (WFPV) that exploits a Wiener filter to attenuate the motion artifacts, a phase vocoder to refine the HR estimate and user-adaptive post-processing to track the subject physiology. Additionally, an offline version of the HR estimation algorithm that uses Viterbi decoding is designed for scenarios that do not require online HR monitoring (WFPV+VD). The performance of the HR estimation systems is rigorously compared with existing algorithms on the publically available database of 23 PPG recordings. Results: On the whole dataset of 23 PPG recordings, the algorithms result in average absolute errors of 1.97 and 1.37 BPM in the online and offline modes, respectively. On the test dataset of 10 PPG recordings which were most corrupted with motion artifacts, WFPV has an error of 2.95 BPM on its own and 2.32 BPM in an ensemble with two existing algorithms. Conclusion: The error rate is significantly reduced when compared with the state-of-the art PPG-based HR estimation methods. Significance: The proposed system is shown to be accurate in the presence of strong motion artifacts and in contrast to existing alternatives has very few free parameters to tune. The algorithm has a low computational cost and can be used for fitness tracking and health monitoring in wearable devices. The MATLAB implementation of the algorithm is provided online.