Miracle-dz/UniFAR-FTUs huggingface dataset:
Osmolality/salinity-responsive enhancers (OSREs) control induction of osmoprotective genes in euryhaline fish

Significance Salinity stress is common in many environments and is predicted to intensify. Such stress increases the expression of numerous genes in fish, but the corresponding regulatory mechanisms are unknown. Our study provides a toolkit for discovering and functionally validating cis-regulatory elements (CREs) that control inducible gene expression in fish. This toolkit was used for experimental identification of the first osmotic/salinity-responsive CREs in fish (OSRE1). Our findings greatly empower novel approaches for deciphering fish osmosensory signaling and gene regulatory networks. Because sequence variation in inducible CREs is critical for the evolution of stress tolerance, knowledge of osmolality/salinity-responsive enhancers is critical for revealing the evolution and function of regulatory networks responsible for euryhalinity of fish. Fish respond to salinity stress by transcriptional induction of many genes, but the mechanism of their osmotic regulation is unknown. We developed a reporter assay using cells derived from the brain of the tilapia Oreochromis mossambicus (OmB cells) to identify osmolality/salinity-responsive enhancers (OSREs) in the genes of O. mossambicus. Genomic DNA comprising the regulatory regions of two strongly salinity-induced genes, inositol monophosphatase 1 (IMPA1.1) and myo-inositol phosphate synthase (MIPS), was isolated and analyzed with dual luciferase enhancer trap reporter assays. We identified five sequences (two in IMPA1.1 and three in MIPS) that share a common consensus element (DDKGGAAWWDWWYDNRB), which we named “OSRE1. ” Additional OSREs that were less effective in conferring salinity-induced trans-activation and do not match the OSRE1 consensus also were identified in both MIPS and IMPA1.1. Although OSRE1 shares homology with the mammalian osmotic-response element/tonicity-responsive enhancer (ORE/TonE) enhancer, the latter is insufficient to confer osmotic induction in fish. Like other enhancers, OSRE1 trans-activates genes independent of orientation. We conclude that OSRE1 is a cis-regulatory element (CRE) that enhances the hyperosmotic induction of osmoregulated genes in fish. Our study also shows that tailored reporter assays developed for OmB cells facilitate the identification of CREs in fish genomes. Knowledge of the OSRE1 motif allows affinity-purification of the corresponding transcription factor and computational approaches for enhancer screening of fish genomes. Moreover, our study enables targeted inactivation of OSRE1 enhancers, a method superior to gene knockout for functional characterization because it confines impairment of gene function to a specific context (salinity stress) and eliminates pitfalls of constitutive gene knockouts (embryonic lethality, developmental compensation).
Parasitophorous vacuole poration precedes its rupture and rapid host erythrocyte cytoskeleton collapse in Plasmodium falciparum egress

Significance Malaria parasites develop within red blood cells inside a membrane-enclosed parasitophorous vacuole. An essential step in their life cycle is the exit of mature parasites from the blood cell, a multistage process termed egress. To do this, the parasites orchestrate a highly regulated sequence of membrane permeabilization and breakage steps culminating in the explosive release of parasites for a new round of infection. Here, we describe a previously unidentified permeabilization of the vacuolar membrane at the start of egress, preceding membrane rupture, suggesting a new initiation step in egress. We also show that, in the final minutes of egress, the blood cell membrane abruptly loses its structural rigidity and collapses around the parasites, showing a precise timing for cytoskeletal breakdown. In the asexual blood stages of malarial infection, merozoites invade erythrocytes and replicate within a parasitophorous vacuole to form daughter cells that eventually exit (egress) by sequential rupture of the vacuole and erythrocyte membranes. The current model is that PKG, a malarial cGMP-dependent protein kinase, triggers egress, activating malarial proteases and other effectors. Using selective inhibitors of either PKG or cysteine proteases to separately inhibit the sequential steps in membrane perforation, combined with video microscopy, electron tomography, electron energy loss spectroscopy, and soft X-ray tomography of mature intracellular Plasmodium falciparum parasites, we resolve intermediate steps in egress. We show that the parasitophorous vacuole membrane (PVM) is permeabilized 10–30 min before its PKG-triggered breakdown into multilayered vesicles. Just before PVM breakdown, the host red cell undergoes an abrupt, dramatic shape change due to the sudden breakdown of the erythrocyte cytoskeleton, before permeabilization and eventual rupture of the erythrocyte membrane to release the parasites. In contrast to the previous view of PKG-triggered initiation of egress and a gradual dismantling of the host erythrocyte cytoskeleton over the course of schizont development, our findings identify an initial step in egress and show that host cell cytoskeleton breakdown is restricted to a narrow time window within the final stages of egress.
Comparison of two fixed activities of radioiodine therapy (370 vs. 555 MBq) in patients with Graves’ disease

OBJECTIVERadioiodine therapy is the most commonly used therapy for patients with Graves’ disease (GD) in the United Kingdom. It is considered safe, effective and relatively inexpensive. The aim of our study was to examine the outcome of 131Iodine therapy in patients with GD when two different activities of 131Iodine were used.DESIGNA retrospective audit was undertaken to compare the efficacy of 370 (10 millicuries) versus 555MBq (15 millicuries) radioiodine therapy in patients with Graves’ disease over a period of ten years.RESULTSOverall, 90% of the patients had a successful outcome from treatment with no significant difference in the success rate between the lower and higher activities or between genders.CONCLUSIONS555 MBq of radioiodine was no more effective than 370 MBq in managing patients with Graves’ disease. We therefore recommend that the higher activity should not be routinely used in these patients.
Learning to Rank Question-Answer Pairs Using Hierarchical Recurrent Encoder with Latent Topic Clustering

In this paper, we propose a novel end-to-end neural architecture for ranking candidate answers, that adapts a hierarchical recurrent neural network and a latent topic clustering module. With our proposed model, a text is encoded to a vector representation from an word-level to a chunk-level to effectively capture the entire meaning. In particular, by adapting the hierarchical structure, our model shows very small performance degradations in longer text comprehension while other state-of-the-art recurrent neural network models suffer from it. Additionally, the latent topic clustering module extracts semantic information from target samples. This clustering module is useful for any text related tasks by allowing each data sample to find its nearest topic cluster, thus helping the neural network model analyze the entire data. We evaluate our models on the Ubuntu Dialogue Corpus and consumer electronic domain question answering dataset, which is related to Samsung products. The proposed model shows state-of-the-art results for ranking question-answer pairs.
Standard cell library design and optimization methodology for ASAP7 PDK: (Invited paper)

Standard cell libraries are the foundation for the entire back-end design and optimization flow in modern application-specific integrated circuit designs. At 7nm technology node and beyond, standard cell library design and optimization is becoming increasingly difficult due to extremely complex design constraints, as described in the ASAP7 process design kit (PDK). Notable complexities include discrete transistor sizing due to FinFETs, complicated design rules from lithography and restrictive layout space from modern standard cell architectures. The design methodology presented in this paper enables efficient and high-quality standard cell library design and optimization with the ASAP7 PDK. The key techniques include exhaustive transistor sizing for cell timing optimization, transistor placement with generalized Euler paths and back-end design prototyping for library-level explorations.
Evidence‐based practice guidelines for prescribing home modifications for clients with bariatric care needs

BACKGROUND/AIM Home modifications maintain people's functional independence and safety. No literature exists to guide the prescription of home modifications for clients with bariatric care needs. With Australia's increasing obesity rate, more evidence is needed to support home modification prescribers. This study aimed to map Australian home modification prescribing practices for clients with bariatric care needs and to establish and evaluate a clinical resource for this prescription process. METHODS The study included two phases. Phase 1 conducted a cross-sectional survey of therapists practicing in Australia, and Australian industry partners who prescribe or install home modifications for clients with bariatric care needs. Phase 2 included design, implementation and evaluation of a clinical resource. Data were analysed with means and frequencies; multivariable regression analysis was used to explore prescribing habits. RESULTS Therapists surveyed (n = 347) reported 11 different bariatric weight definitions. Less than 3% constantly or regularly prescribed home modifications for these clients; rails were most commonly prescribed. Many therapists (n = 171, 58%) 'never' or 'rarely' knew rail load capacity. Therapists' knowledge of rail load capacity was associated with previous experience prescribing home modifications (P = 0.009); rail manufacturer's advice (P = 0.016) and not using advice from builders (P = 0.001). Clinical resources were used by 11% (n = 26) of therapists to support their prescription, and industry sporadically relied on therapists to specify modification design requirements (n = 5, 45%). Post-implementation of a clinical resource increased consensus regarding understanding of the term bariatric and increased consultation with builders and manufacturers. CONCLUSION There was a lack of consistency in bariatric terminology, uncertainty of rail load capacities and minimal use of clinical practice guidelines. Additional resources will assist with consistency in prescribing practices to maximise occupational performance for clients with bariatric care needs.
Loop 3 of Fungal Endoglucanases of Glycoside Hydrolase Family 12 Modulates Catalytic Efficiency

ABSTRACT Glycoside hydrolase (GH) family 12 comprises enzymes with a wide range of activities critical for the degradation of lignocellulose. However, the important roles of the loop regions of GH12 enzymes in substrate specificity and catalytic efficiency remain poorly understood. This study examined how the loop 3 region affects the enzymatic properties of GH12 glucanases using NfEG12A from Neosartorya fischeri P1 and EG (PDB 1KS4 ) from Aspergillus niger. Acidophilic and thermophilic NfEG12A had the highest catalytic efficiency (kcat/Km, 3,001 and 263 ml/mg/s toward lichenin and carboxymethyl cellulose sodium [CMC-Na], respectively) known so far. Based on the multiple-sequence alignment and homology modeling, two specific sequences (FN and STTQA) were identified in the loop 3 region of GH12 endoglucanases from fungi. To determine their functions, these sequences were introduced into NfEG12A, or the counterpart sequence STTQA was removed from EG. These modifications had no effects on the optimal pH and temperature or substrate specificity but changed the catalytic efficiency (kcat/Km) of these enzymes (in descending order, NfEG12A [100%], NfEG12A-FN [140%], and NfEG12A-STTQA [190%]; EG [100%] and EGΔSTTQA [41%]). Molecular docking and dynamic simulation analyses revealed that the longer loop 3 in GH12 may strengthen the hydrogen-bond interactions between the substrate and protein, thereby increasing the turnover rate (kcat). This study provides a new insight to understand the vital roles of loop 3 for GH12 endoglucanases in catalysis. IMPORTANCE Loop structures play critical roles in the substrate specificity and catalytic hydrolysis of GH12 enzymes. Three typical loops exist in these enzymes. Loops 1 and 2 are recognized as the catalytic loops and are closely related to the substrate specificity and catalytic efficiency. Loop 3 locates in the −1 or +1 subsite and varies a lot in amino acid composition, which may play a role in catalysis. In this study, two GH12 glucanases, NfEG12A and EG, which were mutated by introducing or deleting partial loop 3 sequences FN and/or STTQA, were selected to identify the function of loop 3. It revealed that the longer loop 3 of GH12 glucanases may strengthen the hydrogen network interactions between the substrate and protein, consequently increasing the turnover rate (kcat). This study proposes a strategy to increase the catalytic efficiency of GH12 glucanases by improving the hydrogen network between substrates and catalytic loops.
Migraine and invasive epithelial ovarian cancer risk in the Nurses’ Health Study II and the Women's Health Study

Migraine is a common primary headache disorder, which predominantly impacts women. Recently, migraine has been hypothesized to be associated with hormonally related cancers; however, the potential association between migraine and ovarian cancer has not been studied. Therefore, we evaluated the association between migraine and invasive epithelial ovarian cancer risk in two prospective cohorts, the Nurses’ Health Study II (NHSII) and the Women's Health Study (WHS). Our prospective analysis included 113,124 NHSII participants aged 25–42 at study baseline as well as 33,490 participants in the WHS who were 45 years or older at study entry. We used Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) for the association between migraine and ovarian cancer risk in each cohort. In secondary analyses, we stratified by age and menopausal status. After adjusting for potential covariates, there was no statistically significant association between migraine and ovarian cancer risk in either the NHSII (HR = 1.29, 95%CI: 0.96, 1.74) or the WHS (HR = 0.60, 95%CI: 0.34, 1.06). In stratified analysis in the NHSII, there was a statistically significant positive association between migraine and ovarian cancer risk among women <45 years of age (HR = 1.76, 95%CI: 1.01, 3.07). We did not observe a clear association between migraine and ovarian cancer risk in two large prospective cohort studies.
Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics

Significance Gene drive mosquitoes have tremendous potential to help eliminate malaria, and multiple gene drive approaches have recently shown promise in laboratory settings. These approaches include population suppression through fertility disruption, driving-Y chromosomes, and population replacement with genes that limit malaria transmission. Mathematical modeling is used to evaluate these approaches by simulating realistic field settings with seasonality to determine constraints on construct parameters and release strategies. Parameter variation from simulation baselines captures much of sub-Saharan African epidemiology and shows high potential for gene drive constructs to provide transformational tools to facilitate elimination of malaria, even in the most challenging settings. This analysis provides insights into performance characteristics necessary for each approach to succeed that can inform their further development. The renewed effort to eliminate malaria and permanently remove its tremendous burden highlights questions of what combination of tools would be sufficient in various settings and what new tools need to be developed. Gene drive mosquitoes constitute a promising set of tools, with multiple different possible approaches including population replacement with introduced genes limiting malaria transmission, driving-Y chromosomes to collapse a mosquito population, and gene drive disrupting a fertility gene and thereby achieving population suppression or collapse. Each of these approaches has had recent success and advances under laboratory conditions, raising the urgency for understanding how each could be deployed in the real world and the potential impacts of each. New analyses are needed as existing models of gene drive primarily focus on nonseasonal or nonspatial dynamics. We use a mechanistic, spatially explicit, stochastic, individual-based mathematical model to simulate each gene drive approach in a variety of sub-Saharan African settings. Each approach exhibits a broad region of gene construct parameter space with successful elimination of malaria transmission due to the targeted vector species. The introduction of realistic seasonality in vector population dynamics facilitates gene drive success compared with nonseasonal analyses. Spatial simulations illustrate constraints on release timing, frequency, and spatial density in the most challenging settings for construct success. Within its parameter space for success, each gene drive approach provides a tool for malaria elimination unlike anything presently available. Provided potential barriers to success are surmounted, each achieves high efficacy at reducing transmission potential and lower delivery requirements in logistically challenged settings.
Clec9A+ Dendritic Cells Are Not Essential for Antitumor CD8+ T Cell Responses Induced by Poly I:C Immunotherapy

In the steady state, tumors harbor several populations of dendritic cells (DCs) and myeloid cells that are key regulators of the intratumoral immune environment. Among these cells, migratory CD103+ cross-presenting DCs are thought to be critical for tumor-specific CTL responses and tumor resistance. However, it is unclear whether this prominent role also extends to immunotherapy. We used a murine orthotopic mammary tumor model, as well as Clec9A–diphtheria toxin receptor mice that can be depleted of the specialized cross-presenting CD8α+ and CD103+ DC1 subsets, to investigate the role of these DCs in immunotherapy. Treatment with monosodium urate crystals and mycobacteria at the tumor site delayed tumor growth and required DC1s for efficacy. In contrast, treatment with poly I:C was equally effective regardless of DC1 depletion. Neither treatment affected myeloid-derived suppressor cell numbers in the spleen or tumor. Similar experiments using subcutaneous B16 melanoma tumors in BATF3-knockout mice confirmed that CD103+ DCs were not necessary for successful poly I:C immunotherapy. Nevertheless, adaptive immune responses were essential for the response to poly I:C, because mice depleted of CD8+ T cells or all DC subsets were unable to delay tumor growth. In vivo experiments showed that DC1 and DC2 subsets were able to take up tumor Ags, with DC2s making up the larger proportion of lymph node DCs carrying tumor material. Both DC subsets were able to cross-present OVA to OT-I T cells in vitro. Thus, immunotherapy with poly I:C enables multiple DC subsets to cross-present tumor Ag for effective antitumor immune responses.
Scalable data-driven short-term traffic prediction

Short-term traffic prediction has a lot of potential for traffic management. However, most research has traditionally focused on either traffic models — which do not scale very well to large networks, computationally — or on data-driven methods for freeways, leaving out urban arterials completely. Urban arterials complicate traffic predictions, compared to freeways, because the non-linear effects of traffic are more pronounced on short links and with the presence of more crossings, more modalities and non-necessarily conservation of flow (parking). In this paper we consider several data-driven methods and their prediction performance for various situations, including both freeways and urban arterials, for prediction horizons from five minutes up to one week. The focus lies on predicting the traffic flow and speed given available measured data on a certain location. Thus challenges regarding data fusion, state estimation, and other methods providing complete temporal and spatial data is not addressed. The methods evaluated include several naive, parametric and non-parametric methods. For the evaluation of the prediction performance several weeks of data of various locations were used. Performance indicators contained the Root Mean Square Error, Mean Absolute Percentage Error and Mean Absolute Error. Because evaluating average performance might ignore the performance for non-regular traffic conditions, the evaluation also focused on non-regular traffic conditions. Especially these conditions are important in practice, because in these situations the need for accurate information is the highest. Real-world applicability of traffic prediction requires not only accurate results, but also an indication of the accuracy for each prediction. Earlier research has mostly ignored this, leaving this up to the intuition of users of these predictions. This paper introduces a simple way to calculate confidence intervals, applicable to any traffic prediction method. For comparing these confidence intervals between different prediction horizons, an error measure for the accuracy of a confidence interval is defined. Two methods, SARIMA (Seasonal Auto-Regressive Integrated Moving Average) and NLM (Neighborhood Link Method), proved to be the best. The results also indicate key features necessary for accurate traffic prediction with data-driven methods. The results also show reasonably accurate confidence intervals, with those intervals able to adapt well to different traffic situations.
Efecto del peróxido de hidrógeno al 25% sobre la microdureza del esmalte dental

The aim was determinate the effect of two bleaching agents based on hydrogen peroxide 25% on dental enamel microhardness. An experimental study was made to evaluate the effect of hydrogen peroxide 25% on the enamel surface microhardness, it was used 30 extracted premolars with orthodontic purposes, which were sectioned and placed in a mold of 1 cm circumferential in diameter and 1cm thick,filling with acrylic self-curing color red (15) and blue (15) storing in sterile flasks containing physiological serum. An initial measurement was using the BUEHLER MICROMET 2101 microhardness in the Sputtering Laboratory, Faculty of Science, National University of Engineering, applied a load of 100g for 30 seconds, then proceeded to measure the indentation to find the measure of microhardness in kg/mm2. Then group 1 was done bleaching with Peroxgel MCC and group 2 with Zoom2, the next day again measured enamel microhardness. The results of the enamel surface microhardness of the whitening agent: Peroxgel MCC and Zoom2, showed a statistically significant decrease (234.83 Kgf/mm2) and (196.11 Kgf/mm2) respectively, found no significant difference (p = 0.136) when comparing the decline between bleaching agents used in this study. It is concluded that the use of bleaching agents based on hydrogen peroxide 25% decreased significantly the microhardness of the enamel surface.