Miracle-dz/UniFAR-FTUs huggingface dataset:
HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages

Heat shock protein (HSP) 40 has emerged as a key actor in both innate and adaptive immunity, whereas the role of HLJ1, a molecular chaperone in HSP40 family, in modulating endotoxin–induced sepsis severity is still unclear. Here, we use single-cell RNA sequencing to characterize mouse liver nonparenchymal cell populations under LPS (lipopolysaccharide) stimulation, and show that HLJ1 deletion affected IFN-γ-related gene signatures in distinct immune cell clusters. HLJ1 deficiency also leads to reduced serum levels of IL-12 in LPS-treated mice, contributing to dampened production of IFN-γ in natural killer cells but not CD4+ or CD8+ T cells, and subsequently to improved survival rate. Adoptive transfer of HLJ1-deleted macrophages into LPS-treated mice results in reduced IL-12 and IFN-γ levels and protects the mice from IFN-γ–dependent mortality. In the context of molecular mechanisms, HLJ1 is an LPS-inducible protein in macrophages and converts misfolded IL-12p35 homodimers to monomers, which maintains bioactive IL-12p70 heterodimerization and secretion. This study suggests HLJ1 causes IFN-γ–dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activating IL-12/IFN-γ axis.
Acquisition of cross-azole tolerance and aneuploidy in Candida albicans strains evolved to posaconazole

A number of in vitro studies have examined the acquisition of drug resistance to the triazole fluconazole, a first-line treatment for many Candida infections. Much less is known about posaconazole, a newer triazole. We conducted the first in vitro experimental evolution of replicates from eight diverse strains of C. albicans in a high level of the fungistatic drug posaconazole. Approximately half of the 132 evolved replicates survived 50 generations of evolution, biased towards some of the strain backgrounds. We found that although increases in drug resistance were rare, increases in drug tolerance (the slow growth of a subpopulation of cells in a level of drug above the resistance level) were common across strains. We also found that adaptation to posaconazole resulted in widespread cross-tolerance to other azole drugs. Widespread aneuploidy variation was also observed in evolved replicates from some strain backgrounds. Trisomy of chromosomes 3, 6, and R was identified in 11 of 12 whole-genome sequenced evolved SC5314 replicates. These findings document rampant evolved cross-tolerance among triazoles and highlight that increases in drug tolerance can evolve independently of drug resistance in a diversity of C. albicans strain backgrounds.
Oligomerization of peripheral membrane proteins provides tunable control of cell surface polarity

Asymmetric distributions of peripheral membrane proteins define cell polarity across all kingdoms of life. These asymmetries are shaped by membrane binding, diffusion and transport. Theoretical studies have revealed a general requirement for non-linear positive feedback to spontaneously amplify and/or stabilize asymmetries against dispersion by diffusion and dissociation. But how specific molecular sources of non-linearity shape polarization dynamics remains poorly understood. Here we study how oligomerization of peripheral membrane proteins shapes polarization dynamics in simple feedback circuits. We show that size dependent binding avidity and mobility of membrane bound oligomers endow polarity circuits generically with several key properties. Size-dependent binding avidity confers a form of positive feedback in which the effective rate constant for subunit dissociation decreases with increasing subunit density. This combined with additional weak linear positive feedback is sufficient for spontaneous emergence of stably polarized states. Size-dependent oligomer mobility makes symmetry-breaking and stable polarity more robust with respect to variation in subunit diffusivities and cell sizes, and slows the approach to a final stable spatial distribution, allowing cells to ”remember” polarity boundaries imposed by transient external cues. Together, these findings reveal how oligomerization of peripheral membrane proteins can provide powerful and highly tunable sources of non-linear feedback in biochemical circuits that govern cell-surface polarity. Given its prevalence and widespread involvement in cell polarity, we speculate that self-oligomerization may have provided an accessible path to evolving simple polarity circuits. Author summary All cells organize their activities with respect to one or more axes of polarity. Cell polarity is often defined by the asymmetric enrichment of specific polarity proteins at the cell membrane. Absent external cues, stable polarity requires positive feedback in which proteins locally promote their own accumulation at the membrane, and the strength of feedback must depend non-linearly on local protein concentration. Here, we show that this kind of non-linear dependence arises when peripheral membrane proteins form small oligomers that dissociate from the membrane more slowly than single protein monomers. Combining this effect with a little additional linear feedback allows cells to form and stabilize asymmetric distributions of polarity proteins. In addition, we find that size-dependent reduction in oligomer mobility makes the ability to polarize more robust to variation in monomer diffusivity and cell size and makes polarity protein distributions more responsive to external inputs. Since many polarity proteins form small oligomers at the cell membrane, and there are many ways for weak linear feedback to arise in biochemical systems, the combination of oligomerization with a small amount of additional positive feedback may provide a general mechanism for polarizing a wide variety of unrelated cell types.
Proteomic Dissection of a Giant Cell

Many individual proteins have been identified as having defined positions relative to cell polarity axes, raising the question of what fraction of all proteins may have polarized localizations. We took advantage of the giant ciliate Stentor coeruleus to quantify the extent of polarized localization proteome-wide. This trumpet-shaped unicellular organism shows a clear morphological anterior-posterior axis defined by a circular array of cilia known as a membranellar band at one end, and a holdfast at the other end. Because individual Stentor cells are over a millimeter in length, we were able to cut the cells into three pieces along the anterior-posterior axis, followed by proteomic analysis of proteins enriched in each piece. We find that approximately 30% of all detected proteins show a polarized location relative to the anterior-posterior cell axis. Proteins with polarized enrichment include centrin-like proteins, calcium-regulated kinases, orthologs of SFI1 and GAS2, and proteases. At the organelle level, nuclear and mitochondrial proteins are enriched in the anterior half of the cell body, but not in the membranellar band itself, while ribosome related proteins are apparently uniformly distributed. RNAi of signaling proteins enriched in the membranellar band, which is the anterior-most structure in the cell, revealed a protein phosphatase 2 subunit b ortholog required for closure of the membranellar band into the ring shape characteristic of Stentor. These results suggest that a large fraction of the Stentor proteome has a polarized localization, and provide a protein-level framework for future analysis of pattern formation and regeneration in Stentor as well as defining a general strategy for subcellular spatial proteomics based on physical dissection of cells.
Maternal investment evolves with larger body size and higher diversification rate in sharks and rays

Across vertebrates, live-bearing has evolved at least 150 times from ancestral egg-laying into a diverse array of forms and degrees of prepartum maternal investment.1,2 A key question is how this reproductive diversity arose and whether reproductive diversification underlies species diversification? 3–11 To test these questions, we evaluate the most basal jawed vertebrates, sharks, rays, chimaeras of Class Chondrichthyans, which have one of the greatest ranges of reproductive and ecological diversity among vertebrates.2,12 We reconstructed the sequence of reproductive mode evolution across a time-calibrated molecular phylogeny of 610 chondrichthyans.13 We find egg-laying is ancestral, and live-bearing evolved at least seven times. Matrotrophy (i.e. maternal contributions beyond the yolk) evolved at least 15 times, with evidence of one reversal. In sharks, transitions to live-bearing and matrotrophy are more prevalent in larger-bodied species in the tropics. Further, the evolution of live-bearing is associated with a near-doubling of the diversification rate, but, there is only a small increase in diversification associated with the appearance of matrotrophy and increased rates of speciation are associated with the colonization of novel habitats, contrary to what has been demonstrated in teleosts.3,4 This highlights a potential key difference between chondrichthyans and other fishes, specifically a slower rate of reproductive isolation following speciation, suggesting different rate-limiting mechanisms for diversification between these clades.14 The chondrichthyan diversification and radiation, particularly throughout the shallow tropical shelf seas and oceanic pelagic habitats, appears to be associated with the evolution of live-bearing and the proliferation of a wide range of maternal investment in developing offspring.
Function and constraint in enhancers with multiple evolutionary origins

Motivation Thousands of human gene regulatory enhancers are composed of sequences with multiple evolutionary origins. These evolutionarily “complex” enhancers consist of older “core” sequences and younger “derived” sequences. However, the functional relationship between the sequences of different evolutionary origins within complex enhancers is poorly understood. Results We evaluated the function, selective pressures, and sequence variation across core and derived components of human complex enhancers. We find that both components are older than expected from the genomic background, and cores are enriched for derived sequences of similar evolutionary ages. Both components show strong evidence of biochemical activity in massively parallel report assays (MPRAs). However, core and derived sequences have distinct transcription factor (TF) binding preferences that are largely stable across evolutionary origins. Given these signatures of function, both core and derived sequences have substantial evidence of purifying selection. Nonetheless, derived sequences exhibit weaker purifying selection than adjacent cores. Derived sequences also tolerate more common genetic variation and are enriched compared to cores for eQTL associated with gene expression variability in human populations. Conclusions Both core and derived sequences have strong evidence of gene regulatory function, but derived sequences have distinct constraint profiles, TF binding preferences, and tolerance to variation compared with cores. We propose that the step-wise integration of younger derived and older core sequences has generated regulatory substrates with robust activity and the potential for functional variation. Our analyses demonstrate that synthesizing study of enhancer evolution and function can aid interpretation of regulatory sequence activity and functional variation across human populations. Significance Statement Thousands of human gene regulatory enhancers are mosaics of sequences from multiple evolutionary origins, yet how these different segments contribute to enhancer function is poorly understood. By dissecting their regulatory functions, transcription factor binding, constraint, and human genetic variation, we show that both older “core” and younger “derived” sequences in complex enhancers have strong evidence of gene regulatory function, but derived sequences are more likely to harbor genetic variants that influence function. Together, our results support a model in which the integration of sequences of different origins generates regulatory substrates with robust activity and the potential for functional variation.
Regulation of major bacterial survival strategies by transcript sequestration in a membraneless organelle

Liquid-liquid phase separation (LLPS) of proteins was shown in recent years to regulate spatial organization of cell content without the need for membrane encapsulation in eukaryotes and prokaryotes. Yet evidence for the relevance of LLPS for bacterial cell functionality is largely missing. Here we show that the sugar metabolism-regulating clusters, recently shown by us to assemble in the E. coli cell poles by means of the novel protein TmaR, are formed via LLPS. A mutant screen uncovered residues and motifs in TmaR that are important for its condensation. Upon overexpression, TmaR undergoes irreversible liquid-to-solid transition, similar to the transition of disease-causing proteins in human, which impairs bacterial cell morphology and proliferation. Not only does RNA contribute to TmaR phase separation, but by ensuring polar localization and stability of flagella-related transcripts, TmaR enables cell motility and biofilm formation, thus providing a linkage between LLPS and major survival strategies in bacteria.
LIQUID TREATMENTS OF COMMERCIAL CALCIUM CHLORIDE IN WINTER ROAD MAINTENANCE

TWO EXPERIMENTS ARE DESCRIBED USING LIQUID SOLUTIONS OF A COMMERCIAL CALCIUM CHLORIDE TYPE 77-80, ON HIGHWAY 26 AND HIGHWAY 26 EXPRESS FROM THE MONT BLANC TUNNEL IN THE AOSTA VALLEY AND ON HIGHWAY 242 TO GARDENA VALLEY ON THE OCCASION OF THE 1970 MONDIAL SKI CHAMPIONSHIP. THESE EXPERIMENTS WERE PRECEDED BY A METEOROLOGIC STUDY, IN WHICH THE ROAD WAS DIVIDED INTO 3 PARTS CORRESPONDING TO 3 DIFFERENT ALTIMETRICAL BELTS FROM SOME HUNDREDS OF METERS TO 1,400 M ELEVATION AT THE ENTRANCE OF THE TUNNEL ON THE ITALIAN SIDE. THE TOTAL ANNUAL AVERAGE SNOWFALL FORECAST WAS 170 CM. FOR ONE EXPERIMENT, A 15-KM SECTION WAS CHOSEN BETWEEN THE TUNNEL AND MORGEX WHERE, EVEN IF THE SLOPE IS NOT EXCESSIVE, CARS MUST HAVE CHAINS OR CAMION TIRES.THE AMOUNTS USED WERE OF 10 GR/SQUARE M IN THE PREVENTIVE TREATMENTS AND 40 GR/SQUARE M IN THE MAINTENACE TREATMENTS. THE NUMERICAL RATIO AMONG THESE TYPES OF TREATMENTS WAS, ON THE AVERAGE, 1 TO 3. ALSO DESCRIBED IS THE GARDENA VALLEY EXPERIMENT AND THE MODIFICATIONS MADE TO THE EQUIPMENT. /AUTHOR/
Effect of Soil Application of Zinc on Growth, Yield and Zinc Concentration in Rice Varieties

Zinc (Zn) deficiency is widespread nutrient disorder in lowland rice growing areas in Asia, especially in Bangladesh. Intensive cropping with modern varieties causes depletion of inherent nutrient reserves in soils. The application of Zn fertilizers results in higher crop productivity and increases Zn concentration in crops. A field experiment was conducted to evaluate the effect of Zn application on growth, yield, and grain-Zn concentration in eight varieties of rice. The experiment was laid out in a split plot design with a distribution of Zn rates (0 kg ha and 3 kg ha from ZnO) to the main plots and rice varieties (BRRI dhan49, BRRI dhan52, BRRI dhan56, BRRI dhan57, Kalizira, Biroin, Gainja and Khirshapath) to the sub-plots. Zinc application improved effective tillers hill, grains panicle and 1000-grain weight which impacted the grain yield of rice. Among the eight rice varieties, a significant increase of grain yield was recorded in BRRI dhan49, BRRI dhan52, BRRI dhan56 and BRRI dhan57 due to application of Zn. Zinc concentration of grain significantly increased in all rice varieties except Biroin. The highest grain-Zn concentration (19.1 mg kg) was noted in BRRI dhan57 with 3 kg ha Zn and the lowest value (11.3 mg kg) was observed in BRRI dhan52 without Zn application. The highest percent increase of grain Zn concentration over control was obtained in high yielding rice variety BRRI dhan49 and the lowest Zn concentration was found in local rice variety Biroin.
Normal Chest X-Ray in Patients with Pulmonary Embolism May Involve Increased Risk of Massive Pulmonary Embolism

Purpose: Chest radiography is normal in approximately 20-40% of acute pulmonary embolism (PE) patients without cardiopulmonary disease. The aim of this study was to determine whether there is any difference between the patients with normal chest X-ray and those with pathological findings in terms of clinical severity and prognosis. Methods: 178 of PE patients were included in the study. 110 patients had no parenchymal pathology, whereas group 1 (n = 110); group 2 (n = 68) had various pathological parenchymal findings in 68 patients. Clinical and radiological parameters were compared between these groups. Following the diagnosis of PE, the cases were recorded in the fifth year. Results: In 178 participants; those with normal chest X-ray (group 1), with parenchymal pathological findings on the chest X-ray (group 2); echocardiographic systolic pulmonary artery pressure (sPAP) (p = 0.68), gender (p = 0.9) and thrombus type (p = 0.41) were similar. The patients in group 1 were not different in terms of central thrombus detected in computed tomography pulmonary angiogram compared to the patients in group 2; however, the chest radiograph of the patients in group 1 had no parenchymal pathology. Central thrombus group 1, group 2, respectively; 97 (89.0%), 53 (77.9%), p = 0.07. There was no significant difference between the two groups in terms of mortality which was followed up in fifth year (p > 0.05). Conclusions: Normal chest X-ray in PE can determine mortality and may involve increased risk of massive PE.
Radar Echo Spatiotemporal Sequence Prediction Using an Improved ConvGRU Deep Learning Model

Precipitation nowcasting is extremely important in disaster prevention and mitigation, and can improve the quality of meteorological forecasts. In recent years, deep learning-based spatiotemporal sequence prediction models have been widely used in precipitation nowcasting, obtaining better prediction results than numerical weather prediction models and traditional radar echo extrapolation results. Because existing deep learning models rarely consider the inherent interactions between the model input data and the previous output, model prediction results do not sufficiently meet the actual forecast requirement. We propose a Modified Convolutional Gated Recurrent Unit (M-ConvGRU) model that performs convolution operations on the input data and previous output of a GRU network. Moreover, this adopts an encoder–forecaster structure to better capture the characteristics of spatiotemporal correlation in radar echo maps. The results of multiple experiments demonstrate the effectiveness of the proposed model. The balanced mean absolute error (B-MAE) and balanced mean squared error (B-MSE) of M-ConvGRU are slightly lower than Convolutional Long Short-Term Memory (ConvLSTM), but the mean absolute error (MAE) and mean squared error (MSE) of M-ConvGRU are 6.29% and 10.25% lower than ConvLSTM, and the prediction accuracy and prediction performance for strong echo regions were also improved.
Ultrasound evaluation of diaphragm motion in BAG-3 myofibrillar myopathy

Abstract Rationale: Mutations in Bcl-2-associated athanogene-3 (BAG-3) can cause a rare subtype of myofibrillar myopathies (MFMs), characterized by progressive muscle weakness, cardiomyopathy, and severe respiratory insufficiency in childhood. Little is known about diaphragmatic function in BAG-3 MFM. To our knowledge, this is the first case report of detailed evaluation of diaphragmatic function with ultrasound in BAG-3 MFM. Patient concern: We describe the case of a 15-year-old girl who complained of fever and shortness of breath. Diaphragmatic sonography revealed bilateral diaphragmatic paralysis. Shortness of breath progressed to respiratory failure approximately 3 months later. Diagnosis: A neurologist was consulted and genetic sequencing identified a p.Pro209Leu mutation in BAG-3, yielding diagnosis of BAG-3 MFM leading to bilateral diaphragmatic paralysis. Interventions: Respiratory muscle training and long-term mechanical ventilation. Outcomes: It is quite unfortunate for this patient to have a poor prognosis due to the lack of effective treatment for this genetic disorder. Lessons: This case provides more clinical information for this rare disease which may cause severe diaphragm pathological damage leading to respiratory failure in BAG3 MFM and a future study with a systematic evaluation of a greater number of patients will be necessary to characterize this population.
Effective radiative forcing of anthropogenic aerosols in E3SMv1: historical changes, causality, decomposition, and parameterization sensitivities

Abstract. The effective radiative forcing of anthropogenic aerosols (ERFaer) is an important measure of the anthropogenic aerosol effects simulated by a global climate model. Here we analyze ERFaer simulated by the E3SMv1 atmosphere model using both century-long free-running atmosphere-land simulations and short nudged simulations. We relate the simulated ERFaer to characteristics of the aerosol composition and optical properties, and evaluate the relationships between key aerosol and cloud properties. In terms of historical changes from the year 1870 to 2014, our results show that the global mean anthropogenic aerosol burden and optical depth increase during the simulation period as expected, but the regional averages show large differences in the temporal evolution. The largest regional differences are found in the emission-induced evolution of the burden and optical depth of the sulfate aerosol: a strong decreasing trend is seen in the Northern Hemisphere high-latitude region after around 1970, while a continued increase is simulated in the tropics. Consequently, although the global mean anthropogenic aerosol burden and optical depth increase from 1870 to 2014, the ERFaer magnitude does not increase after around year 1970. The relationships between key aerosol and cloud properties (relative changes between preindustrial and present-day conditions) also show evident changes after 1970, diverging from the linear relationships exhibited for the period from 1870 to 2014. The ERFaer in E3SMv1 is relatively large compared to the recently published multi-model estimates; the primary reason is the large indirect aerosol effect (i.e., through aerosol-cloud interactions). Compared to other models, E3SMv1 features a stronger sensitivity of the cloud droplet effective radius to changes in the cloud droplet number concentration. Large sensitivity is also seen in the liquid cloud optical depth, which is determined by changes in both the effective radius and liquid water path. Aerosol-induced changes in liquid and ice cloud properties in E3SMv1 are found to have a strong correlation, as the evolution of anthropogenic sulfate aerosols affects both the liquid cloud formation and the homogeneous ice nucleation in cirrus clouds. The ERFaer estimates in E3SMv1 for the shortwave and longwave components are sensitive to the parameterization changes in both liquid and ice cloud processes. When the parameterization of ice cloud processes is modified, the top-of-atmosphere forcing changes in the shortwave and longwave components largely offset each other, so the net effect is negligible. This suggests that, to reduce the magnitude of the net ERFaer, it would be more effective to reduce the anthropogenic aerosol effect through liquid or mixed-phase clouds.