Prominent Formation Research Articles

TLR7 gain-of-function genetic variation causes human lupus

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1–7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10–12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10–12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.

Human Organotypic Airway and Lung Organoid Cells of Bronchiolar and Alveolar Differentiation Are Permissive to Infection by Influenza and SARS-CoV-2 Respiratory Virus.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has led to the initiation of unprecedented research efforts to understand the pathogenesis mediated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More knowledge is needed regarding the cell type-specific cytopathology and its impact on cellular tropism. Furthermore, the impact of novel SARS-CoV-2 mutations on cellular tropism, alternative routes of entry, the impact of co-infections, and virus replication kinetics along the respiratory tract remains to be explored in improved models. Most applied virology models are not well suited to address the remaining questions, as they do not recapitulate the histoarchitecture and cellular composition of human respiratory tissues. The overall aim of this work was to establish from single biopsy specimens, a human adult stem cell-derived organoid model representing the upper respiratory airways and lungs and explore the applicability of this model to study respiratory virus infection. First, we characterized the organoid model with respect to growth pattern and histoarchitecture, cellular composition, and functional characteristics. Next, in situ expression of viral entry receptors, including influenza virus-relevant sialic acids and SARS-CoV-2 entry receptor ACE2 and TMPRSS2, were confirmed in organoids of bronchiolar and alveolar differentiation. We further showed successful infection by pseudotype influenza A H7N1 and H5N1 virus, and the ability of the model to support viral replication of influenza A H7N1 virus. Finally, successful infection and replication of a clinical isolate of SARS-CoV-2 were confirmed in the organoids by TCID50 assay and immunostaining to detect intracellular SARS-CoV-2 specific nucleocapsid and dsRNA. The prominent syncytia formation in organoid tissues following SARS-CoV-2 infection mimics the findings from infected human tissues in situ. We conclude that the human organotypic model described here may be particularly useful for virology studies to evaluate regional differences in the host response to infection. The model contains the various cell types along the respiratory tract, expresses respiratory virus entry factors, and supports successful infection and replication of influenza virus and SARS-CoV-2. Thus, the model may serve as a relevant and reliable tool in virology and aid in pandemic preparedness, and efficient evaluation of antiviral strategies.

Interactions between fine particles and heavy crude oil: an experimental study using thermo-gravimetric and rheological analyses

The dissolution of fine particles into flowing and stranded fluids is not only one of the most prominent formation damage problems but also, is prejudicial to economic viability of oil-bearing matrices. To this end, the present paper investigates the effect of fine particles dissolution on rheological properties of heavy crude oil (API 16.6°). Because of the siliceous nature of the candidate formation, fine particles were modeled by nanoparticles. Considerations were given to silica oxide (Si-NP), alumina oxide (Al-NP) and iron oxide (Fe- NP). NPs were mixed into the dead heavy oil. Both thermogravimetric and rheological studies were used to evaluate the effect of fine migration on crude oil properties. The former revealed that the dissolution of Si-NP has the most prominent effect on physical properties compared to Al-NP and Fe-NP. The dissolution of Si-NP increased the oil viscosity up to 26 cP which was 22% larger than the oil without Si-NP. Increasing the load in Si-NP enhanced the stripping of the heaviest fractions of the crude oil (asphaltenes) from the bulk. The study attributed these results to the decrease in activation energy. The findings of this study can help for better understanding of crude oil upgrading using NP dissolution.

Shear wave velocities of prominent geologic formations in the Nelson-Tasman region

This paper presents the development of representative shear wave velocity profiles for the prominent geologic formations in the Nelson-Tasman region of New Zealand. Shear wave velocity (VS) profiles to depths of up to 100 m were developed at over 50 sites using a combination of active source and passive source surface wave testing. Using this data and regional geologic information, VS-depth functions were developed for six of the prominent geologic formations. Comparison with existing VS-depth functions from New Zealand and international studies highlighted the significantly higher shear wave velocities of the deposits in this region. VS exceeded 750 m/s for the Moutere Gravels and Port Hills Gravels at relatively shallow depths, representative of rock deposits. However, while the Port Hills Gravels transition to a conglomerate rock below depths of 30 m or less, the Moutere Gravel formation is an uncemented clay-bound gravel. The young gravel and sand deposits have VS higher than those from other regions. As the region is thought to have undergone cycles of geologic uplift, the resulting over-consolidation of these deposits could explain the high VS. Horizontal-to-vertical spectral ratio testing was not able to characterise the fundamental site period across the region, likely due to the weak impedance contrast that would exist at the gravel-rock interface at depth. These outcomes highlight the importance of regional geotechnical and geophysical characterisation to constrain the salient features that control potential seismic site amplification and site classification.

Plasmoid-fed Prominence Formation (PF2) During Flux Rope Eruption

Abstract We report a new, plasmoid-fed scenario for the formation of an eruptive prominence (PF2), involving reconnection and condensation. We use grid-adaptive resistive two-and-a-half-dimensional magnetohydrodynamic simulations in a chromosphere-to-corona setup to resolve this plasmoid-fed scenario. We study a preexisting flux rope (FR) in the low corona that suddenly erupts due to catastrophe, which also drives a fast shock above the erupting FR. A current sheet (CS) forms underneath the erupting FR, with chromospheric matter squeezed into it. The plasmoid instability occurs and multiple magnetic islands appear in the CS once the Lundquist number reaches ∼3.5 × 104. The remnant chromospheric matter in the CS is then transferred to the FR by these newly formed magnetic islands. The dense and cool mass transported by the islands accumulates in the bottom of the FR, thereby forming a prominence during the eruption phase. More coronal plasma continuously condenses into the prominence due to the thermal instability as the FR rises. Due to the fine structure brought in by the PF2 process, the model naturally forms filament threads, aligned above the polarity inversion line. Synthetic views at our resolution of 15 km show many details that may be verified in future high-resolution observations.

The role of asymmetries in coronal rain formation during thermal non-equilibrium cycles

Context. Thermal non-equilibrium (TNE) produces several observables that can be used to constrain the spatial and temporal distribution of solar coronal heating. Its manifestations include prominence formation, coronal rain, and long-period intensity pulsations in coronal loops. The recent observation of abundant periodic coronal rain associated with intensity pulsations allowed for these two phenomena to be unified as the result of TNE condensation and evaporation cycles. On the other hand, many observed intensity pulsation events show little to no coronal rain formation. Aims. Our goal is to understand why some TNE cycles produce such abundant coronal rain, while others produce little to no rain. Methods. We reconstructed the geometry of the periodic coronal rain event, using images from the Extreme Ultraviolet Imager (EUVI) onboard the Solar Terrestrial Relations Observatory (STEREO), and magnetograms from the Helioseismic and Magnetic Imager (HMI). We then performed 1D hydrodynamic simulations of this event for different heating parameters and variations of the loop geometry (9000 simulations in total). We compared the resulting behaviour to simulations of TNE cycles that do not produce coronal rain. Results. Our simulations show that both prominences and TNE cycles (with and without coronal rain) can form within the same magnetic structure. We show that the formation of coronal rain during TNE cycles depends on the asymmetry of the loop and of the heating. Asymmetric loops are overall less likely to produce coronal rain, regardless of the heating. In symmetric loops, coronal rain forms when the heating is also symmetric. In asymmetric loops, rain forms only when the heating compensates for the asymmetry.

Numerical study on effect of brash ice on water exit dynamics of ventilated cavitation cylinder

This study numerically examines the evolution of cavitation, trajectory, and impact load during the process of water exit of a submerged and ventilated cavitation cylinder in a brash ice zone by coupling the computational fluid dynamics (CFD) method with the discrete element method (DEM). A two-way coupling scheme is used to study the influence on the fluid due to the brash ice. The ice conditions off Wilkes Land in the Antarctic marginal ice zone in late winter were used to formulate a DEM particle model without failure limitation. The brash ice zone was established according to random positions of the ice generated by self-programming. The CFD-DEM coupling method was verified through comparisons with both experimental results and empirical formulae in the literature. The results show that the cavity quickly broke while crossing the water surface, and a prominent formation of spikes was observed in brash ice conditions. The displacement and deflection angle of the cylinder had different features in the two directions perpendicular to the axis. Furthermore, strong alternating loads were observed when the water surface was crossed in comparison with those in ice-free conditions.

The voluminous 2.81–2.71 Ga Goldfields Tholeiitic Super Event: Implications for basin architecture in the Yilgarn Craton and global correlations

The time-interval between 2.8 and 2.7 Ga is associated with the worldwide appearance of thick tholeiite-komatiite successions. However, their origin and affiliation, if any, is poorly understood. The Eastern Goldfields Superterrane of the Yilgarn Craton, Western Australia, is dominated by the 2.7 Ga Kalgoorlie and Kurnalpi terranes, both of which consist of well-preserved mafic-ultramafic volcano-stratigraphy. On a local scale, these supracrustal sequences permit reconstruction of volcano-sedimentary environments, which provides important constraints to the local conditions of magmatism and/or deposition. Regionally, these observations can be used to test correlations between greenstone belts, constrain basin architecture and the extent of volcanism. Studies of this nature provide important insights to global, Archean volcano-sedimentary processes.Here we present an integrated field, geochemical and U-Pb geochronological study from the well-preserved West Laverton Greenstone Belt in the Kurnalpi Terrane and compare it to the relatively well constrained Kalgoorlie Terrane. The sequence comprises three volcanic ‘events’ consisting dominantly of low-Th tholeiitic basalt and komatiite derived from depleted mantle sources. Magmatism commenced after 2854 ± 4 Ma and ceased by 2717 ± 4 Ma. Prominent banded iron formations separate volcanic cycles, indicating an overall quiescent subaqueous setting.The West Laverton Sequence is correlated with volcanic events in the neighbouring Kalgoorlie Terrane, where pre-existing basement with remarkably similar character is documented near Norseman, over 360 km away. Both terranes contain basal paragneiss (2.96–2.93 Ga) and epiclastic sediments (∼2.93–2.85 Ga) that are overlain by three variably preserved and widespread tholeiite-dominated volcanic events, here defined as the 2.81–2.71 Ga ‘Goldfields Tholeiitic Super Event’. These correlations support an autochthonous setting for the Kalgoorlie and Kurnalpi terranes with the eruption of volcanic tholeiites onto submerged continental crust.Voluminous tholeiitic volcanism at 2.8–2.7 Ga was a global event. The Zimbabwe and Slave cratons preserve remarkably similar basement overlain by thick basaltic units, that are compositionally similar to the ‘Goldfields Tholeiitic Super Event’. This correlation indicates that a globally significant rifting event at 2.8–2.7 Ga affected much of the continental crust extant.

Sustainable phosphorus management in soil using bone apatite

Soil fertility and phosphorus management by bone apatite amendment are receiving increasing attention, yet further research is needed to integrate the physicochemical and mineralogical transformation of bone apatite and their impact on the supply and storage of phosphorus in soil. This study has examined bone transformation in the field over a span of 10-years using a set of synchrotron-based microscopic and spectroscopic techniques. Transmission X-ray microscopy (TXM) observations reveal the in-situ deterioration of bone osteocyte-canaliculi system and sub-micron microbial tunneling within a year. Extensive organic decomposition, secondary mineral formation and re-mineralization of apatite are evident from the 3rd year. The relative ratio of (v1 + v3) PO43− to v3 CO32− and to amide I increase, and the v3c PO43− peak exhibits a blue-shift in less than 3 years. The carbonate substitution of bone hydroxyapatite (HAp) to AB-type CHAp, and phosphate crystallographic rearrangement become apparent after 10 years’ aging. The overall CO32− peak absorbance increases over time, contributing to a higher acid susceptibility in the aged bone. The X-ray Photoelectron Spectroscopy (XPS) binding energies for Ca (2p), P (2p) and O (1s) exhibit a red-shift after 1 year because of organo-mineral interplay and a blue-shift starting from the 3rd year as a result of the de-coupling of mineral and organic components. Nutrient supply to soil occurs within months via organo-mineral decoupling and demineralization. More phosphorus has been released from the bones and enriched in the associated and adjacent soils over time. Lab incubation studies reveal prominent secondary mineral formation via re-precipitation at a pH similar to that in soil, which are highly amorphous and carbonate substituted and prone to further dissolution in an acidic environment. Our high-resolution observations reveal a stage-dependent microbial decomposition, phosphorus dissolution and immobilization via secondary mineral formation over time. The active cycling of phosphorus within the bone and its interplay with adjacent soil account for a sustainable supply and storage of phosphorus nutrients.

The solar corona as an active medium for magnetoacoustic waves

The presence and interplay of continuous cooling and heating processes maintaining the corona of the Sun at the observed one million K temperature were recently understood to have crucial effects on the dynamics and stability of magnetoacoustic (MA) waves. These essentially compressive waves perturb the coronal thermal equilibrium, leading to the phenomenon of a wave-induced thermal misbalance (TM). Representing an additional natural mechanism for the exchange of energy between the plasma and the wave, TM makes the corona an active medium for MA waves, so that the wave can not only lose but also gain energy from the coronal heating source (similarly to burning gases, lasers and masers). We review recent achievements in this newly emerging research field, focussing on the effects that slow-mode MA waves experience as a back-reaction of this perturbed coronal thermal equilibrium. The new effects include enhanced frequency-dependent damping or amplification of slow waves, and effective, not associated with the coronal plasma non-uniformity, dispersion. We also discuss the possibility to probe the unknown coronal heating function by observations of slow waves and linear theory of thermal instabilities. The manifold of the new properties that slow waves acquire from a thermodynamically active nature of the solar corona indicate a clear need for accounting for the effects of combined coronal heating/cooling processes not only for traditional problems of the formation and evolution of prominences and coronal rain, but also for an adequate modelling and interpretation of magnetohydrodynamic waves.

Synchronous Schwannoma and Gastrointestinal Stromal Tumor in Small Intestine – A Rare Case

Abstract Introduction/Objective Small bowel Schwannoma is a benign neoplasm of nerve sheath cells. The Gastrointestinal stromal tumor (GIST) constitutes only about 1-2% of small bowel spindle cell tumors. The simultaneous presence of two tumors in the small bowel is extremely uncommon. Methods/Case Report We report a case of small bowel GIST co-existing with Schwannoma. A 64-year-old female with a known history of Neurofibromatosis was admitted for excision of a small bowel tumor. MRI of the abdomen revealed two enhancing lesions in the left upper quadrant adjacent to the small bowel. Differential considerations included GIST versus Neurofibroma. Left hemicolectomy with small bowel resection was performed. The proximal small bowel revealed GIST, spindle cell type, low risk (3.5 cm), low grade (<5 mitoses/ 5mm2). Tumor cells were diffusely reactive to CD34, CD117, and DOG1 immunostains and were nonreactive to S100 and SOX10 immunostains confirming the diagnosis of GIST. Another segment of the small bowel revealed a 1.5 cm well-circumscribed, predominantly spindle cell tumor with abundant myxoid stroma and prominent cyst formation. Tumor cells were diffusely reactive to S100 and SOX10 immunostains but nonreactive to CD34, CD117, and DOG1, favoring a diagnosis of Schwannoma. Gastrointestinal Schwannomas may be associated with Neurofibromatosis in some cases. GIST, a KIT- or PGDFRA-signaling driven mesenchymal tumor has also rarely been reported to be associated with Neurofibromatosis type 1. However, synchronous small bowel Schwannoma and GIST represent a rare co-existence of two different histopathologic subtypes of spindle cell tumors. Results (if a Case Study enter NA) NA Conclusion In summary, we present the rare co-existence of two different spindle cell lesions in Neurofibromatosis patient.

Magnetohydrodynamic Spectroscopy of a Non-adiabatic Solar Atmosphere

The quantification of all possible waves and instabilities in a given system is of paramount importance, and knowledge of the full magnetohydrodynamic (MHD) spectrum allows one to predict the (in)stability of a given equilibrium state. This is highly relevant in many (astro)physical disciplines, and when applied to the solar atmosphere it may yield various new insights in processes like prominence formation and coronal loop oscillations. In this work we present a detailed, high-resolution spectroscopic study of the solar atmosphere, where we use our newly developed Legolas code to calculate the full spectrum with corresponding eigenfunctions of equilibrium configurations that are based on fully realistic solar atmospheric models, including gravity, optically thin radiative losses and thermal conduction. Special attention is given to thermal instabilities, known to be responsible for the formation of prominences, together with a new outlook on the thermal and slow continua and how they behave in different chromospheric and coronal regions. We show that thermal instabilities are unavoidable in our solar atmospheric models and that there exist certain regions where both the thermal, slow and fast modes all have unstable wave mode solutions. We also encounter regions where the slow and thermal continua become purely imaginary and merge on the imaginary axis. The spectra discussed in this work illustrate clearly that thermal instabilities (both discrete and continuum modes) and magneto-thermal overstable propagating modes are ubiquitous throughout the solar atmosphere, and may well be responsible for much of the observed fine-structuring and multi-thermal dynamics.

Spikelet differentiation and degeneration in rice varieties with different panicle sizes

AbstractAn essential feature of modern high‐yielding rice varieties is the production of numerous spikelets, but the physiological mechanism underlying spikelet formation in these varieties remains unclear. In this study, we explored the characteristics of spikelet differentiation and degeneration and the relevant physiological characteristics of rice varieties with different panicle sizes. The regulatory effects of alternate wetting and moderate soil drying (AWMD) on spikelet formation were also measured. We determined that the high spikelet number per panicle and grain yields of large‐panicle rice varieties were primarily due to a higher number of differentiated and surviving secondary spikelets. Furthermore, shoot dry weight, plant nitrogen (N) uptake, plant N concentration, non‐structural carbohydrate (NSC) accumulation in stems, leaf area, and leaf photosynthetic rate from branch differentiation stage (BDS) to spikelet differentiation stage (SDS) were positively correlated with the number of differentiated secondary spikelets per panicle. Plant N concentration, NSC accumulation in stems, and leaf photosynthetic rate at pollen mother cell meiosis (PMC) were negatively correlated with the number of degenerated secondary spikelets. Finally, the number of differentiated secondary spikelets of Huaidao 5 (small panicle size) and Yongyou 2640 (large panicle size) varieties was promoted by 19.2% and 6.6%, and the number of degenerated secondary spikelets was reduced by 14.4% and 6.3%, respectively, under AWMD treatment compared to continuously flooded treatment. Prominent spikelet formation under AWMD resulted from the shoot dry weight, plant N uptake, plant N concentration, NSC accumulation in stems, leaf area, and leaf photosynthetic rate. Collectively, improvements in these key aboveground indices mentioned above during the BDS to SDS and the plant N concentration, NSC accumulation in stems, and leaf photosynthetic rate at the PMC stage would benefit spikelet formation by promoting differentiation and reducing degeneration of secondary spikelets, thereby enhancing yield of large‐panicle rice varieties.

Differences in Fracture Healing Between Female and Male C57BL/6J Mice.

BackgroundMice are increasingly used in fracture healing research because of the opportunity to use transgenic animals. While both, male and female mice are employed, there is no consensus in the literature whether fracture healing differs between both sexes. Therefore, the aim of the present study was to analyze diaphyseal fracture healing in female and male C57BL/6J mice, a commonly used mouse strain in bone research.MethodsFor that purpose, 12-week-old Female (17–20 g) and Male mice (22–26 g) received a standardized femur midshaft osteotomy stabilized by an external fixator. Mice were euthanized 10 and 21 days after fracture and bone healing was analyzed by biomechanical testing, μCT, histology, immunohistochemistry and qPCR.ResultsTen days after fracture, Male mice displayed significantly more cartilage but less fibrous tissue in the fracture callus compared to Female mice, whereas the amount of bone did not differ. At day 21, Male mice showed a significantly larger fracture callus compared to Female mice. The relative amount of bone in the fracture callus did not significantly differ between both sexes, whereas its tissue mineral density was significantly higher in Male mice on day 21, indicating more mature bone and slightly more rapid fracture healing. These results were confirmed by a significantly greater absolute bending stiffness of the fractured femurs of Male mice on day 21. On the molecular level, Male mice displayed increased active β-catenin expression in the fracture callus, whereas estrogen receptor α (ERα) expression was lower.ConclusionThese results suggest that Male mice display more rapid fracture healing with more prominent cartilaginous callus formation. This might be due to the higher weight of Male mice, resulting in increased mechanical loading of the fracture. Furthermore, Male mice displayed significantly greater activation of osteoanabolic Wnt/β-catenin signaling, which might also contribute to more rapid bone regeneration.

Slingshot Prominences, Formation, Ejection and Cycle Frequency in Cool Stars

AbstractStars lose mass and angular momentum during their lifetimes. Observations of H-alpha absorption of a number of low mass stars, show prominences transiting the stellar disc and being ejected into the extended stellar wind. Analytic modelling have shown these M-dwarf coronal structures growing to be orders of magnitude larger than their solar counterparts. This makes prominences responsible for mass and angular momentum loss comparable to that due to the stellar wind. We present results from a numerical study which used magnetohydrodynamic simulations to model the balance between gravity, magnetic confinement, and rotational acceleration. This allows us to study the time dependent nature of prominence formation. We demonstrate that a prominence, formed beyond the co-rotation radius, is ejected into the extended stellar wind in the slingshot prominence paradigm. Mass, angular momentum flux and ejection frequency have been calculated for a representative cool star, in the so-called Thermal Non-Equilibrium (TNE) regime.

Gaming the system: suboptimal compliance with loot box probability disclosure regulations in China

AbstractLoot boxes provide randomized rewards in video games; their purchase is linked to disordered gambling and they are present in approximately half of UK video games. The relative novelty of loot boxes means that regulators and policymakers in various jurisdictions are still deciding how to regulate them. The People's Republic of China (PRC) is the first, and presently only, jurisdiction to legally require companies to disclose the probabilities of obtaining randomized loot box rewards – an approach that is also favored by the industry as self-regulation. This study is the first to assess paid loot box prevalence in the PRC and companies’ discretionary interpretations of probability disclosure regulations. Loot boxes were found in 91 of the 100 highest-grossing PRC iPhone games. Of games deemed suitable for children aged 12+, 90.5% contained loot boxes. Probability disclosures could not be found for 4.4% of games containing loot boxes. Disclosures were implemented through various methods both in-game and on the games’ official websites; however, consistent with the concept of ‘sludge,’ only 5.5% used the most prominent format of automatically displaying the probabilities on the in-game loot box purchase page. Loot box probability disclosures should be uniform and visually prominent to best help inform consumers.

Challenging Disease Ontology by Instances of Atypical PKHD1 and PKD1 Genetics.

BackgroundAutosomal polycystic kidney disease is distinguished into dominant (ADPKD) and recessive (ARPKD) inheritance usually caused by either monoallelic (PKD1/PKD2) or biallelic (PKHD1) germline variation. Clinical presentations are genotype-dependent ranging from fetal demise to mild chronic kidney disease (CKD) in adults. Additionally, exemptions from dominant and recessive inheritance have been reported in both disorders resulting in respective phenocopies. Here, we comparatively report three young adults with microcystic-hyperechogenic kidney morphology based on unexpected genetic alterations beyond typical inheritance.MethodsNext-generation sequencing (NGS)-based gene panel analysis and multiplex ligation-dependent probe amplification (MLPA) of PKD-associated genes, familial segregation analysis, and reverse phenotyping.ResultsThree unrelated individuals presented in late adolescence for differential diagnosis of incidental microcystic-hyperechogenic kidneys with preserved kidney and liver function. Upon genetic analysis, we identified a homozygous hypomorphic PKHD1 missense variant causing pseudodominant inheritance in a family, a large monoallelic PKDH1-deletion with atypical transmission, and biallelic PKD1 missense hypomorphs with recessive inheritance.ConclusionBy this report, we illustrate clinical presentations associated with atypical PKD-gene alterations beyond traditional modes of inheritance. Large monoallelic PKHD1-alterations as well as biallelic hypomorphs of both PKD1 and PKHD1 may lead to mild CKD in the absence of prominent macrocyst formation and functional liver impairment. The long-term renal prognosis throughout life, however, remains undetermined. Increased detection of atypical inheritance challenges our current thinking of disease ontology not only in PKD but also in Mendelian disorders in general.

Mixed Properties of Slow Magnetoacoustic and Entropy Waves in a Plasma with Heating/Cooling Misbalance

The processes of coronal plasma heating and cooling were previously shown to significantly affect the dynamics of slow magnetoacoustic (MA) waves, causing amplification or attenuation, and also dispersion. However, the entropy mode is also excited in such a thermodynamically active plasma and is affected by the heating/cooling misbalance too. This mode is usually associated with the phenomenon of coronal rain and formation of prominences. Unlike adiabatic plasmas, the properties and evolution of slow MA and entropy waves in continuously heated and cooling plasmas get mixed. Different regimes of the misbalance lead to a variety of scenarios for the initial perturbation to evolve. In order to describe properties and evolution of slow MA and entropy waves in various regimes of the misbalance, we obtained an exact analytical solution of the linear evolutionary equation. Using the characteristic timescales and the obtained exact solution, we identified regimes with qualitatively different behaviour of slow MA and entropy modes. For some of those regimes, the spatio-temporal evolution of the initial Gaussian pulse is shown. In particular, it is shown that slow MA modes may have a range of non-propagating harmonics. In this regime, perturbations caused by slow MA and entropy modes in a low- $\beta $ plasma would look identical in observations, as non-propagating disturbances of the plasma density (and temperature) either growing or decaying with time. We also showed that the partition of the initial energy between slow MA and entropy modes depends on the properties of the heating and cooling processes involved. The exact analytical solution obtained could be further applied to the interpretation of observations and results of numerical modelling of slow MA waves in the corona and the formation and evolution of coronal rain.

Therapeutic potential of mesenchymal stem cells for peripheral artery disease in a rat model of hindlimb ischemia.

Objective(s):Mesenchymal stem cells are viewed as the first choice in regenerative medicine. This study aimed to elucidate the influence of BM-MSCs transplantation on angiogenesis in a rat model of unilateral peripheral vascular disease. Materials and Methods:Twenty-one rats were arbitrarily allocated into three groups (7/group). Group I: control sham-operated rats, Group II: control ischemic group: Rats were subjected to unilateral surgical ligation of the femoral artery, and Group III: ischemia group: Rats were induced as in group II, 24 hr after ligation, they were intramuscularly injected with BM-MSCs. After scarification, gastrocnemius muscle gene expression of stromal cell-derived factor-1 (SDF-1), CXC chemokine receptor 4 (CXCR4), vascular endothelial growth factor receptor 2 (VEGFR2), von Willebrand factor (vWF), and hypoxia-inducible factor-1α (HIF-1α) were analyzed by quantitative real-time PCR. Muscle regeneration and angiogenesis evaluation was assessed through H&E staining of the tissue. Furthermore, Pax3 and Pax7 nuclear expression was immunohistochemically assessed. Results:Rats treated with BM-MSCs showed significantly raised gene expression levels of SDF-1, CXCR4, VEGFR2, and vWF compared with control and ischemia groups. H&E staining of the gastrocnemius showed prominent new vessel formation. Granulation tissue within muscles of the ischemic treated group by BM-MSCs showed cells demonstrating nuclear expression of Pax3 and Pax7. Conclusion:BM-MSCs transplantation has an ameliorating effect on muscle ischemia through promoting angiogenesis, detected by normal muscle architecture restoration and new blood vessel formations observed by H&E, confirmed by increased gene expression levels of SDF-1, CXCR4, VEGFR2, and vWF, decreased HIF-1α gene expression, and increased myogenic Pax7 gene expression.

3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway

Exposure to environmental and occupational contaminants leads to lung cancer. 3-Nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one, 3-NBA) is a potential carcinogen in ambient air or diesel particulate matter. Studies have revealed that short-term exposure to 3-NBA induces cell death, reactive oxygen species activation, and DNA adduct formation and damage. However, details of the mechanism by which chronic exposure to 3-NBA influences lung carcinogenesis remain largely unknown. In this study, human lung epithelial BEAS-2B cells were continuously exposed to 0-10-μM 3-NBA for 6 months. NanoString analysis was conducted to evaluate gene expression in the cells, revealing that 3-NBA-mediated transformation results in a distinct gene expression signature including carbon cancer metabolism, metastasis, and angiogenesis. Alterations in tumor-promoting genes such as EREG (epiregulin), SOX9, E-cadherin, TWIST, and IL-6 were involved in epithelial cell aggressiveness. Kaplan-Meier plotter analyses indicated that increased EREG and IL-6 expressions in early-stage lung cancer cells are correlated with poor survival. In vivo xenografts on 3-NBA-transformed cells exhibited prominent tumor formation and metastasis. EREG knockout cells exposed to 3-NBA for a short period exhibited high apoptosis and low colony formation. By contrast, overexpression of EREG in 3-NBA-transformed cells markedly activated the PI3K/AKT and MEK/ERK signaling pathways, resulting in tumorigenicity. Furthermore, elevated IL-6 and EREG expressions synergistically led to STAT3 signaling activation, resulting in clonogenic cell survival and migration. Taken together, chronic exposure of human lung epithelial cells to 3-NBA leads to malignant transformation, in which the EREG signaling pathway plays a pivotal mediating role. • Short-term exposure of lung epithelial cells to 3-NBA can lead to ROS production and cell apoptosis. • Long-term chronic exposure to 3-NBA upregulates the levels of tumor-promoting genes such as EREG and IL-6. • Increased EREG expression in 3-NBA-transformed cells markedly contributes to tumorigenesis through PI3K/AKT and MEK/ERK activation and synergistically enhances the IL-6/STAT3 signaling pathway, which promotes tumorigenicity.