bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hedgehog pathway inhibitors significantly reduce the formation of heterotopic ossification in a direct trauma/burn mouse model
Authors: Chakraborty Atanu , Gvozdenovic-Jeremic Jelena , Wang Fang , Hoag Stephen W. , Vert-Wong Ekaterina , Pearson Ryan M. 
Published: February 2021

AbstractHeterotopic ossification (HO), either acquired or hereditary, is featured by ectopic bone formation outside of the normal skeleton. The acquired form of HO is a debilitating and common complication of musculoskeletal trauma, central nervous system injury, burns, combat trauma, hip and elbow fractures, and total joint replacement surgeries. It can be characterized as abnormal bone formation that occurs mostly by endochondral ossification. Recent studies have implicated inflammation and dysregulation of Hedgehog (Hh) signaling as major early contributors to HO formation. Here, we demonstrate that administration of the Hh pathway inhibitor, arsenic trioxide (ATO), prevented acquired HO in a clinically-relevant trauma/burn mouse model. We further evaluated the effects of two additional Hh pathway antagonists: cholecalciferol and pravastatin on mitigating osteoblast differentiation. Finally, we assessed the effect of a combination of Hh pathway inhibitors on reducing systemic proinflammatory responses. A targeted combination approach using Hh pathway inhibitors may offer potential therapeutic benefits though targeting differential components of the Hh pathway. Taken together, our study demonstrates that the administration of single or multiple Hh pathway inhibitors may have the potential to reduce the formation of acquired HO.
The Prognostic Value of Tumor-Infiltrating Immune Cells in Gynecologic Cancers
Authors: Chen Waichung , Hu Tuo , He Chunbo 
Published: February 2021

AbstractImmunotherapy has changed the standard of treatment for many cancers. However, only a small number of gynecologic cancer patients benefit from immunotherapy. The intra-tumoral immune landscapes are suggested as a predictor of the response to immunotherapies, but there are no studies that provide a comprehensive immune characterization for gynecologic cancers. To characterize cellular compositions of the immune infiltrates and investigate if the immune landscape is a predictor for patient prognosis in gynecologic cancers, we analyzed tumor immune infiltrates of ovarian cancer, cervical cancer, and uterine cancer from The Cancer Genome Atlas Program (TCGA) using QuanTIseq and EPIC. Ovarian cancer had the highest percentage of total immune cells. Cervical cancer and uterine corpus endometrial carcinoma have lower percentages of immune cells with 17% and 16%, respectively. Furthermore, ovarian cancer had a significantly higher monocyte and M2-liked macrophage percentage, but a lower percentage for CD8 T cells and neutrophils compared to cervical cancer and uterine cancer. Cervical cancer had the highest percentage for M1-liked macrophages and the lowest for CD4 T cells. Uterine cancer had the highest percentage of dendritic cells. In cervical cancer, higher cell infiltration of CD8 T-Cells and M2-liked macrophages was associated with a better prognosis. In uterine cancer, patients with a higher number of dendritic cells and CD8 T-Cells had significantly better clinical outcomes. However, higher CD4 T-cell infiltration was associated with a poor prognosis in uterine cancer. Interestingly, the patient survival was not affected by the infiltration of any individual immune cells which we analyzed in ovarian cancer. We identified and validated four immune subtypes associated with distinct immune cell infiltration in gynecologic cancers. Cervical and uterine cancer patients from an immune-desert subtype that had the least amount of lymphocyte infiltration and a high level of monocyte had the worst prognosis. By contrast, cervical and uterine cancer patients from an immune-warm subtype that had higher infiltration of CD8 T-cell, natural killer (NK) cells, and dendritic cells (DCs) had the best prognosis. However, the survival rate of ovarian cancer patients is similar among the four different subtypes. Our study provides a conceptual framework to understand the tumor immune microenvironment of different gynecologic cancers.
Effect of Silicon Application on Leaf mineral Composition of Eucalyptus
Authors: Kumar Rahul , Reddy Dilip Kumar , Kaushik Prashant 
Published: February 2021

AbstractEucalyptus is a commonly planted tree in North India and its cultivation area is increasing. Leaves of Eucalyptus are used for tea which has healing properties and many other economic uses. Silicon is the second most abundant element in the earth’s crust next to oxygen. Silicon (Si) can improve photosynthesis, decrease transpiration, increase water use efficiency and provide resistance against biotic and abiotic stress. The clear information was not available regarding Silicon nourishment in tree species like Eucalyptus. Although a positive in plant development and overall dry matter production was noticed in Eucalyptus with Si application. The amount of nitrogen (N), phosphorus (P), and potassium (K) were inclined leaf whereas Calcium (Ca) and magnesium (Mg) content was not affected by Si application potassium silicate (K2SiO3). Finally results revealed that upon Si application significant increase in the leaf mineral content in almost all genotypes was recorded. Correlation studies revealed that leaf N and P were highly and significantly correlated with leaf copper (Cu) and iron (Fe) content, leaf Mg and leaf Cu were positively and significantly correlated with leaf N, manganese (Mn) and Fe content, leaf Mn and Fe content were highly and significantly correlated with leaf N, Mg and Cu content. To our detailed knowledge this is the first ever study conducted in Eucalyptus. Here the influence of potassium silicate on popular North Indian cultivars’ leaf mineral content Nevertheless, more studies are required to analyze the effect of Si application in tree species like Eucalyptus.
Outer Hair Cell Function is Normal in βV Spectrin Knockout Mice
Authors: Stankewich Michael C. , Bai Jun-Ping , Stabach Paul R. , Khan Saaim , Tan Winston J.T. , Surguchev Alexei , Song Lei , Morrow Jon S. , Santos-Sacchi Joseph , Navaratnam Dhasakumar S. 
Published: February 2021

ABSTRACTReports have proposed a putative role for βV spectrin in outer hair cells (OHCs) of the cochlea. In an ongoing investigation of the role of the cytoskeleton in electromotility, we tested mice with a targeted exon deletion of βV spectrin (Spnb5), and unexpectedly find that Spnb5(-/-)animals’ auditory thresholds are unaffected. Similarly, these mice have normal OHC electromechanical activity (otoacoustic emissions) and non-linear capacitance. In contrast, magnitudes of auditory brainstem response (ABR) wave 1-amplitudes are significantly reduced. Evidence of a synaptopathy was absent with normal hair cell CtBP2 counts. In Spnb5(-/-)mice, the number of afferent and efferent nerve fibers is decreased. Consistent with this data, Spnb5 mRNA is present in Type I and II spiral ganglion neurons, but undetectable in OHCs. Together, these data establish that βV spectrin is important for hearing, affecting neuronal structure and function. Significantly, these data exclude βV spectrin as functionally important to OHCs as has been previously suggested.
A Reproducibility Analysis-based Statistical Framework for Residue-Residue Evolutionary Coupling Detection
Authors: Si Yunda , Zhang Yi , Yan Chengfei 
Published: February 2021

AbstractDirect coupling analysis (DCA) has been widely used to infer evolutionary coupled residue pairs from the multiple sequence alignment (MSA) of homologous sequences. However, effectively selecting residue pairs with significant evolutionary couplings according to the result of DCA is a non-trivial task. In this study, we developed a general statistical framework for significant evolutionary coupling detection, referred to as IDR-DCA, which is based on reproducibility analysis of the coupling scores obtained from DCA on manually created MSA replicates. IDR-DCA was applied to select residue pairs for contact prediction for monomeric proteins, protein-protein interactions and monomeric RNAs, in which three different versions of DCA were applied. We demonstrated that with the application of IDR-DCA, the residue pairs selected using a universal threshold always yielded stable performance for contact prediction. Comparing with the application of carefully tuned coupling score cutoffs, IDR-DCA always showed better performance. The robustness of IDR-DCA was also supported through the MSA down-sampling analysis. We further demonstrated the effectiveness of applying constraints obtained from residue pairs selected by IDR-DCA to assist RNA secondary structure prediction.
LncRNA XIST knockdown suppresses cell proliferation and promotes apoptosis in diabetic cataract via miR-34a/SMAD2 axis
Authors: Wang Chao , Zhao Ruiling , Zhang Suhong 
Published: February 2021

AbstractEmerging evidence has manifested that long non-coding RNAs (lncRNAs) played critical roles in diabetes. The present research aimed to investigate the role and mechanism of XIST on proliferation, migration and apoptosis in diabetic cataract (DC). In the present study, lens epithelial cells (SRA01/04) were treated by high glucose (HG). The levels of XIST, miR-34a and SMAD2 were examined by RT-qPCR. MTT, transwell, wound healing and TUNEL assays were employed to examine cell proliferation, invasion, migration and apoptosis. The interaction between miR-34a and XIST or SMAD2 was verified by luciferase reporter assay. It was found that XIST expression was increased and miR-34a level was decreased in DC tissues and HG-induced SRA01/04 cells. XIST knockdown or miR-34a addition attenuated cell proliferation and migration, and induced apoptosis in SRA01/04 cells under HG. XIST targeted miR-34a and regulated DC progression via miR-34a. SMAD2 was a target gene of miR-34a and was positively modulated by XIST. SMAD2 addition accelerated cell proliferation, migration and inhibited the apoptosis in HG-stimulated SRA01/04 cells, which were abrogated by XIST depletion. In conclusion, XIST facilitated the proliferation, migration and invasion, and inhibited the apoptosis via miR-34a/SMAD2 axis in DC.
Nelfinavir markedly improves lung pathology in SARS-CoV-2-infected Syrian hamsters despite lack of an antiviral effect
Authors: Foo Caroline S. , Abdelnabi Rana , Kaptein Suzanne J. F. , Zhang Xin , ter Horst Sebastiaan , Mols Raf , Delang Leen , Rocha-Pereira Joana , Coelmont Lotte , Leyssen Pieter , Dallmeier Kai , Vergote Valentijn , Heylen Elisabeth , Vangeel Laura , Chatterjee Arnab K. , Annaert Pieter , Augustijns Patrick , De Jonghe Steven , Jochmans Dirk , Weynand Birgit , Neyts Johan 
Published: February 2021

AbstractIn response to the ongoing COVID-19 pandemic, repurposing of drugs for the treatment of SARS-CoV-2 infections is being explored. The HIV protease inhibitor Nelfinavir, widely prescribed in combination with other HIV inhibitors, has been shown to inhibitin vitroSARS-CoV-2 replication. We here report on the effect of Nelfinavir in the Syrian hamster SARS-CoV-2 infection model. Although treatment of infected hamsters with either 15 or 50 mg/kg BID Nelfinavir [for four consecutive days, initiated on the day of infection] does not reduce viral RNA loads nor infectious virus titres in the lungs compared to the vehicle control, the drug reduced virus-induced lung pathology to nearly the baseline scores of healthy animals. A substantial interstitial infiltration of neutrophils is observed in the lungs of treated (both infected and uninfected) animals. The protective effect of Nelfinavir on SARS-CoV-2-induced lung pathology (at doses that are well tolerated and that result in exposures nearing those observed in HIV-infected patients) may lay the foundation for clinical studies with this widely used drug.
Sequential delivery of LAIV and SARS-CoV-2 in the ferret model can reduce SARS-CoV-2 shedding and does not result in enhanced lung pathology
Authors: Ryan Kathryn A. , Schewe Katarzyna E. , Crowe Jonathan , Fotheringham Susan A. , Hall Yper , Humphreys Richard , Marriott Anthony C. , Paterson Jemma , Rayner Emma , Salguero Francisco J. , Watson Robert J. , Whittaker Catherine J. , Carroll Miles W. , Dibben Oliver 
Published: February 2021

AbstractCo-circulation of SARS-CoV-2 and influenza viruses could pose unpredictable risks to health systems globally, with recent studies suggesting more severe disease outcomes in co-infected patients. The lack of a readily available COVID-19 vaccine has reinforced the importance of influenza vaccine programmes during the COVID-19 pandemic. Live Attenuated Influenza Vaccine (LAIV) is an important tool in protecting against influenza, particularly in children. However, it is unknown whether LAIV administration might influence the outcomes of acute SARS-CoV-2 infection or disease. To investigate this, quadrivalent LAIV (QLAIV) was administered to ferrets 3 days pre- or post-SARS-CoV-2 infection. LAIV administration did not exacerbate SARS-CoV-2 disease course or lung pathology with either regimen. Additionally, LAIV administered prior to SARS-CoV-2 infection significantly reduced SARS-CoV-2 replication and shedding in the upper respiratory tract (URT). We conclude that LAIV administration in close proximity to SARS-CoV-2 infection does not exacerbate mild disease and can reduce SARS-CoV-2 shedding.
Synapomorphic variations in the THAP domains of the human THAP protein family and its homologs
Authors: Sanghavi Hiral M. , Majumdar Sharmistha 
Published: February 2021

AbstractThe THAP (Thanatos-associatedprotein) domain is a DNA-binding domain which binds DNA via a zinc coordinating C2CH motif. Although THAP domains share a conserved structural fold, they bind different DNA sequences in different THAP proteins which in turn perform distinct cellular functions. In this study, we investigate (using multiple sequence alignment,in silicomotif and secondary structure prediction) THAP domain conservation within the homologs of the human THAP (hTHAP) protein family. We report that there is significant variation in sequence and predicted secondary structure elements across hTHAP homologs. Interestingly, we report that the THAP domain can be either longer or shorter than the conventional 90 residues and the amino terminal C2CH motif within the THAP domain serves as a hotspot for insertion or deletion. Our results lay the foundation for future studies which will further our understanding of the evolution of THAP domain and regulation of its function.
MDA5 autoimmune disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
Authors: Yu Qin , del Valle Alba Herrero , Singh Rahul , Modis Yorgo 
Published: February 2021

AbstractOur innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoimmune disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more tightly to synthetic Alu:Alu dsRNA. CryoEM structures MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 side-chain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle-RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via a novel allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides new insights on how MDA5 recognizes dsRNA in health and disease.
Long noncoding RNAVENTHEARTis required for cardiomyocyte specification and function
Authors: Dashi Albert , Tan Wilson L.W. , Anene-Nzelu Chukwuemeka George , Pan Bangfen , Ilmari Autio Matias , Tiang Zenia , Hartman Robin J.G. , Stenzig Justus , Wei Heming , Bin Chen Gao , Ackers-Johnson Matthew Andrew , Lim Bing , Walentinsson Anna , Iyer Vidhya Vardharajan , Jonsson Malin K.B. , Foo Roger S. 
Published: February 2021

ABSTRACTRationaleLong noncoding RNAs (lncRNAs) control cardiac gene expression during heart development and disease. It is accordingly plausible for the same lncRNA to regulate both cardiac development, as well as play a role in adult heart disease progression. lncRNA regulators of early cardiomyocyte (CM) lineage commitment have been identified and characterised, however those controlling later CM specification remain unknown.ObjectivesIn this study we identified a novel lncRNA required for CM specification, maturation and function, and also discovered its suggested relevance to heart disease.Methods and ResultsWe performed single cell RNA-seq on human embryonic stem cell derived cardiomyocytes at 2, 6 and 12 weeks of differentiation. Weighted correlation network analysis (WGCNA) identified core gene modules, including lncRNAs highly abundant and uniquely expressed in the human heart. A lncRNA (we callVENTHEART,VHRT) co-expressed with cardiac maturation and ventricular-specific genesMYL2andMYH7, as well as in adult human ventricular tissue. CRISPR-mediated excision ofVHRTled to impaired CM sarcomere formation, and loss of the CM specification gene program.VHRTknockdown (KD) in hESC-CMs confirmed its regulatory role for key cardiac contraction, calcium hemostasis and heart development genes, includingMYH6andRYR2. Functional evaluation afterVHRTKD using impedance-based technology and action potential recordings, proved reduced contraction amplitude and loss of the ventricular-like action potential in CM, respectively. Through an integrative analysis of genome-wide association studies (GWAS), expression quantitative trait locus (eQTL) and gene co-expression network, we foundVHRTto be co-regulated with core cardiac contractile genes, and the likely source of a heart failure genetic association signal overlapping theVHRTgene locus. Finally,VHRTKD and human failing heart transcriptome comparison validates the consistent downregulation again of cardiac contractile and calcium regulatory genes (P<0.05).ConclusionWe conclude thatVHRTlncRNA is required for proper CM specification and function. Furthermore, reducedVHRTmay contribute to the development or progression of human heart disease.
Evidence for efficient non-evaporative leaf-to-air heat dissipation in a pine forest under drought conditions
Authors: Muller Jonathan D. , Rotenberg Eyal , Tatarinov Fyodor , Oz Itay , Yakir Dan 
Published: February 2021

AbstractDrier climates predicted for many regions can result in reduced evaporative cooling leading to leaf heat stress and enhanced mortality. To what extent non-evaporative cooling can contribute to plant resilience to the increasingly stressful conditions is poorly known at present.Using a novel, high accuracy infrared system for continuous measurements of leaf temperature in mature trees under field conditions, we assessed leaf-to-air temperature differences ΔTleaf−airof pine needles during drought.On mid-summer days, ΔTleaf−airremained <1.5 °C, both in trees exposed to summer drought, and in those provided with a supplement irrigation having a 10× higher transpiration rate. The non-evaporative cooling in the drought-exposed trees must be facilitated by low resistance to heat transfer generating largeH. ΔTleaf−airwas weakly related to variations in the radiation load and mean wind speed in the lower part of the canopy, but highly dependent on canopy structure and within-canopy turbulence that enhanced the sensible heat fluxH.Non-evaporative cooling is demonstrated as an effective cooling mechanism in needle-leaf trees, which can be a critical factor in forest resistance to drying climates. The generation of a largeHat the leaf scale provides a basis for the development of the previously identified canopy-scale ‘convector effect’.
Host PDZ-containing proteins targeted by SARS-Cov-2
Authors: Caillet-Saguy Célia , Durbesson Fabien , Rezelj Veronica V. , Gogl Gergö , Tran Quang Dinh , Twizere Jean-Claude , Vignuzzi Marco , Vincentelli Renaud , Wolff Nicolas 
Published: February 2021

AbstractSmall linear motif targeting protein interacting domains called PDZ have been identified at the C-terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins E, 3a, and N. Using a high-throughput approach of affinity-profiling against the full human PDZome, we identified sixteen human PDZ binders of SARS-CoV-2 proteins E, 3A and N showing significant interactions with dissociation constants values ranging from 3 μM to 82 μM. Six of them (TJP1, PTPN13, HTRA1, PARD3, MLLT4, LNX2) are also recognized by SARS-CoV while three (NHERF1, MAST2, RADIL) are specific to SARS-CoV-2 E protein. Most of these SARS-CoV-2 protein partners are involved in cellular junctions/polarity and could be also linked to evasion mechanisms of the immune responses during viral infection. Seven of the PDZ-containing proteins among binders of the SARS-CoV-2 proteins E, 3a or N affect significantly viral replication under knock-down gene expression in infected cells. This PDZ profiling identifying human proteins potentially targeted by SARS-CoV-2 can help to understand the multifactorial severity of COVID19 and to conceive effective anti-coronaviral agents for therapeutic purposes.