bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal investment evolves with larger body size and higher diversification rate in sharks and rays
Authors: Mull Christopher G , Pennell Matthew W , Yopak Kara E , Dulvy Nicholas K 
Published: January 2022

SummaryAcross 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.1,2A key question is how this reproductive diversity arose and whether reproductive diversification underlies species diversification?3–11To 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.2,12We reconstructed the sequence of reproductive mode evolution across a time-calibrated molecular phylogeny of 610 chondrichthyans.13We 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.3,4This 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.14The 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.
Genome characteristic of Bordetella parapertussis isolated from Iran
Authors: Safarchi Azadeh , Saedi Samaneh , Tay Chin Yen , Lamichhane Binit , Lotfi Masoumeh Nakhost , Shahcheraghi Fereshteh 
Published: January 2022

AbstractPertussis also known as whooping cough is a respiratory infection in humans particularly in infants and usually caused by Bordetella pertussis. However, Bordetella parapertussis can also cause a similar clinical syndrome. During 2012 to 2015, from nasal swabs sent from different provinces to the pertussis reference laboratory of Pasture Institute of Iran for pertussis confirmation, seven B. parapertussis isolates were identified by bacterial culture, biochemical tests, and the presence of IS1001 insertion in the genome by real-time PCR. Furthermore, the expression of pertactin (Prn) as one the major virulence factor for bacterial adhesion was investigated using western blot. Moreover, the genomic characteristic of one recently collected isolate, IRBP134, from a seven-month infant was investigated using Illumina NextSeq sequencing protocol. The results revealed the genome with G+C content 65% and genome size 4.7 Mbp. A total of 81 single nucleotide polymorphisms (SNPs) and 13 short insertion and deletions were found in the genome compared to the B. parapertussis 12822 as a reference genome showing ongoing evolutionary changes in our isolate. A phylogeny relationship of IRBP134 was also investigated using global B. parapertussis available genomes.
Age-Related Impairment of Innate and Adaptive Immune Responses Following Intranasal Herpes Simplex Infection
Authors: Srivastava Ruchi , Agrawal Anshu , Vahed Hawa , BenMohamed Lbachir 
Published: January 2022

ABSTRACTImmune function declines with age, leading to an increased vulnerability to respiratory viral infections. The mechanisms by which aging negatively impacts the innate and adaptive immune system leading to enhanced susceptibility to infections remain to be fully elucidated. In the present study, we used a mouse model of intranasal infection with herpes simplex virus type 1 (HSV-1), a virus that can enter the lungs through the nasal route causing pneumonia, a serious health concern in the elderly. Following intranasal inoculation of young (6 weeks), adult (36 weeks), and aged (68 weeks) with HSV-1 (KOS strain) we: (i) compared the local and systemic innate and adaptive immune response to infection; and (ii) correlated the level and type of immune response to protection against HSV-1 infection. Compared to young and adult mice, aged mice displayed: (i) increased basal level activation of epithelial cells with a decreased expression of TLR3; (ii) increased activation of dendritic cells with increased expression of MHC-1, MHC-II and CD80/86; and (iii) decreased production of type-I interferons upon stimulation; (iv) a delay in cytokines and chemokines production in the lungs; and (v) an impairment in function (CD107 and IFN-γ production) of HSV-specific CD8+T cells. These impairment in innate and adaptive immune responses in aged mice following intranasal HSV-1 inoculation was associated with symptomatic herpes infection. The findings suggest an age-related impairment of both innate and adaptive immune responses which may exacerbate herpes infection and disease in the elderly.IMPORTANCEImmune function declines with age, leading to an increased vulnerability of the elderly to respiratory viral infections. The mechanisms by which aging negatively impacts the innate and adaptive immune system leading to enhanced susceptibility to respiratory infections remain to be fully elucidated. The present study showed that, compared to young and adult mice, aged mice displayed increased basal level activation of epithelial cells with a decreased expression of TLR3 increased activation of dendritic cells associated with an impairment of HSV-specific CD8+T cell responses. These immune dysregulations were associated with to symptomatic herpes infection. The findings suggest an age-related impairment of both innate and adaptive immune responses which may exacerbate herpes infection and disease in the elderly.
Hantaan virus replication is promoted via AKT activated mitochondria OXPHOS
Authors: Dong Yuhang , Zhang Xiaoxiao , Li Mengyang , Ying Qikang , Feng Yunan , Li Zhoupeng , Wu Xingan , Wang Fang 
Published: January 2022

AbstractOxidative phosphorylation (OXPHOS) is a vital pathway provides ATP for intracellular activities. Here, we found that Hantaan virus (HTNV) exploited mitochondria OXPHOS to assist its replication in host cells and Protein Kinase B/AKT played a major function in this process. Inhibiting AKT activation by BEZ treatment can inhibit HTNV replication and prevent the increase of OXPHOS level caused by HTNV infection. We also found that HTNV infection can promote AKT translocation to mitochondria, where AKT phosphorylates Polynucleotide phosphorylase (PNPT). Taken together, our research demonstrates that HTNV replication exploits OXPHOS in host cells and it increases OXPHOS function by AKT-PNPT interaction in mitochondria.IMPORTANCEVirus depends on metabolic pathways in host cells to favor its replication. This is a vital process which needs complicated host-virus interaction and targeting this process is a new strategy for antiviral drug development. Hantaan virus (HTNV) is the major pathogen which causes Hemorrhagic Fever with Renal Syndrome (HFRS) in China. However, there are neither effective therapeutic drugs nor FDA-licensed vaccine against HFRS, a deeper understanding of HTNV infection characteristics is of great significance for global public health and safety. This research means to elucidate the major metabolic pathway exploited by HTNV during its replication in host cells and its underlying molecular mechanism, which can enrich our understanding about HTNV biological characteristics and pathogenesis, also provide a new view on anti-HTNV drug development.
Innate immune responses in patients treated with SBRT irradiation enhances prostate cancer remissions
Authors: Cheema Amrita K , Li Yaoxiang , Collins Sean , Suy Simeng , Ventimiglia Mary , Kowalczyk Keith , Hankins Ryan , Lynch John , Janowski Einsley-Marie , Grindrod Scott , Villagra Alejandro , Dritschilo Anatoly 
Published: January 2022

AbstractStereotactic body radiation therapy (SBRT) is a curative therapeutic modality employing large fractional doses of highly conformal radiation therapy for cancer treatment. To understand the mechanisms underlying clinical responses to radiation therapy, SBRT offers a unique window for high-throughput analysis of post-radiation molecular events to inform predictive biomarker discovery and strategies for multi-disciplinary therapeutics. We performed longitudinal analysis of plasma proteins and metabolites from patients treated with prostate SBRT, comparing cohorts of patients in clinical remission to cohorts experiencing PSA-determined cancer progression. We observed onset of post-SBRT DNA Damage Response (DDR), cell cycle arrest, and immune response signaling in patients within one hour of treatment and innate immune response signaling that persisted for up to three months following treatment. Furthermore, patients in remission experienced more robust immune responses and metabolite elevations consistent with a pro-inflammatory, M1-mediated innate immune activation in the short-term following SBRT, whereas patients with disease progression had less robust immune responses and M2-mediated metabolite elevations. We interpret these data to support a critical role for innate immune activation in the clinical outcomes of patients receiving radiation therapy for prostate cancer potentially improving future multidisciplinary therapeutic strategies.One Sentence SummaryFollowing SBRT, proteomic and metabolomic profiles reveal a robust immune activation that correlates with prostate cancer remission
Genome-wide Discovery for Diabetes-Dependent Triglycerides-Associated Loci
Authors: Selvaraj Margaret Sunitha , Paruchuri Kaavya , Haidermota Sara , Bernardo Rachel , Rich Stephen S. , Peloso Gina M. , Natarajan Pradeep 
Published: January 2022

AbstractWe aimed to discover loci associated with triglyceride (TG) levels in the context of type 2 diabetes (T2D). We conducted a genome-wide association study (GWAS) in 424,120 genotyped participants of the UK Biobank (UKB) with T2D status and TG levels. We stratified the cohort based on T2D status and conducted association analyses of TG levels for genetic variants with minor allele count (MAC) at least 20 in each stratum. Effect differences of genetic variants by T2D status were determined by Cochran’s Q-test and we validated the significantly associated variants in the Mass General Brigham Biobank (MGBB). Among 21,176 T2D and 402,944 non-T2D samples from UKB, stratified GWAS identified 19 and 315 genomic risk loci significantly associated with TG levels, respectively. Only chr6p21.32 exhibited genome-wide significant heterogeneity (I2=98.4%; pheterogeneity=2.1×10−15), with log(TG) effect estimates of -0.066 (95%CI: - 0.082, -0.050) and 0.002 (95%CI: -0.002, 0.006) for T2D and non-T2D, respectively. The lead variant rs9274619:A (allele frequency 0.095) is located 2Kb upstream of the HLA-DQB1 gene. We replicated this finding among 25,137 participants (6,951 T2D cases) of MGBB (pheterogeneity=9.5×10−3). Phenome-wide interaction association analyses showed that the lead variant was strongly associated with a concomitant diagnosis of type 1 diabetes (T1D) as well as diabetes-associated complications. In conclusion, we identified an intergenic variant near HLA-DQB1 significantly associates with decreased triglycerides only among those with T2D and highlights an immune overlap with T1D.
Benefits and Cost of a $35 Insulin Cost-Sharing Cap for Medicare Patients
Authors: Chua Kao-Ping , Lee Joyce M. , Tucker Joshua E. , Seo Dominique , Conti Rena M. 
Published: January 2022

ABSTRACTBACKGROUNDTo improve insulin affordability, Congress is considering capping insulin cost-sharing to $35 per 30-day supply for Medicare patients. The potential benefits and cost of this cap are unclear. Additionally, it is unknown whether the benefits of this cap would vary between Medicare patients with type 1 versus type 2 diabetes.METHODSWe conducted a cross-sectional analysis of the IQVIA Longitudinal Prescription Database, which reports prescriptions dispensed from 92% of U.S. pharmacies, and the Optum Clinformatics Data Mart, a national claims database from Medicare Advantage patients. The IQVIA analysis included patients who only had dispensed insulin prescriptions paid by Medicare in 2019. We estimated the proportion of Medicare patients who would benefit from an insulin cost-sharing cap of $35 per 30-day supply. Among these patients, we calculated the mean annual decrease in insulin out-of-pocket spending. We summed this decrease across patients to estimate the cap’s cost to the federal government. The Optum analysis included Medicare Advantage patients with diabetes and ≥1 dispensed insulin prescription in 2019. We used linear regression to compare the proportion of patients who would benefit from a $35 cap and annual savings among these patients by diabetes type, adjusting for demographic characteristics and payer type.RESULTSThe IQVIA analysis included 2,227,229 patients who only had dispensed insulin prescriptions paid by Medicare in 2019. Mean (SD) age was 69.2 (11.4) years. The $35 cap would benefit 887,051 (39.0%) of patients, lowering annual insulin out-of-pocket spending by $338, from $687 to $349. Across all patients in the sample, aggregate savings (i.e., the cap’s cost to the federal government) would be $299,402,402, or a mean of $134.4 per patient. Among the 60,300 Medicare Advantage patients in the Optum Analysis, mean age was 72.6 (9.3) years; 2,686 (4.5%) had type 1 diabetes and 57,614 (95.6%) had type 2 diabetes. The $35 cap would benefit a higher proportion of patients with type 1 diabetes (64.0%) compared with patients with type 2 diabetes (59.4%). Among patients with type 1 diabetes who would benefit from the cap, annual savings would be greater ($284) compared with their counterparts with type 2 diabetes ($231; p<.001 in adjusted analyses for all comparisons).CONCLUSIONSA $35 insulin cost-sharing cap would benefit a sizable proportion of Medicare patients using insulin and may particularly lower out-of-pocket spending for patients with type 1 diabetes. The estimated cost of this cap to the federal government would be $134.4 per Medicare patient using insulin.
DWV 3C protease uncovers the diverse catalytic triad in insect RNA viruses
Authors: Yuan Xuye , Kadowaki Tatsuhiko 
Published: January 2022

AbstractDeformed wing virus (DWV) is the most prevalent Iflavirus that is infecting honey bees worldwide. However, the mechanisms of its infection and replication in host cells are poorly understood. In this study, we analyzed the structure and function of DWV 3C protease (3Cpro), which is necessary for the cleavage of the polyprotein to synthesize mature viral proteins. We found that the 3Cpros of DWV and picornaviruses share common enzymatic properties, including sensitivity to the same inhibitors, such as rupintrivir. The predicted structure of DWV 3Cpro by AlphaFold2, the predicted rupintrivir binding domain, and the protease activities of mutant proteins revealed that it has a Cys-His-Asn catalytic triad. Moreover, 3Cpros of other Iflaviruses and Dicistrovirus appear to contain Asn, Ser, Asp, or Glu as the third residue of the catalytic triad, suggesting diversity in insect RNA viruses. Both precursor 3Cpro with RNA-dependent RNA polymerase and mature 3Cpro are present in DWV-infected cells, suggesting that they may have different enzymatic properties and functions. DWV 3Cpro is the first 3Cpro characterized among insect RNA viruses, and our study uncovered both the common and unique characteristics among 3Cpros of Picornavirales. Furthermore, the specific inhibitors of DWV 3Cpro could be used to control DWV infection in honey bees.
A Saturation-Mutagenesis Analysis of the Interplay Between Stability and Activation in Ras
Authors: Hidalgo Frank , Nocka Laura M. , Shah Neel H. , Gorday Kent , Latorraca Naomi R. , Bandaru Pradeep , Templeton Sage , Lee David , Karandur Deepti , Pelton Jeffery G. , Marqusee Susan , Wemmer David E. , Kuriyan John 
Published: January 2022

AbstractCancer mutations in Ras occur predominantly at three hotspots: Gly 12, Gly 13, and Gln 61. Previously, we reported that deep mutagenesis of H-Ras using a bacterial assay identified many other activating mutations (Bandaru et al. eLife, 2017). We now show that the results of saturation mutagenesis of H-Ras in mammalian Ba/F3 cells correlate well with results of bacterial experiments in which H-Ras or K-Ras are co-expressed with a GTPase-activating protein (GAP). The prominent cancer hotspots are not dominant in the Ba/F3 data. We used the bacterial system to mutagenize Ras constructs of different stabilities and discovered a feature that distinguishes the cancer hotspots. While mutations at the cancer hotspots activate Ras regardless of construct stability, mutations at lower-frequency sites (e.g., at Val 14 or Asp 119) can be activating or deleterious, depending on the stability of the Ras construct. We characterized the dynamics of three non-hotspot activating Ras mutants by using NMR to monitor hydrogen-deuterium exchange (HDX). These mutations result in global increases in HDX rates, consistent with the destabilization of Ras. An explanation for these observations is that mutations that destabilize Ras increase nucleotide dissociation rates, enabling activation by spontaneous nucleotide exchange. A further stability decrease can lead to insufficient levels of folded Ras – and subsequent loss of function. In contrast, the cancer hotspot mutations are mechanism-based activators of Ras that interfere directly with the action of GAPs. Our results demonstrate the importance of GAP surveillance and protein stability in determining the sensitivity of Ras to mutational activation.
Development and Validation of Fluorinated Amino Acid Parameters for use with the AMBER ff15ipq Protein Force Field
Authors: Yang Darian T. , Gronenborn Angela M. , Chong Lillian T. 
Published: January 2022

AbstractWe developed force field parameters for fluorinated aromatic amino acids enabling molecular dynamics (MD) simulations of fluorinated proteins. These parameters are tailored to the AMBER ff15ipq protein force field and enable the modeling of 4, 5, 6, and 7F-tryptophan, 3F- and 3,5F-tyrosine, and 4F- or 4-CF3-phenylalanine. The parameters include 181 unique atomic charges derived using the Implicitly Polarized Charge (IPolQ) scheme in the presence of SPC/Eb explicit water molecules and 9 unique bond, angle, or torsion terms. Our simulations of benchmark peptides and proteins maintain expected conformational propensities on the μs-timescale. In addition, we have developed an open-source Python program to calculate fluorine relaxation rates from MD simulations. The extracted relaxation rates from protein simulations are in good agreement with experimental values determined by 19F NMR. Collectively, our results illustrate the power and robustness of the IPolQ lineage of force fields for modeling structure and dynamics of fluorine containing proteins at the atomic level.
Acetyl-CoA mediated autoacetylation of fatty acid synthase in de novo lipogenesis
Authors: Miao Ting , Kim Jinoh , Kang Ping , Bai Hua 
Published: January 2022

SUMMARYDe novo lipogenesis (DNL) is a highly regulated metabolic process, which is known to be activated through transcriptional regulation of lipogenic genes, including fatty acid synthase (FASN). Unexpectedly, we find that the expression of FASN protein remains unchanged during Drosophila larval development when lipogenesis is hyperactive. Instead, acetylation modification of FASN is highly upregulated in fast-growing larvae. We further show that lysine K813 is highly acetylated in developing larvae, and its acetylation is required for upregulated FASN activity, body fat accumulation, and normal development. Intriguingly, K813 is rapidly autoacetylated by acetyl-CoA in a dosage-dependent manner, independent of known acetyltransferases. Furthermore, the autoacetylation of K813 is mediated by a conserved P-loop-like motif (N-xx-G-x-A). In summary, this work uncovers a novel role of acetyl-CoA-mediated autoacetylation of FASN in developmental lipogenesis and reveals a self-regulatory system that controls metabolic homeostasis by linking acetyl-CoA, lysine acetylation, and DNL.Graphical Abstract:Highlights:Acetylation modification of FASN, but not protein expression, positively correlates with de novo lipogenesis during Drosophila larval developmentSite-specific acetylation at K813 residue enhances FASN enzymatic activityK813 residue is autoacetylated by acetyl-CoA, independent of KATsA novel N-xx-G-x-A motif is required for autoacetylation of K813
LIX1 controls digestive mesenchyme-derived cell fate decision by regulating cristae organization in mitochondria
Authors: Guérin Amandine , Angebault Claire , Kinet Sandrina , Cazevieille Chantal , Rojo Manuel , Fauconnier Jérémy , Lacampagne Alain , Mourier Arnaud , Taylor Naomi , de Santa Barbara Pascal , Faure Sandrine 
Published: January 2022

ABSTRACTLimb Expression 1 (LIX1) is a master regulator of digestive mesenchymal progenitor and GastroIntestinal Stromal Tumor (GIST) cell proliferation by controlling the expression of the Hippo effectors YAP1/TAZ and KIT. However, the underlying mechanisms of these LIX1-mediated regulations and tumor promotion remain to be elucidated. Here, we report that LIX1 is S-palmitoylated on cysteine 84 and localized in mitochondria. LIX1 knock-down affects the mitochondrial ultrastructure, resulting in decreased respiration and mitochondrial reactive oxygen species production. This is sufficient to downregulate YAP1/TAZ and reprogram KIT-positive GIST cells towards the smooth muscle cell lineage with reduced proliferative and invasive capacities. Mechanistically, LIX1 knock-down impairs the stability of the mitochondrial proteins PHB2 and OPA1 that are found in complexes with mitochondrial-specific phospholipids and are required for cristae organization. Supplementation with unsaturated fatty acids counteracts the effects of LIX1 knock-down on mitochondrial morphology and ultrastructure, restores YAP1/TAZ signaling, and consequently KIT levels. Altogether, our findings demonstrate that LIX1 contributes to GIST aggressive potential by modulating YAP1/TAZ and KIT levels, a process that depends on mitochondrial remodeling. Our work brings new insights into the mechanisms that could be targeted in tumors in which YAP1 and TAZ are implicated.
Stimulating thesir2-pgc-1ɑaxis rescues exercise capacity and mitochondrial respiration inDrosophila tafazzinmutants
Authors: Damschroder Deena , Zapata-Pérez Rubén , Houtkooper Riekelt H. , Wessells Robert 
Published: January 2022

AbstractCardiolipin (CL) is a phospholipid required for proper mitochondrial function. Tafazzin remodels CL to create highly unsaturated fatty acid chains. However, whentafazzinis mutated, CL remodeling is impeded, leading to mitochondrial dysfunction and the disease Barth syndrome. Patients with Barth syndrome often have severe exercise intolerance, which negatively impacts their overall quality of life. Boosting NAD+levels can improve symptoms of other mitochondrial diseases, but its effect in the context of Barth syndrome has not been examined. We demonstrate for the first time that nicotinamide riboside (NR) can rescue exercise tolerance and mitochondrial respiration in aDrosophila tafazzinmutant and that the beneficial effects are dependent onsir2andpgc-1α. Overexpressingpgc-1αincreased the total abundance of cardiolipin in mutants. In addition, muscles and neurons were identified as key targets for future therapies becausesir2orpgc-1αoverexpression in either of these tissues is sufficient to restore the exercise capacity ofDrosophila tafazzinmutants.Summary StatementNicotinamide riboside rescues the exercise capacity and mitochondrial function of aDrosophilamodel of Barth syndrome in a Sir2/Pgc-1ɑ dependent manner.