bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of hyperactive cyclin dependent kinase 5/p25 is protective in the 6-hydroxydopamine model of Parkinson’s disease
Authors: Bernardo Ashley , Amin Niranjana , Binukumar BK , Pant Harish , Mishra Ram 
Published: October 2022

AbstractBackgroundCyclin-dependent kinase 5 (CDK5) is a multifunctional enzyme involved in neuronal development, maturation and survival. CDK5 activity is tightly regulated by association with regulatory proteins p35 and p39. Upon neuronal insults, increased intracellular calcium activates calpain, cleaving p35 into p25, which has a higher affinity for CDK5. p25 hyperactivates CDK5, initiating apoptotic cascades that lead to significant dopaminergic (DAergic) loss that can leads to neurodegenerative disorders, such as Parkinson’s disease (PD).ObjectiveThis study investigates hyperactivation of CDK5/p25 in the 6-hydroxydopamine (6-OHDA) rat model of PD and specific inhibition of CDK5/p25 by truncated peptide 5 (TP5). TP5 was investigated for amelioration of 6-OHDA induced behaviour impairments and significant protection of dopamine neurons through tyrosine hydroxylase (TH).Methods6-OHDA induced motor impairments and reduced TH. Motor assessments included locomotor activity, beam transversal, fixed speed rotarod and amphetamine-induced rotations. Immunohistochemistry investigated DAergic neurodegeneration using TH levels and immunoprecipitation and assay investigated CDK5 activity.ResultsPre-administration of TP5 maintained locomotor activity, preserved beam transversal scores, protected motor coordination and attenuated amphetamine induced rotations in 6-OHDA lesioned rats, all indicative of neuroprotection by TP5. 6-OHDA without pretreatment of TP increased CDK5 activation. CDK5 activity in TP5+6-OHDA animals was not significantly different from artificial cerebrospinal fluid (aCSF) treated sham surgery controls. Immunohistochemistry revealed significant TH protection within the substantia nigra (SN) of TP5 pretreated animals.Conclusions6-OHDA increases CDK5 activity. Hyperactive CDK5/p25 inhibition in the 6-OHDA model has neuroprotective capability, protecting against the development of a toxin-based induction of PD-like motor phenotypes and pathology. This supports CDK5/p25 specific inhibition as a target for further neuroprotective therapeutic development.
Multi-omic network analysis identified betacellulin as a novel target of omega-3 fatty acid attenuation of western diet-induced nonalcoholic steatohepatitis
Authors: Padiadpu Jyothi , Garcia-Jaramillo Manuel , Newman Nolan K. , Pederson Jacob W. , Rodrigues Richard , Li Zhipeng , Singh Sehajvir , Monnier Philip , Trinchieri Giorgio , Brown Kevin , Dzutsev Amiran K. , Shulzhenko Natalia , Jump Donald B. , Morgun Andrey 
Published: October 2022

AbstractClinical and preclinical studies have established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH). Herein, we used multi-omic network analysis to unveil novel mechanistic targets of ω3 PUFA effects in a preclinical mouse model of western diet induced NASH. After identifying critical molecular processes responsible for the effects of ω3 PUFA, we next performed meta-analysis of human liver cancer transcriptomes and uncovered betacellulin as a key EGFR-binding protein that was induced in liver cancer and downregulated by ω3 PUFAs in animals with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, stimulating transforming growth factor–β2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti-inflammatory and antifibrotic effects of ω3 PUFA during NASH.SynopsisMulti-omic network analysis points to mitochondrial cardiolipin precursors as candidate key lipids whereby ω3 fatty acids restore mitochondrial functioning.Multi-omic network analysis suggests betacellulin (BTC) as one of the key mediators of NASH suppressed by ω3 polyunsaturated fatty acids.Reduction of liver fibrosis by omega-3 fatty acids (especially by docosahexaenoic acid, DHA) is accomplished by simultaneous inhibition of betacellulin and TLR agonists.BTC promotes collagen production and induces TGFB2 in hepatic stellate cells.BTC together with TLR2/4 agonists stimulate expression of integrins in macrophages.DHA suppresses BTC-EGFR pathway in NASH animal model potentially preventing progression to hepatocellular carcinoma.
Multicolor Light-Induced Immune Activation via Polymer Photocaged Cytokines
Authors: Birnbaum Lacey A , Sullivan Emily C. , Do Priscilla , Uricoli Biaggio , Porter Christopher C , Henry Curtis J , Dreaden Erik C 
Published: October 2022

ABSTRACTCytokines act as potent, extracellular signals of the human immune system and can elicit striking treatment responses in patients with autoimmune disease, tissue damage, and cancer. Yet despite their therapeutic potential, recombinant cytokine-mediated immune responses remain difficult to control as their administration is often systemic whereas their intended sites of action are localized. To address the challenge of spatially and temporally constraining cytokine signals, we recently devised a strategy whereby recombinant cytokines are reversibly inactivated via chemical modification with photo-labile polymers that respond to visible LED light. Extending this approach to enable both in vivo and multicolor immune activation, here we describe a strategy whereby cytokines appended with heptamethine cyanine-polyethylene glycol are selectively re-activated ex vivo using tissue-penetrating near-infrared (NIR) light. We show that NIR LED light illumination of caged, pro-inflammatory cytokines restores cognate receptor signaling and potentiates the activity of T cell-engager cancer immunotherapies ex vivo. Using combinations of visible- and NIR-responsive cytokines, we further demonstrate multi-wavelength optical control of T cell cytolysis ex vivo, as well as the ability to perform Boolean logic using multicolored light and orthogonally photocaged cytokine pairs as inputs, and T cell activity as outputs. Together, this work demonstrates a novel approach to control extracellular immune cell signals using light, a strategy that in the future may improve our understanding of and ability to treat cancer and other diseases.
The multifaceted roles of R2R3 transcription factor HlMYB7 in the regulation of flavonoid and bitter acids pathways, development and biotic stress in hop (Humulus lupulus L.)
Authors: Mishra Ajay Kumar , Kocábek Tomáš , Nath Vishnu Sukumari , Khan Ahamed , Matoušek Jaroslav , Hazzouri Khaled M , Sudalaimuthuasari Naganeeswaran , Krofta Karel , Amiri Khaled M.A. 
Published: October 2022

AbstractHop (Humulus lupulus) biosynthesizes the highly economically valuable secondary metabolites, which include flavonoids, bitter acids, polyphenols and essential oils. These compounds have important pharmacological properties and are widely implicated in the brewing industry owing to bittering flavor, floral aroma and preservative activity. Our previous studies documented that ternary MYB-bHLH-WD40 (MBW) and binary WRKY1-WD40 (WW) protein complexes transcriptionally regulate the accumulation of bitter acid (BA) and prenylflavonoids (PF). In the present study, we investigated the regulatory functions of the R2R3-MYB repressor HlMYB7 transcription factor, which contains a conserved N-terminal domain along with the repressive motif EAR, in regulating the PF- and BA-biosynthetic pathway and their accumulation in hop. Constitutive expression of HlMYB7 resulted in transcriptional repression of structural genes involved in the terminal steps of biosynthesis of PF and BA, as well as stunted growth, delayed flowering, and reduced tolerance to viroid infection in hop. Furthermore, yeast two-hybrid and transient reporter assays revealed that HlMYB7 targets both PF and BA pathway genes and suppresses MBW and WW protein complexes. Heterologous expression of HlMYB7 leads to down-regulation of structural genes of flavonoid pathway in Arabidopsis thaliana, including a decrease in anthocyanin content in Nicotiana tabacum. The combined results from functional and transcriptomic analyses highlight the important role of HlMYB7 in fine-tuning and balancing the accumulation of secondary metabolites at the transcriptional level, thus offer a plausible target for metabolic engineering in hop.
Calcium transients in nNOS neurons underlie distinct phases of the neurovascular response to barrel cortex activation in awake mice
Authors: Ahn Sung Ji , Anfray Antoine , Anrather Josef , Iadecola Costantino 
Published: October 2022

AbstractNeuronal nitric oxide (NO) synthase (nNOS), a Ca2+ dependent enzyme, is expressed by distinct populations of neocortical neurons. Although neuronal NO is well known to contribute to the blood flow increase evoked by neural activity, the relationships between nNOS neurons activity and vascular responses in the awake state remain unclear. We imaged the barrel cortex in awake, head-fixed mice through a chronically implanted cranial window. The Ca2+ indicator GCaMP7f was expressed selectively in nNOS neurons using adenoviral gene transfer in nNOScre mice. Air-puffs directed at the contralateral whiskers or spontaneous motion induced Ca2+ transients in 30.2±2.2% or 51.6±3.3% of nNOS neurons, respectively, and evoked local arteriolar dilation. The greatest dilatation (14.8±1.1%) occurred when whisking and motion occurred simultaneously. Ca2+ transients in individual nNOS neurons and local arteriolar dilation showed various degrees of correlation, which was strongest when the activity of whole nNOS neuron ensemble was examined. We also found that some nNOS neurons became active immediately prior to arteriolar dilation, while others were activated gradually after arteriolar dilatation. Discrete nNOS neuron subsets may contribute either to the initiation or to the maintenance of the vascular response, suggesting a previously unappreciated temporal specificity to the role of NO in neurovascular coupling.
A neural model of proximity to reward
Authors: Botros P. , Vendrell-Llopis N. , Costa R. M. , Carmena J. M. 
Published: October 2022

AbstractThroughout learning, refinement of cortical activity in cortex, a process termed “credit assignment”, underlies the refinement of behavioral actions leading to reward. While previous research shows striatum’s role in linking behavior to reward, striatum’s role in linking the underlying behaviorally-relevant cortical activity to reward remains unclear. Leveraging a neuroprosthetic task while recording from the rat cortex and striatum, we demonstrate that the striatum encodes the dynamics of the proximity of cortical activity to reward. Such encoding was independent from external task feedback and emerged as cortical activity consolidated over learning, with dorsal and ventral striatum playing complementary yet distinct roles. Striatal activity thus constitutes a neural model of cortical progress towards reward, suggesting one mechanism by which the brain implements credit assignment to refine behavior.
CryoFIB milling large tissue samples for cryo-electron tomography
Authors: Wang Sihan , Zhou Heng , Chen Wei , Jiang Yifeng , Yan Xuzhen , You Hong , Li Xueming 
Published: October 2022

AbstractCryo-electron tomography (cryoET), a powerful tool for exploring the molecular structure of large organisms. However, technical challenges still limit cryoET applications on large samples. In particular, locating and cutting out objects of interest from a large tissue sample is an important but difficult step. In this study, we report a sample thinning strategy and workflow for tissue samples based on cryo-focused ion beam (cryoFIB) milling. This workflow provides a full solution for isolating objects of interest by starting from a millimeter-sized tissue sample and ending with hundred-nanometer thin lamellae. The workflow involves sample fixation, pre-sectioning, a two-step milling strategy, and locating the object of interest using cellular secondary electron imaging (CSEI). The two-step milling strategy introduces a coarse milling method to solve the milling efficiency problem for samples as thick as tens of microns, followed by a fine milling method to create a furrow-ridge structure. The furrow-ridge structure guarantees the generation of large, thin lamellae with enhanced mechanical stability and charge-reducing design. CSEI is highlighted in the workflow, which provides conventional, on-the-fly locating during cryoFIB milling. Tests of the complete workflow were conducted to demonstrate the high efficiency and high feasibility of the proposed method.
Debt, health and HIV spending after the COVID-19 crisis: Assessing alternatives for relief mechanisms and additional financing through a cross-country macroeconomic study
Authors: Dyson Edward , Murray-Zmijewski Alexandra , Izazola-Licea Jose-Antonio , Lievens Tomas 
Published: October 2022

AbstractThis study addresses the following policy questions: What forms of debt relief and additional financing are most effective in mitigating the fiscal impact of the COVID-19 pandemic in countries that are at risk of or facing debt distress? What would the subsequent impact be on government health and HIV financing up until 2030? To answer these questions, five debt relief and additional financing options are hypothetically applied to seven Sub-Saharan African countries using a macro-fiscal programming framework and debt scenario modelling. Aggregate impacts demonstrate that, on average, the COVID-19 period has had a significant impact on government health and HIV-related expenditure. Each of the five presented options studied are shown to have an iteratively greater impact in mitigating the effects of the pandemic on government health and HIV-related expenditure. However, none of the debt relief and additional financing options succeed in offsetting the loss of health and HIV fiscal space that has occurred during the COVID-19 pandemic. Adequate solutions to make up for this shortfall require the consideration of options beyond the current policy dialogue.
Sex-dependent placental mQTL provide insight into the prenatal origins of childhood-onset traits and conditions
Authors: Casazza William , Inkster Amy M. , Del Gobbo Giulia F. , Yuan Victor , Delahaye Fabien , Marsit Carmen , Park Yongjin P. , Robinson Wendy P. , Mostafavi Sara , Dennis Jessica K 
Published: October 2022

SummaryMolecular quantitative trait loci (QTL) allow us to understand the biology captured in genome-wide association studies (GWAS). The placenta regulates fetal development, and shows sex differences in DNA methylation. We therefore hypothesized that placental methylation QTL (mQTL) explains variation in genetic risk for childhood-onset traits, and does so differentially by sex. We analyzed 411 term placentas from two studies and found 49,252 methylation (CpG) sites with methylation QTL (mQTL) and 2,489 CpG sites with sex-dependent mQTL. All mQTL were enriched in regions active in prenatal tissues that typically affect gene expression. All mQTL were enriched in GWAS results for growth- and immune-related traits, but male- and female-specific mQTL were more enriched than cross-sex mQTL. mQTL colocalized with trait loci at 777 CpG sites, with 216 (28%) specific to males or females. Overall, mQTL specific to male and female placenta capture otherwise overlooked variation in childhood traits.
Prevalence of dental caries and associated risk factors among HIV-positive and HIV-negative adults at an HIV clinic in Kigali, Rwanda
Authors: Murererehe Julienne , Malele-Kolisa Yolanda , Niragire Francois , Yengopal Veerasamy 
Published: October 2022

AbstractBackgroundDental caries is among the most frequent oral conditions in HIV-positive (HIV+) persons. There is a lack of baseline information on dental caries prevalence and associated risk factors among HIV+ individuals in comparison to HIV-negative (HIV−) people in Rwanda.ObjectiveThis study was conducted to determine the prevalence of dental caries and associated risk factors among HIV+ and HIV-adults at an HIV clinic of Kigali Teaching Hospital (CHUK) in Kigali, Rwanda.MethodsA comparative cross-sectional study was conducted among 200 HIV+ and 200 HIV-adults aged 18 years and above attending the HIV clinic of CHUK. An oral examination was performed by a calibrated examiner. Caries was assessed using the WHO Decayed (D), Missing (M), and Filled Teeth (F) index (DMFT). Descriptive statistics, Chi-square, t-tests, and multiple logistic regression were used to analyze data.ResultsOverall, a higher prevalence (50.5%) of HIV+ adults had dental caries experience (DMFT>0) compared to HIV-counterparts (40.5%) (p=0.045). The prevalence of Decayed teeth (D) was also higher (23.5%) among HIV+ participants compared to HIV-persons (13.6%) (p=0.011). The Mean(SD) DMFT scores among HIV+ and HIV-participant were 2.28 (3.68) and 1.29 (2.21) respectively (p=0.001). After performing multiple logistic regression analysis, the predictors of dental caries in HIV+ persons were being a female (OR= 2.33; 95%CI= 1.14-4.75), frequent dental visits (OR= 4.50; 95% CI=1.46-13.86) and detectable RNA viral load (OR= 4.50; 95% CI=1.46-13.86). In HIV-participants, the middle age range (36-45 years), and frequent dental visits were significantly associated with dental caries (OR= 6.61; 95%CI=2.14-20.37) and (OR=3.42; 95%CI: 1.337-8.760) respectively.ConclusionThe prevalence of dental caries was higher in HIV+ adults than in HIV-counterparts. The reported higher prevalence of caries in HIV+ persons was associated with being a female, detectable viral load, and frequent dental visits. Therefore, there is a need for effective oral health interventions specific to HIV+ individuals in Rwanda to raise awareness of the risk of dental caries and provide preventive oral health services among this population. To ensure timely oral health care among HIV+ persons, there is a need for an effort from policymakers and other stakeholders to integrate oral health care services within the HIV treatment program in Rwanda.
The Etiology of Hypothyroidism Is Revealed by Alternative Genetics Association Study Methodologies
Authors: Stern Amos , Zucker Roei , Linial Michal 
Published: October 2022

AbstractHypothyroidism is a common disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. About 12% of the population in the USA will develop substantial thyroid deficiency over their lifetime, mostly as a result of iodine deficiency. The hypothyroidism phenotype also includes individuals that suffer from thyroid development abnormalities (congenital hypothyroidism, CH). Using a large population study, we aimed to identify the functional genes associated with an increase or decreased risk for hypothyroidism (ICD-10, E03). To this end, we used the gene-based proteome-wide association study (PWAS) method to detect associations mediated by the effects of variants on the protein function of all coding genes. The UK-Biobank (UKB) reports on 13,687 cases out of 274,824 participants of European ancestry, with a prevalence of 7.5% and 2.0% for females and males, respectively. The results from PWAS for ICD-10 E03 are a ranked list of 77 statistically significant genes (FDR-q-value <0.05) and an extended list of 95 genes with a weaker threshold (FDR-q-value <0.1). Validation was performed using the FinnGen Freeze 7 (Fz7) database across several GWAS with 33.5k to 44.5k cases. We validated 9 highly significant genes across the two independent cohorts. About 12% of the PWAS reported genes are strictly associated with a recessive inheritance model that is mostly overlooked by GWAS. Furthermore, PWAS performed by sex stratification identified 9 genes in males and 63 genes in females. However, resampling and statistical permutation tests confirmed that the genes involved in hypothyroidism are common to both sexes. Many of these genes function in the recognition and response of immune cells, with a strong signature of autoimmunity. Additional genetic association protocols, including PWAS, TWAS (transcriptional WAS), Open Targets (OT, unified GWAS) and coding-GWAS, revealed the complex etiology of hypothyroidism. Each association method highlights a different facet of the disease, including the developmental program of CH, autoimmunity, gene dysregulation, and sex-related gene enrichment. We conclude that genome association methods are complementary while each one reveals different aspects of hypothyroidism. Applying a multiple-protocol approach to complex diseases is expected to improve interpretability and clinical utility.
Graphene Field Effect Biosensor for Concurrent and Specific Detection of SARS-CoV-2 and Influenza
Authors: Kumar Neelotpala , Towers Dalton , Myers Samantha , Galvin Cooper , Kireev Dmitry , Ellington Andrew D. , Akinwande Deji 
Published: October 2022

AbstractThe SARS-CoV-2 pandemic has highlighted the need for devices capable of carrying out rapid differential detection of viruses that may manifest similar physiological symptoms yet demand tailored treatment plans. Seasonal influenza may be exacerbated by COVID-19 infections, increasing the burden on healthcare systems. In this work, we demonstrate a technology, based on liquid-gated graphene field-effect transistors, for rapid and ultraprecise detection and differentiation of influenza and SARS-CoV-2 surface protein. Most distinctively, our device consists of 4 onboard graphene field-effect electrolyte-gated transistors arranged in a quadruple architecture, where each quarter is functionalized individually (with either antibodies or chemically passivated control) but measured collectively. Our sensor platform was tested against a range of concentrations of viral surface proteins from both viruses with the lowest tested and detected concentration at ∼50 ag/mL, or 88 zM for COVID-19 and 227 zM for Flu, which is 5-fold lower than the values reported previously on a similar platform. Unlike the classic Real-Time Polymerase Chain Reaction (RT-PCR) test, which has a turnaround time of a few hours, our technology presents an ultrafast response time of ∼10 seconds even in complex media such as saliva. Thus, we have developed a multi-analyte, highly sensitive, and fault-tolerant technology for rapid diagnostic of contemporary, emerging, and future pandemics.