bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenome-Wide Analysis of DNA Methylation and Optimism in Women and Men
Authors: Wang Cuicui , DeMeo Dawn L. , Kim Eric S. , Cardenas Andres , Fong Kelvin C. , Lee Lewina O. , Spiro Avron , Whitsel Eric A. , Horvath Steve , Hou Lifang , Baccarelli Andrea A. , Li Yun , Stewart James D. , Manson JoAnn E. , Grodstein Francine , Kubzansky Laura D. , Schwartz Joel D.
Published: October 2022

Objective

Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic.

Methods

Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities (n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the “number of independent degrees of freedom” approach: effective degrees of freedom correction using the number of principal components (PCs), explaining >95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software.

Results

We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders.

Conclusion

Our findings provide new insights into possible mechanisms underlying optimism and health.
Whole genome sequence analysis of ESBL-producing Escherichia coli recovered from New Zealand freshwater sites
Authors: Burgess Sara A. , Moinet Marie , Brightwell Gale , Cookson Adrian L.
Published: October 2022

Extended-spectrum beta lactamase (ESBL)-producing

Escherichia coli

are often isolated from humans with urinary tract infections and may display a multidrug-resistant phenotype. These pathogens represent a target for a One Health surveillance approach to investigate transmission between humans, animals and the environment. This study examines the multidrug-resistant phenotype and whole genome sequence data of four ESBL-producing

E

.

coli

isolated from freshwater in New Zealand. All four isolates were obtained from a catchment with a mixed urban and pastoral farming land-use. Three isolates were sequence type (ST) 131 (CTX-M-27-positive) and the other ST69 (CTX-M-15-positive); a phylogenetic comparison with other locally isolated strains demonstrated a close relationship with New Zealand clinical isolates. Genes associated with resistance to antifolates, tetracyclines, aminoglycosides and macrolides were identified in all four isolates, together with fluoroquinolone resistance in two isolates. The ST69 isolate harboured the bla
CTX-M-15 gene on a IncHI2A plasmid, and two of the three ST131 isolates harboured the bla
CTX-M-27 genes on IncF plasmids. The last ST131 isolate harboured bla
CTX-M-27 on the chromosome in a unique site between gspC and gspD. These data highlight a probable human origin of the isolates with subsequent transmission from urban centres through wastewater to the wider environment.
Activation of TnSmu1, an integrative and conjugative element, by an ImmR-like transcriptional regulator in Streptococcus mutans
Authors: King Shawn , Quick Allison , King Kalee , Walker Alejandro R. , Shields Robert C.
Published: October 2022

Integrative and conjugative elements (ICEs) are chromosomally encoded mobile genetic elements that can transfer DNA between bacterial strains. Recently, as part of efforts to determine hypothetical gene functions, we have discovered an important regulatory module encoded on an ICE known as TnSmu1 on the

Streptococcus mutans

chromosome. The regulatory module consists of a cI-like repressor with a helix-turn-helix DNA binding domain immR
Smu (immunity repressor) and a metalloprotease immA
Smu (anti-repressor). It is not possible to create an in-frame deletion mutant of immR
Smu and repression of immR
Smu with CRISPRi (CRISPR interference) causes substantial cell defects. We used a bypass of essentiality (BoE) screen to discover genes that allow deletion of the regulatory module. This revealed that conjugation genes, located within TnSmu1, can restore the viability of an immR
Smu mutant. Deletion of immR
Smu also leads to production of a circular intermediate form of TnSmu1, which is also inducible by the genotoxic agent mitomycin C. To gain further insights into potential regulation of TnSmu1 by ImmRSmu and broader effects on

S. mutans

UA159 physiology, we used CRISPRi and RNA-seq. Strongly induced genes included all the TnSmu1 mobile element, genes involved in amino acid metabolism, transport systems and a type I-C CRISPR-Cas system. Lastly, bioinformatic analysis shows that the TnSmu1 mobile element and its associated genes are well distributed across

S. mutans

isolates. Taken together, our results show that activation of TnSmu1 is controlled by the immRA
Smu module, and that activation is deleterious to

S. mutans

, highlighting the complex interplay between mobile elements and their host.
Incidence and risk factors for medical adhesive-related skin injury in catheters of critically ill patients – A prospective cohort study
Authors: Frota Oleci Pereira , Pinho Jéssica do Nascimento , Ferreira-Júnior Marcos Antonio , Sarti Elaine Cristina Fernandes Baez , Paula Fabiana Martins de , Ferreira Danielle Neris
Published: October 2022

Aim

To investigate the incidence and risk factors for medical adhesive-related skin injury (MARSI) in catheters of critically ill patients.

Methods

A prospective cohort study was conducted in adult intensive care units of two Brazilian university hospitals. A total of 150 patients (439 catheters) were included. Skin exposed to the catheter fixation adhesives (central venous, nasogastric, nasoenteral and indwelling urinary) was examined daily by four trained researchers. The patients’ sociodemographic and clinical data were collected from their electronic medical records. The association between independent variables and MARSI was investigated by bivariate statistics, followed by multiple logistic regression.

Results

The MARSI incidence was 42% (8.64 MARSIs per 100 patients/day). Advanced age, prolonged hospital stay, dry skin, repetitive adhesive removal, low Braden Scale score and hypoalbuminemia were associated with MARSI (p < .05). According to multivariate logistic regression, dry skin increased the chance of MARSI by 5.21 times (odds ratio [OR] 5.21; 95% confidence interval [95% CI] 2.43-11.11), while the Braden Scale score was a protective factor, showing 31% less chance of MARSI for each added score (OR 0.69; 95% CI 0.57-0.85). A higher incidence of MARSI was observed in nasoenteral catheters and in those fixed with adhesive using natural rubber. The MARSI types were predominantly mechanical (70.3%): skin stripping (41.3%), skin tear (26.1%) and tension injury or blister (2.9%).

Conclusions

MARSI is a common event in adult intensive care units and most risk factors are modifiable. Preventive actions are potentially capable of reducing incidence, optimizing financial resources and improving clinical results.
Unsupervised co-optimization of a graph neural network and a knowledge graph embedding model to prioritize causal genes for Alzheimer’s Disease
Authors: Prabhakar Vignesh , Liu Kai
Published: October 2022

1.

Data obtained from clinical trials for a given disease often capture reliable empirical features of the highest quality which are limited to few studies/experiments. In contrast, knowledge data extracted from biomedical literature captures a wide range of clinical information relevant to a given disease that may not be as reliable as the experimental data. Therefore, we propose a novel method of training that co-optimizes two AI algorithms on experimental data and knowledge-based information from literature respectively to supplement the learning of one algorithm with that of the other and apply this method to prioritize/rank causal genes for Alzheimer’s Disease (AD). One algorithm generates unsupervised embeddings for gene nodes in a protein-protein interaction network associated with experimental data. The other algorithm generates embeddings for the nodes/entities in a knowledge graph constructed from biomedical literature. Both these algorithms are co-optimized to leverage information from each other’s domain. Therefore; a downstream inferencing task to rank causal genes for AD ensures the consideration of experimental and literature data available to implicate any given gene in the geneset. Rank-based evaluation metrics computed to validate the gene rankings prioritized by our algorithm showed that the top ranked positions were highly enriched with genes from a ground truth set that were experimentally verified to be causal for the progression of AD.
Radiomics analysis to predict pulmonary nodule malignancy using machine learning approaches
Authors: Warkentin Matthew T. , Al-Sawaihey Hamad , Lam Stephen , Liu Geoffrey , Diergaarde Brenda , Yuan Jian-Min , Wilson David O. , Tammemägi Martin C. , Atkar-Khattra Sukhinder , Grant Benjamin , Brhane Yonathan , Khodayari-Moez Elham , Campbell Kieran R. , Hung Rayjean J.
Published: October 2022

Purpose

Screening with low-dose computed tomography can reduce lung cancer-related mortality. However, most screen-detected pulmonary abnormalities do not develop into cancer and it remains challenging to identify high-risk nodules among those with indeterminate appearance. We aim to develop and validate prediction models to discriminate between benign and malignant pulmonary lesions based on radiological features.

Methods

Using four international lung cancer screening studies, we extracted 2,060 radiomic features for each of 16,797 nodules among 6,865 participants. After filtering out redundant and low-quality radiomic features, 642 radiomic and 9 epidemiologic features remained for model development. We used cross-validation and grid search to assess three machine learning models (XGBoost, Random Forest, LASSO) for their ability to accurately predict risk of malignancy for pulmonary nodules. We fit the top-performing ML model in the full training set. We report model performance based on the area under the curve (AUC) and calibration metrics in the held-out test set.

Results

The ML models that yielded the best predictive performance in cross-validation were XGBoost and LASSO, and among these models, LASSO had superior model calibration, which we considered to be the optimal model. We fit the final LASSO model based on the optimized hyperparameter from cross-validation. Our radiomics model was both well-calibrated and had a test-set AUC of 0.930 (95% CI: 0.901-0.957) and out-performed the established Brock model (AUC=0.868, 95% CI: 0.847-0.888) for nodule assessment.

Conclusion

We developed highly-accurate machine learning models based on radiomic and epidemiologic features from four international lung cancer screening studies that may be suitable for assessing suspicious, but indeterminate, screen-detected pulmonary nodules for risk of malignancy.
Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID
Authors: Williams Elizabeth S. C. P. , Martins Thomas B. , Hill Harry R. , Coiras Mayte , Shah Kevin S. , Planelles Vicente , Spivak Adam M.
Published: October 2022

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood. We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of interferon gamma (IFNγ) and interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID. We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.
The Relationship Between Treatment Center Services and Number of Opioid-related Deaths in the United States Before and After a Declaration of a National Opioid Crisis
Authors: Hatton Courtney L. , Davis Brittany N. , Jama Mahamed A. , Samdani Nidha S.
Published: October 2022

Opioid-related deaths are a national problem that have increased over the past two decades. Multiple policy interventions have been enacted to decrease opioid misuse and expand treatment. The Comprehensive Addiction and Recovery Act (CARA) was passed in July 2016, just before declaring the opioid epidemic a National Emergency in 2017. CARA was enacted to combat the opioid epidemic by providing more funding yearly for items including but not limited to prevention, treatment, and opioid overdose reversal. To evaluate the impact of these policy changes, we carried out secondary data analysis for the period 2011-2019 using the CDC’s Wide-ranging Online Data for Epidemiologic Research and National Survey of Substance Abuse Treatment Services databases.

Research variables included: a comparison of the 50 states across the 2011-2019 timeframe, the number of opioid treatment centers, the percentage of government funding for facilities per state, percentage of opioid treatment facilities which offer free/low-income services and the opioid death rate. We also assessed differences in low-income access to opioid treatment services by comparing Medicaid expansion states versus non-Medicaid expansion states.

While both the number of treatment facilities per state and opioid death rates nearly doubled during this time, there was little to no association between them (R2 ranging from: 0.094-0.188 for years 2013-2019). Our research suggests that while state-level differences in opioid use disorder treatment facility characteristics related to access to care, they were only weakly associated with opioid-related deaths. This analysis may be used in the planning of subsequent actions against the national opioid epidemic and invites further inquiry into the impact of state Medicaid expansion on drug-specific opioid usage and mortality.
A roadmap for implementation of kV-CBCT online adaptive radiation therapy and initial first year experiences
Authors: Stanley Dennis N. , Harms Joseph , Pogue Joel A. , Belliveau Jean-Guy , Marcrom Samuel R. , McDonald Andrew M. , Dobelbower Michael C. , Boggs Drexell H. , Soike Michael H. , Fiveash John A. , Popple Richard A. , Cardenas Carlos E.
Published: October 2022

Purpose

Online Adaptive Radiation Therapy(oART) follows a different treatment paradigm than conventional radiotherapy and, because of this, the resources, implementation, and workflows needed are unique. The purpose of this report is to outline our institution’s experience establishing, organizing, and implementing an oART program using the Ethos therapy system.

Methods

We include resources used; operational models utilized, program creation timelines, and our institutional experiences with implementation and operation of an oART program. Additionally, we provide a detailed summary of our first year’s clinical experience where we delivered over 1000 daily adaptive fractions. For all treatments, the different stages of online adaption, primary patient set-up, initial kV-CBCT acquisition, contouring review and edit of influencer structures, target review and edits, plan evaluation and selection, Mobius3D 2ndcheck and adaptive QA, 2ndkV-CBCT for positional verification, treatment delivery, and patient leaving the room, were analyzed.

Results

We retrospectively analyzed data from ninety-seven patients treated from August 2021-August 2022. 1677 individual fractions were treated and analyzed, 632(38%) were non-adaptive and 1045(62%) were adaptive. 74 of the 97 patients (76%) were treated with standard fractionation and 23 (24%) received stereotactic treatments. For the adaptive treatments, the generated adaptive plan was selected in 92% of treatments. On average(±std), adaptive sessions took 34.52±11.42 minutes from start to finish. The entire adaptive process (from start of contour generation to verification CBCT), performed by the physicist (and physician on select days), was 19.84±8.21 minutes.

Conclusion

We present our institution’s experience commissioning an oART program using the Ethos therapy system. It took us 12 months from project inception to treatment of our first patient and 12 months to treat 1000 adaptive fractions. Retrospective analysis of delivered fractions showed that average overall treatment time was approximately 35 minutes and average time for the adaptive component of treatment was approximately 20 minutes.
Association of Women-Specific Health Factors in the Severity of Parkinson’s Disease
Authors: Rao Shilpa C , Li Yadi , Lapin Brittany , Pattipati Sreya , Ghosh Galvelis Kamalini , Naito Anna , Guitierrez Nicolas , Peixoto Leal Thiago , Salim Amira , Salles Philippe A. , De Leon Maria , Mata Ignacio F
Published: October 2022

Background

Parkinson’s disease (PD) is an age-related neurological disorder known for the observational differences in its risk, progression, and severity between men and women. While estrogen has been considered to be a protective factor in the development of PD, there is little known about the role that fluctuations in hormones and immune responses from sex-specific health experiences have in the disease’s development and severity.

Objective

We sought to identify women-specific health experiences associated with PD severity by developing and distributing a women-specific questionnaire across the United States.

Design

We created a questionnaire that addresses women’s specific experiences and their PD clinical history and deployed it through The Parkinson’s Foundation: PD Generations. To determine the association between women-specific health factors and PD severity, we constructed multivariable logistic regression models based on the MDS-UPDRS scale and the participants’ questionnaire responses, genetics, and clinical data.

Results

For our initial launch in November 2021, we had 304 complete responses from PD GENEration. Univariate and multivariate logistic modeling found significant associations between major depressive disorder, perinatal depression, natural childbirth, LRRK2 genotype, B12 deficiency, total hysterectomy and increased PD severity.

Conclusions

This study is the first nationally available questionnaire for women’s health and PD. It shifts the paradigm in understanding PD etiology and acknowledging how sex-specific experiences may contribute to PD severity. In addition, the work in this study sets the foundation for future research to investigate the reasons behind the sex differences in PD.
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

Background

Cyclin-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).

Objective

This 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).

Methods

6-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.

Results

Pre-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.

Conclusions

6-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

Clinical 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.

Synopsis

Multi-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

Cytokines 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

Hop (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

Neuronal 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

Throughout 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

Cryo-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

This 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

Molecular 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

Background

Dental 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.

Objective

This 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.

Methods

A 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.

Results

Overall, 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.

Conclusion

The 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.
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

The 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.
Using Deep Learning to Determine Amyloid Deposition through PET and Clinical Data for Alzheimer’s Prognosis
Authors: Maddury Sucheer , Desai Krish
Published: October 2022

Amyloid deposition is a vital biomarker in the process of Alzheimer’s diagnosis. Florbetapir PET scans can provide valuable imaging data to determine cortical amyloid quantities. However the process is labor and doctor intensive, requiring extremely specialized education and resources that may not be accessible to everyone, making the amyloid calculation process inefficient.

Deep learning is a rising tool in Alzheimer’s research which could be used to determine amyloid deposition. Using data from the Alzheimer’s Disease Neuroimaging Initiative, we identified 2980 patients with PET imaging, clinical, and genetic data. We tested various ResNet and EfficientNet convolutional neural networks and later combined them with Gradient Boosting Decision Tree algorithms to predict standardized uptake value ratio (SUVR) of amyloid in each patient session. We tried several configurations to find the best model tuning for regression-to-SUVR.

We found that the EfficientNetV2-Small architecture combined with a grid search-tuned Gradient Boosting Decision Tree with 3 axial input slices and clinical and genetic data achieved the lowest loss. Using the mean-absolute-error metric, the loss converged to an MAE of 0.0466, equating to 96.11% accuracy across the 596 patient test set.

We showed that this method is more consistent and accessible in comparison to human readers from previous studies, with lower margins of error and substantially faster calculation times. Deep learning algorithms could be used in hospitals and clinics with resource limitations for amyloid deposition, and shows promise for more imaging tasks as well.
Reversible restriction of electron flow across cytochrome b6f in dark acclimated cells limited for downstream electron sinks
Authors: Saroussi Shai , Karns Devin , Thomas Dylan C. , Redekop Petra , Wittkopp Tyler M. , Posewitz Matthew C. , Grossman Arthur R.
Published: October 2022

Photosynthetic organisms frequently experience abiotic stresses that restrict their growth and development. Under such circumstances, most absorbed solar energy cannot be used for CO2 fixation and can cause the photoproduction of reactive oxygen species (ROS) that can damage the photosynthetic reaction centers, photosystems I and II (PSI and PSII), resulting in a decline in primary productivity. This work describes a biological ‘switch’ in the green alga Chlamydomonas reinhardtii that reversibly restricts photosynthetic electron transport (PET) at the cytochrome b6f complex when reductant and ATP generated by PET are in excess of the capacity of carbon metabolism to utilize these products; we specifically show a restriction at this switch when sta6 mutant cells, which cannot synthesize starch, are limited for nitrogen (growth inhibition) and subjected to a dark-to-light transition. This restriction, which may be a form of photosynthetic control, causes diminished electron flow to PSI, which prevents PSI photodamage. When electron flow is blocked the plastid alternative oxidase (PTOX) may also become activated, functioning as an electron valve that dissipates some of the excitation energy absorbed by PSII thereby lessening PSII photoinhibition. Furthermore, illumination of the cells following the dark acclimation gradually diminishes the restriction at cytochrome b6f complex. Elucidating this photoprotective mechanism and its modulating factors may offer new insights into mechanisms associated with photosynthetic control and offer new directions for optimizing photosynthesis.
Reconstruct a eukaryotic chromosome arm by de novo design and synthesis
Authors: Jiang Shuangying , Luo Zhouqing , Yu Kang , Zhao Shijun , Cai Zelin , Yu Wenfei , Wang Hui , Cheng Li , Liang Zhenzhen , Gao Hui , Monti Marco , Schindler Daniel , Huang Linsen , Zeng Cheng , Zhang Weimin , Zhou Chun , Tang Yuanwei , Li Tianyi , Ma Yingxin , Cai Yizhi , Boeke Jef D. , Dai Junbiao
Published: October 2022

The genome of an organism is inherited from its ancestor and keeps evolving over time, however, how much the current version could be altered remains unknown. Here, we use the left arm of chromosome XII (chrXIIL) as an example to probe the genome plasticity in Saccharomyces cerevisiae. A neochromosome was designed to harbor originally dispersed genes. The essentiality of sequences in chrXIIL was dissected by targeted DNA removal, chromosome truncation and random deletion. Notably, 12 genes were sufficient for survival, while 25 genes are required to retain robust fitness. Next, we demonstrated these genes could be reconstructed using synthetic regulatory sequences and recoded open-reading frames with “one-amino-acid-one-codon” strategy. Finally, we built a neochromsome, which could substitute for chrXIIL for cell viability, with these reconstructed genes. Our work not only highlights the high plasticity of yeast genome, but also illustrates the possibility of making functional chromosomes with completely artificial sequences.

HIGHLIGHTS

A neochromosome was designed to facilitate the assembly of exogenous DNA for stable expression in yeast

The left arm of chrXII could be minimized to just 12 genes to maintain viability, but additional genes were required to retain robust fitness

Comprehensive recoding and transcriptional refactoring using artificial regulatory sequences produced a functional chromosome arm

A completely reconstructed neochromosome could replace the chrXIIL to maintain comparable fitness
Modelling the effectiveness of targeting Rift Valley fever virus vaccination using imperfect network information
Authors: Sulaimon Tijani A. , Chaters Gemma L. , Nyasebwa Obed M. , Swai Emanuel S. , Cleaveland Sarah , Enright Jessica , Kao Rowland R. , Johnson Paul C. D.
Published: October 2022

Livestock movements contribute to the spread of several infectious diseases. Data on livestock movements can therefore be harnessed to guide policy on targeted interventions for controlling infectious livestock diseases, including Rift Valley fever (RVF) — a vaccine-preventable arboviral fever. While detailed livestock movement data are available in many countries, such data are generally lacking in others, including many in East Africa, where multiple RVF outbreaks have been reported in recent years. Available movement data are imperfect, and the impact of imperfect movement data on targeted vaccination is not fully understood. Here, we used a network simulation model to describe the spread of RVF within and between 398 wards in northern Tanzania connected by cattle movements, on which we evaluated the impact of targeting vaccination using imperfect movement data. We show that pre-emptive vaccination guided by only market movement permit data could prevent large outbreaks. Targeted control (either by the risk of RVF introduction or onward transmission) at any level of imperfect movement information is preferred over random vaccination, and any improvement in information reliability is advantageous to their effectiveness. Our modelling approach demonstrates how targeted interventions can be carefully applied to inform animal and public health policies on disease control planning in settings where detailed data on livestock movements are unavailable or imperfect due to a lack of data-gathering resources.
Mechanosensitive channel-based optical membrane tension biosensor
Authors: Hsu Yen-Yu , Irizarry Agnes M. Resto , Fu Jianping , Liu Allen P.
Published: October 2022

Plasma membrane tension functions as a global physical organizer of cellular activities. Technical limitations of current membrane tension measurement techniques have hampered in-depth investigation of cellular membrane biophysics and the role of plasma membrane tension in regulating cellular processes. Here, we develop an optical membrane tension biosensor by repurposing anE. colimechanosensitive channel via insertion of circularly permuted GFP (cpGFP), which undergoes a large conformational rearrangement associated with channel activation and thus fluorescence intensity changes under increased membrane tension.