bluuebunny/crossref_metadata_2025 huggingface dataset:
Emotional Reactivity, Emotion Regulation, and Regulatory Choice in Somatic Symptom Disorder
Authors: Schnabel Katharina , Schulz Stefan M. , Witthöft Michael
Published: August 2022

Objective

Despite the transdiagnostic importance of emotional dysregulation in psychopathology, the exact nature of emotional dysregulation in somatic symptom disorders (SSDs) is still unclear. The present study compared measures of emotional reactivity, emotion regulation (ER), and regulatory choice between n = 62 individuals with SSD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) and n = 61 healthy participants.

Methods

Participants underwent two ER tasks, assessing a) efficacy of reappraisal and suppression, and 2) regulatory choice, while electrodermal activity and heart rate variability were recorded. In addition, self-reports (Emotion Reactivity Scale, Emotion Regulation Questionnaire, Difficulties in Emotion Regulation Scale) regarding habitual emotional reactions and regulation strategies were assessed.

Results

Individuals with SSD reported significantly higher trait emotional reactivity (Emotion Reactivity Scale; p < .001, d = 1.61), significantly more trait ER difficulties (Difficulties in Emotion Regulation Scale; p < .001, d = 1.62), and significantly lower reappraisal use in daily life (Emotion Regulation Questionnaire; p < .001, d = −0.75). On a behavioral and physiological levels, no significant group differences were found regarding emotional reactivity (subjective ratings of emotional stimuli in task 1, p values = .653–.667; electrodermal activity: p values = .224–.837), ER (task 1: p values = .077–.731; heart rate variability: p values = .522–.832), or regulatory choice (task 2: p = .380). Although individuals with SSD were equally effective in state ER (task 1), they perceived ER during the task as significantly more effortful (p = .038, d = −0.38).

Conclusions

Results suggest that dysregulated emotions might not result from lacking abilities in implementing ER effectively, but rather could arise from less frequent ER initiation because ER is perceived as more effortful.
Pain Is Associated With Depressive Symptoms, Inflammation, and Poorer Physical Function in Older Adults With HIV
Authors: Derry-Vick Heather M. , Johnston Carrie D. , Brennan-Ing Mark , Burchett Chelsie O. , Glesby Nina , Zhu Yuan-Shan , Siegler Eugenia L. , Glesby Marshall J.
Published: August 2022

Objective

People living with HIV (PLWH) frequently experience pain, which often co-occurs with psychological symptoms and may impact functional outcomes. We investigated cross-sectional associations between pain, depressive symptoms, and inflammation, and then explored whether pain was related to poorer physical function among older PLWH.

Methods

We examined data from PLWH aged 54 to 78 years (n = 162) recruited from a single outpatient program for a larger study on HIV and aging. Participants reported depressive symptoms (10-item Center for Epidemiological Studies Depression Scale) and then attended a biomedical visit in which they reported past-month pain (Medical Outcomes Study-HIV pain subscale), completed physical function assessments, and provided blood samples (assayed for interleukin 6, interferon-γ, tumor necrosis factor α, and C-reactive protein). Links between pain, depressive symptoms, inflammation, and physical function were tested using linear regression models.

Results

PLWH with greater depressive symptoms experienced more pain than did those with fewer depressive symptoms (B = 1.31, SE = 0.28, p < .001), adjusting for age, sex, race, body mass index, smoking, disease burden, time since HIV diagnosis, and medication use. Higher composite cytokine levels were associated with worse pain (B = 5.70, SE = 2.54, p = .027 in adjusted model). Poorer physical function indicators, including slower gait speed, weaker grip strength, recent falls, and prefrail or frail status, were observed among those with worse pain. Exploratory mediation analyses suggested that pain may partially explain links between depressive symptoms and several physical function outcomes.

Conclusions

Pain is a potential pathway linking depressive symptoms and inflammation to age-related health vulnerabilities among older PLWH; longitudinal investigation of this pattern is warranted. PLWH presenting with pain may benefit from multidisciplinary resources, including behavioral health and geriatric medicine approaches.
Soluble CD14-associated DNA methylation sites predict mortality among men with HIV infection
Authors: Titanji Boghuma K. , Wang Zeyuan , Chen Junyu , Hui Qin , So-Armah Kaku , Freiberg Matthew , Justice Amy C. , Ke Xu , Marconi Vincent C. , Sun Yan V.
Published: August 2022

Objectives:

Elevated plasma levels of sCD14 predict all-cause mortality in people with HIV (PWH). Epigenetic regulation plays a key role in infection and inflammation. To reveal the epigenetic relationships between sCD14, immune function and disease progression among PWH, we conducted an epigenome-wide association study (EWAS) of sCD14 and investigated the relationship with mortality.

Design and methods:

DNA methylation (DNAm) levels of peripheral blood samples from PWH in the Veterans Aging Cohort Study (VACS) were measured using the Illumina Infinium Methylation 450K (n = 549) and EPIC (850K) BeadChip (n = 526). Adjusted for covariates and multiple testing, we conducted an epigenome-wide discovery, replication, and meta-analysis to identify significant associations with sCD14. We then examined and replicated the relationship between the principal epigenetic sites and survival using Cox regression models.

Findings:

We identified 118 DNAm sites significantly associated with sCD14 in the meta-analysis of 1075 PWH. The principal associated DNAm sites mapped to genes (e.g. STAT1, PARP9, IFITM1, MX1, and IFIT1) related to inflammation and antiviral response. Adjusting for multiple testing, 10 of 118 sCD14-associated DNAm sites significantly predicted survival time conditional on sCD14 levels.

Conclusion:

The identification of DNAm sites independently predicting survival may improve our understanding of prognosis and potential therapeutic targets among PWH.
Brief Report: Virologic Impact of the Dolutegravir Transition: Prospective Results From the Multinational African Cohort Study
Authors: Allahna Esber , Nicole Dear , Neha Shah , Hannah Kibuuka , Jonah Maswai , John Owuoth , Valentine Singoei , Emmanuel Bahemana , Michael Iroezindu , Trevor A. Crowell , Christina S. Polyak , Joseph S. Cavanaugh , Julie A. Ake ,   on behalf of the AFRICOS Study Group
Published: August 2022

Background:

The real-world impact on viral suppression of switching from non–dolutegravir-based therapy to tenofovir/lamivudine/dolutegravir (TLD) is not thoroughly characterized in Africa. We described the virologic consequences of switching regimens in the African Cohort Study (AFRICOS), an observational cohort in Nigeria, Kenya, Uganda, and Tanzania.

Methods:

Among antiretroviral-experienced people living with HIV (PLWH) in AFRICOS, we compared viral load (VL) nonsuppression (VL ≥ 1000 copies/mL) among those who switched with those who never switched to TLD, restricting to participants who had at least 1 visit with a recorded VL after the countrywide rollout of TLD. We calculated Kaplan–Meier curves and conducted Cox proportional hazards modeling to estimate adjusted hazard ratios and 95% confidence intervals for factors potentially associated with nonsuppression.

Results:

As of September 1, 2021, there were 3108 PLWH enrolled. Among 1576 participants who switched to TLD, 1486 (94.3%) remained suppressed after transition, 12 (0.8%) remained unsuppressed, and 38 (2.4%) lost suppression, compared with 652 (82.1%), 75 (9.4%), and 46 (5.8%), respectively, of 797 participants who did not switch (P < 0.001). After adjustment for sex, age, study site, and self-reported antiretroviral therapy adherence, virally suppressed participants who did not switch to TLD had significantly higher rates of losing viral suppression compared with those who switched (adjusted hazard ratio: 4.26; 95% confidence interval: 2.72 to 6.68).

Conclusions:

PLWH transitioning to TLD had higher rates of viral suppression compared with those who remained on other regimens. Even within a highly suppressed population, TLD transition provided significant benefits for achieving or maintaining viral suppression.
Childhood trauma in patients with epileptic versus non-epileptic seizures
Authors: Yang Tianren , Roberts Caitlin , Winton-Brown Toby , Lloyd Michael , Kwan Patrick , O’Brien Terence J , Velakoulis Dennis , Rayner Genevieve , Malpas Charles B
Published: August 2022

Objective

Childhood trauma has been implicated as a risk factor for the aetiology of psychogenic non-epileptic seizures (PNES). Relatively little attention has been paid to whether profiles of specific trauma types differ between patients with epilepsy and PNES. Investigating childhood trauma profiles in these patient groups may identify psychological vulnerabilities the predispose to developing PNES, and aid early diagnoses, prevention, and treatment.

Methods

Data were collected from two cohorts (nRetrospective=203;nProspective=209) admitted to video-EEG monitoring units in Melbourne Australia. The Childhood Trauma Questionnaire domain score differences between patient groups were investigated using standardised effect sizes and general linear mixed-effects models (GLMMs). Receiver operating characteristic curves were used to investigate classification accuracy.

Results

In the retrospective cohort, patients diagnosed with PNES reported greater childhood emotional abuse, emotional neglect, physical abuse, sexual abuse, and physical neglect relative to epilepsy patients. These differences were replicated in the prospective cohort, except for physical abuse. GLMMs revealed significant main effects for group in both cohorts, but no evidence for any group by domain interactions. Reported sexual abuse showed the best screening performance of PNES, although no psychometric scores were adequate as isolated measures.

Significance

Patients with PNES report greater frequency of childhood trauma than patients with epilepsy. This effect appears to hold across all trauma types, with no strong evidence emerging for a particular trauma type that is more prevalent in PNES. From a practical perspective, inquiring regarding a history of sexual abuse shows the most promise as a screening measure.

Relatively little attention has been paid to whether profiles of specific trauma types differ between patients with epilepsy and PNES.

We collected self-reported childhood trauma information from two independent cohorts of patients undergoing VEM

Patients with PNES report greater frequency of childhood trauma than patients with epilepsy.

This effect appears to hold across all trauma types, with no strong evidence emerging for a particular trauma type that is more prevalent in PNES.

Inquiring regarding a history of sexual abuse shows the most promise as a screening measure.
COADREADx: A comprehensive algorithmic dissection unravels salient biomarkers and actionable insights into the discrete progression of colorectal cancer
Authors: Palaniappan Ashok , Muthamilselvan Sangeetha , Sarathi Arjun
Published: August 2022

Colorectal cancer is a common condition with an uncommon burden of disease, heterogeneity in manifestation, and no definitive treatment in the advanced stages. Against this backdrop, renewed efforts to unravel the genetic drivers of colorectal cancer progression are paramount. Early-stage detection contributes to the success of cancer therapy and increases the likelihood of a favorable prognosis. Here, we have executed a comprehensive computational workflow aimed at uncovering the discrete stagewise genomic drivers of colorectal cancer progression. Using the TCGA COADREAD expression data and clinical metadata, we constructed stage-specific linear models as well as contrast models to identify stage-salient differentially expressed genes. Stage-salient differentially expressed genes with a significant monotone trend of expression across the stages were identified as progression-significant biomarkers. Among the biomarkers identified are: CRLF1, CALB2, STAC2, UCHL1, KCNG1 (stage-I salient), KLHL34, LPHN3, GREM2, ADCY5, PLAC2, DMRT3 (stage-II salient), PIGR, HABP2, SLC26A9 (stage-III salient), GABRD, DKK1, DLX3, CST6, HOTAIR (stage-IV salient), and CDH3, KRT80, AADACL2, OTOP2, FAM135B, HSP90AB1 (top linear model genes). In particular the study yielded 31 genes that are progression-significant such as ESM1, DKK1, SPDYC, IGFBP1, BIRC7, NKD1, CXCL13, VGLL1, PLAC1, SPERT, UPK2, and interestingly three members of the LY6G6 family. Significant monotonic linear model genes included HIGD1A, ACADS, PEX26, and SPIB. The stage-salient genes were benchmarked using normals-augmented dataset, and cross-referenced with existing knowledge. In addition, the signature of a multicellular immuno-cyte community specific to colorectal cancer relative to normal tissue was identified. The candidate biomarkers were used to construct the feature space for learning an optimal model for the digital screening of early-stage colorectal cancers. A feature space of just seven biomarkers, namely ESM1, DHRS7C, OTOP3, AADACL2, LPHN3, GABRD, and LPAR1, was sufficient to optimize a RandomForest model that achieved >98% balanced accuracy (and performant recall) on blind validation with external datasets. Survival analysis yielded a panel of three stage-IV salient genes, namely HOTAIR, GABRD, and DKK1, for the design of an optimal multivariate model for patient risk stratification. Integrating the above results, we have developed COADREADx, a web-server for assisting the screening and prognosis of colorectal cancers. COADREADx has been deployed at:https://apalanialab.shinyapps.io/coadreadx/for academic research and further refinement.
Plant conservation assessment at scale: rapid triage of extinction risks
Authors: AuBuchon-Elder Taylor , Minx Patrick , Bookout Bess , Kellogg Elizabeth A.
Published: August 2022

The IUCN Red List criteria are widely used to determine extinction risks of plant and animal life. Here, we use The Red List’s criterion B, Geographic Range Size, to provide preliminary conservation assessments of the members of a large tribe of grasses, the Andropogoneae, with ∼1100 species, including maize, sorghum, and sugarcane and their wild relatives.

We use georeferenced occurrence data from the Botanical Information and Ecology Network (BIEN) and automated individual species assessments using ConR to demonstrate efficacy and accuracy in using time-saving tools for conservation research. We validate our results with those from the IUCN-authorized assessment tool, GeoCAT.

We discovered a remarkably large gap in digitized information, with slightly more than 50% of the Andropogoneae lacking sufficient information for assessment. ConR and GeoCAT largely agree on which taxa are of least concern (>90%) or possibly threatened (<10%), highlighting that automating assessments with ConR is a viable strategy for preliminary conservation assessments of large plant groups. Results for crop wild relatives are similar to those for the entire data set.

Increasing digitization and collection needs to be a high priority. Available rapid assessment tools can then be used to identify species that warrant more comprehensive investigation.

Societal Impact Statement

The current rate of global biodiversity loss creates a pressing need to increase efficiency and throughput of extinction risk assessments in plants. We must assess as many plant species as possible, working with imperfect knowledge, to address the habitat loss and seemingly countless extinction threats of the Anthropocene. Large-scale, preliminary conservation assessments can play a fundamental role in setting priorities for more in-depth investigation.
Combined BRCA2 and MAGEC3 expression predict outcome in Advanced Ovarian Cancers
Authors: Omole Emmanuel B. , Aijaz Iqbal , Ellegate James , Isenhart Emily , Desouki Mohamed M. , Mastri Michalis , Humphrey Kristen , Dougherty Emily M. , Rosario Spencer R. , Nastiuk Kent L. , Ohm Joyce E. , Eng Kevin H.
Published: August 2022

Like BRCA2, MAGEC3 is an ovarian cancer predisposition gene that has been shown to have prognostic significance in ovarian cancer patients. Despite the clinical significance of each individual gene, no studies have been done to assess the clinical significance of their combined expression. We therefore sought to determine the relationship between MAGEC3 and BRCA2 expression in ovarian cancer and their association with patient characteristics and outcomes. Immuno-histochemical staining was quantitated on tumor microarrays of human tumor samples obtained from 357 patients with epithelial ovarian cancer to ascertain BRCA2 expression levels. In conjunction with our previously published MAGEC3 expression data, we observed a weak inverse correlation of MAGEC3 with BRCA2 expression (r= -0.15; p<0.05) in cases with full-length BRCA2. Patients with optimal cytoreduction, loss of MAGEC3, and detectable BRCA2 expression had better overall (median OS: 127.9 vs 65.3 months, p=0.035) and progression-free (median PFS: 85.3 vs 18.8 months, p=0.002) survival compared to patients that were BRCA2 expressors with MAGEC3 normal levels. Our results suggest that combined expression of MAGEC3 and BRCA2 serves as a better predictor of prognosis than each marker alone.

Simple Summary

Early detection of ovarian cancer is a significant clinical challenge, with most women presenting with advanced stages of disease at initial diagnosis. The aim of this study was to evaluate the role of MAGEC3 and BRCA2 in epithelial ovarian cancer progression. We evaluated the effect of MAGEC3 and BRCA2 on the other’s expression. We tested this in humans using immunohistochemical staining of human tumor samples obtained from patients with epithelial ovarian cancer (n = 357). We found a weak inverse correlation between MAGEC3 and BRCA2 expression in epithelial ovarian cancers. Further, our data suggests that the combined expression of MAGEC3 and BRCA2 may be a better predictor of outcomes in patients than the individual markers alone.
A Pair Formation Model with Recovery: Application to Monkeypox
Authors: Betti Matthew I , Farrell Lauren , Heffernan Jane
Published: August 2022

The current global outbreaks of Monkeypox is a unique infectious disease in the way it seems to be transmitting: it has been observed to be highly concentrated in communities of men who have sex with men (MSM) through pair formation, and also provides immunity. This framework of mostly close, prolonged contact spreading a disease that admits immunity after infection is unlike similar infections which either offer little to no immunity post-infection or are lifelong infections. This creates the need for a new model framework that incorporates pair formation structure with recovery. While seemingly a straight forward model, we show how new dynamics arise from the combination of pair formation and recovery that are not present in a standard model with recovery and also not present in a pair formation model without recovery. We see that the combination of these two properties allows for waves of infection that are not seen in a standard SIR model. These dynamics suggest that outbreaks of monkeypox around the world may require special attention from public health. We also derive a reproduction number for this model and estimate the reproduction number of human monkeypox to be ≈ 2.3 using global and Canadian data. The expression derived for R0 can help estimate key parameters for diseases transmission and public health interventions and compare to equivalent models without pair formation.

Significance Statement

With outbreaks of Monkeypox being observed around the world, a modeling framework which takes into account the unique properties of this emerging disease is necessary for understanding the disease and public health mitigation. Monkeypox seems to be unique in that it requires close, prolonged contact with an infected individual in order to spread, but also provides immunity after infection. We develop a model for this situation and show how this differs from simpler models which are currently being used for disease dynamics.
promor: a comprehensive R package for label-free proteomics data analysis and predictive modeling
Authors: Ranathunge Chathurani , Patel Sagar S. , Pinky Lubna , Correll Vanessa L. , Chen Shimin , Semmes O. John , Armstrong Robert K. , Combs C. Donald , Nyalwidhe Julius O.
Published: August 2022

We present promor, a comprehensive, user-friendly R package that streamlines label-free (LFQ) proteomics data analysis and building machine learning-based predictive models with top protein candidates.

Availability and implementation

promor is freely available as an open source R package on the Comprehensive R Archive Network (CRAN)(https://CRAN.R-project.org/package=promor) and distributed under the Lesser General Public License (version 2.1 or later). Development version of promor is maintained on GitHub (https://github.com/caranathunge/promor) and additional documentation and tutorials are provided on the package website (https://caranathunge.github.io/promor/).

Contact

caranathunge86@gmail.com
Cancer tissue of origin constrains the growth and metabolism of metastases
Authors: Sivanand Sharanya , Gultekin Yetis , Winter Peter S. , Vermeulen Sidney Y. , Tchourine Konstantine , Abbott Keene L. , Danai Laura V. , Gourgue Florian , Do Brian T. , Crowder Kayla , Kunchok Tenzin , Lau Allison N. , Darnell Alicia M. , Jefferson Alexandria , Morita Satoru , Duda Dan G. , Aguirre Andrew , Wolpin Brian M. , Henning Nicole , Spanoudaki Virginia , Maiorino Laura , Irvine Darrell J. , Yilmaz Omer H. , Lewis Caroline A. , Vitkup Dennis , Shalek Alex K. , Vander Heiden Matthew G.
Published: August 2022

Metastases arise from a subset of cancer cells that disseminate from the primary tumor; however, the factors that contribute to proliferation of cancer cells in a secondary site are incompletely understood. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize. Specific cancer types metastasize to consistent subsets of tissues, suggesting that factors associated with the primary tumor influence the tissue environments where cancers can grow. Using pancreatic cancer as a model, we find that primary and metastatic tumors share many metabolic similarities and that the tumor initiating capacity and proliferation of both primary- and metastasis-derived cells is favored in the primary site relative to the metastatic site. Moreover, propagating lung or liver metastatic cells in vivo to enrich for tumor cells adapted to grow in the lung or the liver does not enhance their relative ability to form large tumors in those sites, change their preference to grow in the primary site, nor stably alter some aspects of their metabolism relative to primary tumors. We also analyzed primary liver and lung cancer cells and find that these cells also exhibit a preference to grow in their primary site relative to metastatic sites. Together, these data suggest that the cancer tissue-of-origin influences the metabolism of both primary and metastatic tumors and may impact whether cancer cells can thrive in a metastatic site.
Loss of Rer1 causes proteotoxic stress that drives cell competition and inhibits Myc-driven overgrowth
Authors: Paul Pranab Kumar , S Rishana Farin , Annaert Wim , Chaudhary Varun
Published: August 2022

Cell competition is a developmental phenomenon that allows the selection of healthier cells in a developing tissue. In this process, cells with reduced fitness, conceivably due to harmful mutations, acquire the ‘loser’ status and are eliminated by the fitter (winner) neighboring cells via juxtacrine cell-cell interactions. How various mutations trigger cell competition is an extensively studied question. However, the mechanism of cell competition remains largely elusive. In this study, we reveal previously unknown functions of an ER and Golgi localized protein Rer1 in the regulation of cell competition in the developing Drosophila wing epithelium. Our data show that loss of Rer1 leads to the proteotoxic stress marked by the increased phosphorylation of eIF2α. The increased proteotoxic stress in the rer1 mutant cells led to their elimination via cell competition. Interestingly, we find that Rer1 levels are upregulated upon Myc overexpression, which generates super-competitive cells that overgrow at the expense of the normal neighboring cells. Loss of Rer1 also restricts the growth of Myc-induced super-competitive cells. Moreover, consistent with its known function as a negative regulator of the Notch pathway, our results show that the increased levels of Rer1 in Myc-overexpression led to the downregulation of Notch activity. In summary, these observations provide the first characterization of Rer1 in Drosophila and reveal its role in triggering cell competition via the regulation of proteotoxic stress.
Design, fabrication, and preclinical testing of a miniaturized, multispectral, chip-on-tip, imaging probe for intraluminal fluorescence imaging of the gastrointestinal tract
Authors: Slomka Bridget , Duan Suzann , Sontz Ricky , Merchant Juanita L. , Sawyer Travis W.
Published: August 2022

Gastrointestinal cancers continue to account for a disproportionately large percentage of annual cancer deaths in the US. Advancements in miniature imaging technology combined with a need for precise and thorough tumor detection in gastrointestinal cancer screenings fuel the demand for new, small-scale, and low-cost methods of localization and margin identification with improved accuracy. Here, we report the development of a miniaturized, chip-on-tip, multispectral, fluorescence imaging probe designed to port through a gastroscope working channel with the aim of detecting cancerous lesions in point-of-care endoscopy of the gastrointestinal lumen. Preclinical testing has confirmed fluorescence sensitivity and supports that this miniature probe can locate structures of interest via detection of fluorescence emission from exogenous contrast agents. This work demonstrates the design and preliminary performance evaluation of a miniaturized, single-use, chip-on-tip fluorescence imaging system, capable of detecting multiple fluorochromes, and devised for deployment via the accessory channel of a standard gastroscope.
MMP14 cleaves PTH1R in the chondrocyte derived osteoblast lineage, curbing signaling intensity for proper bone anabolism
Authors: Chu Tsz Long , Chen Peikai , Yu Anna Xiaodan , Kong Mingpeng , Tan Zhijia , Tsang Kwok Yeung , Zhou Zhongjun , Cheah Kathryn S.E.
Published: August 2022

Bone homeostasis is regulated by hormones such as parathyroid hormone (PTH). While PTH can stimulate osteo-progenitor expansion and bone synthesis, how PTH-signaling intensity in progenitors is controlled is unclear. Endochondral bone osteoblasts arise from perichondrium-derived osteoprogenitors and hypertrophic chondrocytes (HC). We found, via single-cell transcriptomics, HC descendent cells activate membrane-type 1 metalloproteinase 14 (MMP14) and the PTH pathway as they transition to osteoblasts in neonatal and adult mice. Unlike Mmp14 global knockouts, HC lineage-specific Mmp14 null mutants (Mmp14ΔHC) produce more bone. Mechanistically, MMP14 cleaves the extracellular domain of PTH1R, dampening PTH signaling and PTH signaling is enhanced in Mmp14ΔHC mutants. We found HC-derived osteoblasts contribute ∼50% of osteogenesis promoted by treatment with PTH 1-34 and this response was amplified in Mmp14ΔHC. MMP14 control of PTH signaling likely applies also to both HC- and non- HC-derived osteoblasts because their transcriptomes are highly similar. Our study identifies a novel paradigm of MMP14 activity-mediated titration of PTH signaling in the osteoblast lineage, contributing new insights into bone metabolism with therapeutic significance for bone-wasting diseases.
AICAR prevents doxorubicin-induced heart failure in rats by ameliorating cardiac atrophy and improving fatty acid oxidation
Authors: Choksey Anurag , Thackray Benjamin D. , Ball Vicky , Ha Lea Hong Tuan , Sharma Eshita , Kennedy Brett W. C. , Carter Ryan D. , Broxholme John , Murphy Michael P , Heather Lisa C , Tyler Damian J , Timm Kerstin N
Published: August 2022

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to functional cardiac decline and ultimately, congestive heart failure (HF). Impaired mitochondrial function and energetics are thought to be key factors driving progression into HF. We have previously shown in a rat model of chronic intravenous DOX-administration that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and oxidative metabolism, including fatty acid oxidation. We hypothesized that AMPK activation could restore mitochondrial number and function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. We therefore set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this clinically relevant rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. We show that this could be due to normalisation of substrate supply to the heart, as AICAR prevented DOX-induced dyslipidaemia. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, despite no increase in mitochondrial number. In addition, we found that AICAR prevented excessive myocardial atrophy, and RNAseq analysis showed that this may be due to normalisation of protein synthesis pathways, which are impaired in DOX-treated rat hearts. Taken together, these results show promise for use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac mass and improve cardiac function.
CRISPR interference for Sequence-Specific Regulation of Fibroblast Growth Factor Receptor A in Schistosoma mansoni
Authors: Du Xiaofeng , McManus Donald P. , French Juliet D. , Collinson Natasha , Sivakumaran Haran , MacGregor Skye R. , Fogarty Conor E. , Jones Malcolm K. , You Hong
Published: August 2022

Employing the flatworm parasite Schistosoma mansoni as a model, we report the first application of CRISPR interference (CRISPRi) in parasitic helminths for loss-of-function targeting the SmfgfrA gene which encodes the stem cell marker, fibroblast growth factor receptor A. SmFGFRA is essential for maintaining schistosome stem cells and critical in the schistosome-host interplay. The SmfgfrA gene was targeted in S. mansoni adult worms, eggs and schistosomula using a catalytically dead Cas9 (dCas9) fused to a transcriptional repressor KRAB. We showed that SmfgfrA repression resulted in considerable phenotypic differences in the modulated parasites compared with controls, including reduced levels of SmfgfrA transcription and decreased protein expression of SmFGFRA, a decline in EdU (thymidine analog 5-ethynyl-2’-deoxyuridine, which specifically stains schistosome stem cells) signal, and an increase in cell apoptosis. Notably, reduced SmfgfrA transcription was evident in miracidia hatched from SmfgfrA-repressed eggs, and resulted in a significant change in miracidial behavior, indicative of a durable repression effect caused by CRISPRi. Intravenous injection of mice with SmfgfrA-repressed eggs resulted in granulomas that were markedly reduced in size and a decline in the level of serum IgE, emphasizing the importance of SmFGFRA in regulating the host immune response induced during schistosome infection. Our findings show the feasibility of applying CRISPRi for effective, targeted transcriptional repression in schistosomes, and provide the basis for employing CRISPRi to selectively perturb gene expression in parasitic helminths on a genome-wide scale.
Uncovering brain tissue architecture across scales with super-resolution light microscopy
Authors: Michalska Julia M. , Lyudchik Julia , Velicky Philipp , Korinkova Hana , Watson Jake F. , Cenameri Alban , Sommer Christoph , Venturino Alessandro , Roessler Karl , Czech Thomas , Siegert Sandra , Novarino Gaia , Jonas Peter , Danzl Johann G.
Published: August 2022

Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanoscopic synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS leverages fixation-compatible extracellular labeling and advanced optical readout, in particular stimulated-emission depletion and expansion microscopy, to comprehensively delineate cellular structures. It enables 3D-reconstructing single synapses and mapping synaptic connectivity by identification and tailored analysis of putative synaptic cleft regions. Applying CATS to the hippocampal mossy fiber circuitry, we demonstrate its power to reveal the system’s molecularly informed ultrastructure across spatial scales and assess local connectivity by reconstructing and quantifying the synaptic input and output structure of identified neurons.
Comparison of progressive hold and progressive response schedules of reinforcement
Authors: Alvarez-Sekely Celeste Sofia , Toscano-Zapien Ana Laura , Salles-Ize Paloma , Lopez-Guzman Maria Almudena , Velázquez-Martinez David N.
Published: August 2022

Progressive ratio (PR) schedules had been widely used to study motivation to work for a reinforcer. After a post-reinforcer pause, subjects engage pressing a lever until a reinforcer is obtained. However, the discrete nature of lever presses allows alternative behaviors during inter-response time and had lead to the suggestion of several behavioral categories to explain pauses and work time. A progressive hold-down (PH) is incompatible with alternative responses and may allow a precise estimation of work time. Performance of rats trained in both PR and PH that received sucrose or intracranial self-stimulation (ICSS) as reinforcer were compared. We observed that rats mastered the PR and PH schedules. Post-reinforcer pauses, work time and inter-reinforcer time increased as a function of the response or hold requirement. However, rat’s performance suggest that the PH progression may be experienced by the rats as easier that the PR progression. Elimination of consummatory behavior with ICSS reduced PSRP and in accordance with predictions of explanatory models of fixed and variable schedules of reinforcement. In the case of PH performance, intermediate requirements leveled off pauses but inceased rapidly on later requirements; since rats controlled pause length and work time was close to hold requirement, time allocation between PR and PH schedules diverged. Finally, the Mathematical Principles of Reinforcement model of Bradshaw and Killeen (Psychopharmacology 2012, 222: 549) rendered a good description of the performance in both PR and PH schedules.
Differentially expressed gene profile and relevant pathways of the inhibition of LAMP5 on MLL-rearranged leukemias
Authors: Qian Zhiwen , Zhang Wei
Published: August 2022

LAMP5 is a lysosome-related protein, which showed increased expression levels in MLL-r leukemia. Recent findings showed that LAMP5 is involved in MLL-fusion protein but the specific mechanism is still unclear. In our study, we aim to identify the transcriptional landscapes of the LAMP5-shRNA-treated MLL-r leukemia cells. We used the gene enrichment analyses such as KEGG and GO to further analyze the potential signaling pathways. Moreover, we constructed the PPI network and Reactome map to further identify the biological processes. We found that Lysosome and Cell Cycle are the major signaling pathways involved in the LAMP5-shRNA treated MLL-r leukemia cells. We identified the top ten interactive genes including CDK1, TOP2A, PLK1, CCNA2, ASPM, BUB1, BUB1B, CCNB1, AURKA, and KIF11. Our study may provide novel mechanisms for the treatment of MLL-r leukemia by inhibiting LAMP5.
Distinct effects of intracellular vs. extracellular acidic pH on the cardiac metabolome during ischemia and reperfusion
Authors: Milliken Alexander S. , Ciesla Jessica H. , Nadtochiy Sergiy M. , Brookes Paul S.
Published: August 2022

Tissue ischemia results in intracellular pH (pHIN) acidification, and while accumulation of metabolites such as lactate is a known driver of acidic pHIN, less is known about how acidic pHIN regulates metabolism. Furthermore, acidic extracellular (pHEX) during early reperfusion confers cardioprotection, but how this impacts metabolism is unclear. Herein we employed LCMS based targeted metabolomics to analyze perfused mouse hearts exposed to: (i) control perfusion, (ii) hypoxia, (iii) ischemia, (iv) enforced acidic pHIN, (v) control reperfusion, and (vi) acidic pHEX (6.8) reperfusion. Surprisingly little overlap was seen between metabolic changes induced by hypoxia, ischemia, and acidic pHIN. Acidic pHIN elevated metabolites in the top half of glycolysis, and enhanced glutathione redox state. Acidic pHEX reperfusion induced substantial metabolic changes in addition to those seen in control reperfusion. This included elevated metabolites in the top half of glycolysis, prevention of purine nucleotide loss, and an enhancement in glutathione redox state. These data led to parallel hypotheses regarding potential roles for methylglyoxal inhibiting the mitochondrial permeability transition pore, and for acidic inhibition of ecto-5’-nucleotidase, as potential mediators of cardioprotection by acidic pHEX reperfusion. However, neither hypothesis was supported by subsequent experiments. In contrast, analysis of cardiac effluents revealed complex effects of pHEX on metabolite transport, suggesting that mildly acidic pHEX may protect in part by enhancing succinate release during reperfusion. Overall, each intervention had distinct and overlapping metabolic effects, suggesting acidic pH is an independent metabolic regulator regardless which side of the cell membrane it is imposed.

HIGHLIGHTS

Hypoxia, ischemia and acidic pHIN each induce unique cardiac metabolic profiles.

Acidic pHEX at reperfusion prevents purine loss and enhances succinate release.
Genetic and ecological drivers of molt in a migratory bird
Authors: Contina Andrea , Bossu Christen M. , Allen Daniel , Wunder Michael B. , Ruegg Kristen C.
Published: August 2022

The ability of animals to sync the timing and location of molting (the replacement of hair, skin, exoskeletons or feathers) with peaks in resource availability has important implications for their ecology and evolution. In migratory birds, the timing and location of pre-migratory feather molting, a period when feathers are shed and replaced with newer, more aerodynamic feathers, can vary within and between species. While hypotheses to explain the evolution of intraspecific variation in the timing and location of molt have been proposed, little is known about the genetic basis of this trait or the specific environmental drivers that may result in natural selection for distinct molting phenotypes. Here we take advantage of intraspecific variation in the timing and location of molt in the iconic songbird, the Painted Bunting (Passerina ciris) to investigate the genetic and ecological drivers of distinct molting phenotypes. Specifically, we use genome-wide genetic sequencing in combination with stable isotope analysis to determine population genetic structure and molting phenotype across thirteen breeding sites. We then use genome-wide association analysis (GWAS) to identify a suite of genes associated with molting and pair this with gene-environment association analysis (GEA) to investigate potential environmental drivers of genetic variation in this trait. Associations between genetic variation in molt-linked genes and the environment are further tested via targeted SNP genotyping in 25 additional breeding populations across the range. Together, our integrative analysis suggests that molting is in part regulated by genes linked to feather development and structure (GLI2 and CSPG4) and that genetic variation in these genes is associated with seasonal variation in precipitation and aridity. Overall, this work provides important insights into the genetic basis and potential selective forces behind phenotypic variation in what is arguably one of the most important fitness-linked traits in a migratory bird.
A PATHWAY FOR T3 SIGNALING IN THE BRAIN TO IMPROVE THE VARIABLE EFFECTIVENESS OF THERAPY WITH L-T4
Authors: Salas-Lucia Federico , Fekete Csaba , Sinkó Richárd , Egri Péter , Rada Kristóf , Ruska Yvette , Bocco Barbara , Fonseca Tatiana , Gereben Balázs , Bianco Antonio C.
Published: August 2022

The effectiveness of therapy for hypothyroidism with levothyroxine (L-T4) depends on patients’ ability to activate T4 to T3 —altered in carriers of a common deiodinase polymorphism (Thr92Ala-DIO2). Some patients that exhibit impaired mood and cognition improve with liothyronine (L-T3), but the underlying mechanisms remain unknown. Here we show that the T3-indicator mouse carrying the Thr92Ala-DIO2 polymorphism exhibits a hippocampal-specific reduction in T3 activation and signaling that limits the effectiveness of L-T4 therapy. To understand the L-T3 effect, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering relatively large amounts of T3 to the cell nucleus, doubling the expression of the T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and the type 3 deiodinase (Dio3), which transports and inactivates T3, respectively. Notwithstanding, T3 gets away from degradation because D3 active center is in the cytosol. These findings provide (i) a basis for the variable effectiveness of L-T4 therapy, (ii) a pathway for L-T3 to reach neurons, and (iii) resolve the paradox of T3 signaling in the brain amid high D3 activity.
Timing of Transcranial Direct Current Stimulation at M1 Does Not Affect Motor Sequence Learning
Authors: Kim Hakjoo , King Bradley R. , Verwey Willem B. , Buchanan John J. , Wright David L.
Published: August 2022

Administering anodal tDCS at the primary motor cortex (M1) at various temporal loci relative to motor training is reported to affect subsequent performance gains. Stimulation administered in conjunction with motor training appears to offer the most robust benefit that emerges during offline epochs. This conclusion is made, however, based on between-experiment comparisons that involved varied methodologies. The present experiment addressed this shortcoming by administering the same 15-minute dose of anodal tDCS at M1 before, during, or after practice of a serial reaction time task (SRTT). It was anticipated that exogenous stimulation during practice with a novel SRTT would facilitate offline gains. Ninety participants were randomly assigned to one of four groups: tDCS before practice, tDCS during practice, tDCS after practice, or no tDCS. Each participant was exposed to 15 minutes of 2 mA of tDCS and motor training of an eight-element SRTT. The anode was placed at right M1 with the cathode at left M1, and the left hand was used to execute the SRTT. Test blocks were administered 1 and 24 hours after practice concluded. The results revealed significant offline gain for all conditions at the 1-hour and 24-hour test blocks. Importantly, exposure to anodal tDCS at M1 at any point before, during, or after motor training failed to change the trajectory of skill development as compared to the no stimulation control condition. These data add to the growing body of evidence questioning the efficacy of exogenous stimulation as an adjunct to motor training for fostering skill learning.

Highlights

Time-dependent consolidation of a novel motor skill occurred within 1 hour after the first practice block

Further consolidation of this memory still occurred 24 hours after practice

tDCS at M1 before, during, or after the initial bout of practice did not modify online or offline performance gains
A microbiota-derived metabolite instructs peripheral efferocytosis
Authors: Saavedra Pedro H. V. , Trzeciak Alissa , Wang Zhaoquan , Saitz Rojas Waleska , Zago Giulia , Docampo Melissa D. , Verter Jacob G. , van den Brink Marcel R. M. , Lucas Christopher D. , Anderson Christopher J. , Rudensky Alexander Y. , Perry Justin S. A.
Published: August 2022

The phagocytic clearance of dying cells, termed efferocytosis, is essential for both tissue homeostasis and tissue health during cell death-inducing treatments. Failure to efficiently clear dying cells augments the risk of pathological inflammation and has been linked to a myriad of autoimmune and inflammatory diseases. Although past studies have elucidated local molecular signals that regulate efferocytosis in a tissue, whether signals arising distally also regulate efferocytosis remains elusive. Interestingly, clinical evidence suggests that prolonged use of antibiotics is associated with an increased risk of autoimmune or inflammatory disease development. We therefore hypothesized that intestinal microbes produce molecular signals that regulate efferocytotic ability in peripheral tissue phagocytes. Here, we find that macrophages, the body’s professional phagocyte, display impaired efferocytosis in peripheral tissues in both antibiotic-treated and germ-free mice in vivo, which could be rescued by fecal microbiota transplantation. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency and capacity in mouse and human macrophages, with both intestinal and local delivery of butyrate capable of rescuing antibiotic-induced peripheral efferocytosis defects. Bulk mRNA sequencing of primary macrophages treated with butyrate in vitro and single cell mRNA sequencing of macrophages isolated from antibiotic-treated and butyrate-rescued mice revealed specific regulation of phagocytosis-associated transcriptional programs, in particular the induction of programs involved in or supportive of efferocytosis. Surprisingly, the effect of butyrate on efferocytosis was not mediated through G protein-coupled receptor signaling, but instead acted by inhibition of histone deacetylase 3. Strikingly, peripheral efferocytosis was impaired well-beyond withdrawal of antibiotics and, importantly, antibiotic-treated mice exhibited a poorer response to a sterile efferocytosis-dependent inflammation model. Collectively, our results demonstrate that a process essential for tissue homeostasis, efferocytosis, relies on distal molecular signals, and suggest that a defect in peripheral efferocytosis may contribute to the clinically-observed link between broad-spectrum antibiotics use and inflammatory disease.
Parallel molecular computation on digital data stored in DNA
Authors: Wang Boya , Wang Siyuan S. , Chalk Cameron , Ellington Andrew D. , Soloveichik David
Published: August 2022

DNA is an incredibly dense storage medium for digital data, but computing on the stored information is expensive and slow (rounds of sequencing,in silicocomputation, and DNA synthesis). Augmenting DNA storage with “in-memory” molecular computation, we use strand displacement reactions to algorithmically modify data stored in the topological modification of DNA. A secondary sequence-level encoding allows high-throughput sequencing-based readout. We show multiple rounds of binary counting and cellular automaton Rule 110 computation on 4-bit data registers, as well as selective access and erasure. Avoiding stringent sequence design, we demonstrate large strand displacement cascades (122 distinct steps) on naturally-occurring DNA sequences. Our work merges DNA storage and DNA computing, setting the foundation of entirely molecular algorithms for parallel manipulation of digital information kept in DNA.