bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Utility of SPECT in the Heart Transplant Population: Analysis From a Single Large-volume Center
Authors: Aguilar Jack , Miller Robert J. H. , Otaki Yuka , Tamarappoo Balaji , Hayes Sean , Friedman John , Slomka Piotr J. , Thomson Louise E. J. , Kittleson Michelle , Patel Jignesh K. , Kobashigawa Jon A. , Berman Daniel S.
Published: April 2021

Background.

Survival after heart transplant has greatly improved, with median survival now over 12 years. Cardiac allograft vasculopathy (CAV) has become a major source of long-term morbidity and mortality. Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is used for CAV surveillance, but there is limited data on its prognostic utility.

Methods.

We retrospectively identified patients undergoing SPECT MPI for CAV surveillance at a single, large-volume center. Images were assessed with semiquantitative visual scoring (summed stress score [SSS] and summed rest score) and quantitatively with total perfusion defect (TPD).

Results.

We studied 503 patients (mean age 62.5, 69.3% male) at a median of 9.0 years post-transplant. During mean follow-up of 5.1 ± 2.5 years, 114 (22.6%) patients died. The diagnostic accuracy for significant CAV (ISHLT grade 2 or 3) was highest for SSS with an area under the curve of 0.650 and stress TPD (area under the curve, 0.648), with no significant difference between SSS and stress TPD (P = 0.061). Stress TPD (adjusted hazard ratio, 1.07; P = 0.018) was independently associated with all-cause mortality, while SSS was not (P = 0.064). The prognostic accuracy of quantitative assessment of perfusion tended to be higher compared with semiquantitative assessment, with the highest accuracy for stress TPD (area under the receiver operating curve 0.584).

Conclusions.

While SPECT MPI identified a cohort of higher risk patients, with quantitative analysis of perfusion demonstrating higher prognostic accuracy. However, the overall prognostic accuracy was modest and alternative noninvasive modalities may be more suitable for CAV surveillance.
Solid Organ Transplantation From Deceased Donors With Infective Endocarditis: The UK Experience
Authors: Greenhall George H. B. , Robb Matthew L. , Brown Chloe , Johnson Rachel J. , Tomlinson Laurie A. , Callaghan Chris J. , Watson Christopher J. E.
Published: April 2021

Background.

There is little evidence regarding the use of organs from deceased donors with infective endocarditis. We performed a retrospective analysis of the utilization, safety, and long-term survival of transplants from donors with infective endocarditis in the United Kingdom.

Methods.

We studied deceased donor transplants over an 18-y period (2001–2018) using data from the UK Transplant Registry. We estimated the risk of infection transmission, defined as a microbiological isolate in the recipient matching the causative organism in the donor in the first 30 days posttransplant. We examined all-cause allograft failure up to 5 years in kidney and liver recipients, comparing transplants from donors with endocarditis with randomly selected matched control transplants.

Results.

We studied 88 transplants from 42 donors with infective endocarditis. We found no cases of infection transmission. There was no difference in allograft failure between transplants from donors with infective endocarditis and matched control transplants, among either kidney (hazard ratio, 1.48; 95% CI, 0.66-3.34) or liver (hazard ratio, 1.14; 95% CI, 0.54-2.41) recipients. Compared with matched controls, donors with infective endocarditis donated fewer organs (2.3 versus 3.2 organs per donor; P < 0.001) and were less likely to become kidney donors (odds ratio, 0.29; 95% CI, 0.16-0.55).

Conclusions.

We found acceptable safety and long-term allograft survival in transplants from selected donors with infective endocarditis in the United Kingdom. This may have implications for donor selection and organ utilization.
Plasma Levels of SERCA2a as a Noninvasive Biomarker of Primary Graft Dysfunction After Heart Transplantation
Authors: Lozano-Edo Silvia , Sánchez-Lázaro Ignacio , Portolés Manuel , Roselló-Lletí Esther , Tarazón Estefania , Arnau-Vives Miguel Angel , Ezzitouny Meryem , Lopez-Vilella Raquel , Almenar-Bonet Luis , Martínez-Dolz Luis
Published: April 2021

Background.

Noninvasive detection of primary graft dysfunction (PGD) remains a major challenge. SERCA2a plays an important role in cardiac homeostasis and its dysregulation has been associated with ventricular dysfunction and rejection. This study aimed to determine the potential utility of plasma levels of SERCA2a as a biomarker of PGD.

Methods.

One hundred thirty-five plasma samples were collected from adult recipients 2–6 hours before heart transplantation (HT). Plasma concentrations of SERCA2a were determined using a specific sandwich ELISA. Variables related to the recipient, the donor, and the periprocedural were collected to determine a multivariate predictive model of PGD.

Results.

Levels of SERCA2a were decreased in patients who developed PGD (median 0.430 ng/mL [interquartile range, 0.260–0.945] versus 0.830 ng/mL [interquartile range, 0.582–1.052]; P = 0.001). Receiver operating characteristic curve analysis revealed that SERCA2a discriminated between patients with and without PGD (AUC = 0.682; P = 0.001), and a cutoff point ≥ 0.60 ng/mL was a protective independent predictor of PGD (odds ratio 0.215 [P = 0.004]). Three independent predictors of PGD in this study were reduced levels of pre-HT SERCA2a, increased bilirubin levels, and short-term mechanical circulatory support bridge to transplantation. The analysis of the receiver operating characteristic curve of the model obtained a significant AUC 0.788, P = 0.0001.

Conclusions.

Our findings suggest that assessment of SERCA2a plasma levels may improve risk prediction for the occurrence of PGD and could be considered as a novel noninvasive biomarker in patients undergoing HT.
Cigarette craving modulation is more feasible than resistance modulation for heavy cigarette smokers: empirical evidence from functional MRI data
Authors: Kim Dong-Youl , Tegethoff Marion , Meinlschmidt Gunther , Yoo Seung-Schik , Lee Jong-Hwan
Published: April 2021

Background

Modulation of cigarette craving and neuronal activations from nicotine-dependent cigarette smokers using real-time functional MRI (rtfMRI)-based neurofeedback (rtfMRI-NF) has been previously reported.

Objectives

The aim of this study was to evaluate the efficacy of rtfMRI-NF training in reducing cigarette cravings using fMRI data acquired before and after training.

Methods

Treatment-seeking male heavy cigarette smokers (N = 14) were enrolled and randomly assigned to two conditions related to rtfMRI-NF training aiming at resisting the urge to smoke. In one condition, subjects underwent conventional rtfMRI-NF training using neuronal activity as the neurofeedback signal (activity-based) within regions-of-interest (ROIs) implicated in cigarette craving. In another condition, subjects underwent rtfMRI-NF training with additional functional connectivity information included in the neurofeedback signal (functional connectivity-added). Before and after rtfMRI-NF training at each of two visits, participants underwent two fMRI runs with cigarette smoking stimuli and were asked to crave or resist the urge to smoke without neurofeedback. Cigarette craving-related or resistance-related regions were identified using a general linear model followed by paired t-tests and were evaluated using regression analysis on the basis of neuronal activation and subjective craving scores (CRSs).

Results

Visual areas were mainly implicated in craving, whereas the superior frontal areas were associated with resistance. The degree of (a) CRS reduction and (b) the correlation between neuronal activation and CRSs were statistically significant (P < 0.05) in the functional connectivity-added neurofeedback group for craving-related ROIs.

Conclusion

Our study demonstrated the feasibility of altering cigarette craving in craving-related ROIs but not in resistance-related ROIs via rtfMRI-NF training.
Predictors of long-acting injectable antipsychotic treatment discontinuation in outpatients with schizophrenia: relevance of the Drug Attitude Inventory-10
Authors: Tatini Lorenzo , D’Anna Giulio , Pietrini Francesco , Calligaris Eugenia , Ballerini Andrea , Ricca Valdo
Published: April 2021

Given the importance of patients’ subjective experience and attitudes in the management of severe mental illness, the present study evaluated their potential role as predictors of future continuation of long-acting injectable antipsychotic maintenance treatment (LAI-AMT) in clinically stable outpatients with schizophrenia switching from an oral therapy. Retrospective data from 59 subjects receiving LAI-AMT for at least 6 months were collected. Patients who continued LAI treatment (n = 32) were compared to those who discontinued it (n = 27), assessing baseline socio-demographic and clinical characteristics, psychopathological features (Positive And Negative Syndrome Scale, Montgomery–Åsberg Depression Rating Scale and Young Mania Rating Scale) and patient-reported experience of treatment through Drug Attitude Inventory 10-item (DAI-10) and Subjective Well-being under Neuroleptics short form. Binary logistic and Cox regression analyses explored the predictive role of the mentioned variables on treatment discontinuation. The Kaplan–Meier estimator compared dropout from LAI treatment in subsamples with different characteristics. Unemployment and lower baseline DAI-10 scores predicted LAI-AMT discontinuation. No major differences were detected in other socio-demographic, clinical or psychometric indexes. When switching from oral to LAI-AMT, the preliminary assessment of attitude towards drug might be clinically relevant, allowing the identification of patients at risk for treatment discontinuation.
Oxidative stress specifically inhibits replication of dengue virus
Authors: Khan Naseem Ahmed , Kar Meenakshi , Panwar Aleksha , Wangchuk Jigme , Kumar Saurabh , Das Asim , Pandey Anil Kumar , Lodha Rakesh , Medigeshi Guruprasad R.
Published: April 2021

Reactive oxygen species (ROS) are chemically active species which are involved in maintaining cellular and signalling processes at physiological concentrations. Therefore, cellular components that regulate redox balance are likely to play a crucial role in viral life-cycle either as promoters of viral replication or with antiviral functions. Zinc is an essential micronutrient associated with anti-oxidative systems and helps in maintaining a balanced cellular redox state. Here, we show that zinc chelation leads to induction of reactive oxygen species (ROS) in epithelial cells and addition of zinc restores ROS levels to basal state. Addition of ROS (H2O2) inhibited dengue virus (DENV) infection in a dose-dependent manner indicating that oxidative stress has adverse effects on DENV infection. ROS affects early stages of DENV replication as observed by quantitation of positive and negative strand viral RNA. We observed that addition of ROS specifically affected viral titres of positive strand RNA viruses. We further demonstrate that ROS specifically altered SEC31A expression at the ER suggesting a role for SEC31A-mediated pathways in the life-cycle of positive strand RNA viruses and provides an opportunity to identify drug targets regulating oxidative stress responses for antiviral development.
Developing and comparing machine learning models to detect sleep apnoea using single-lead electrocardiogram (ECG) monitoring
Authors: Hedman Marcel , Rojas Alex , Arora Anmol , Ola David
Published: April 2021

Background

Sleep apnoea has a high disease burden but remains underdiagnosed, in part due to the expensive and resource intensive nature of polysomnography, its definitive investigation. Emerging literature suggests that it may be possible to detect sleep apnoea using single-lead ECG signals, such as those obtained from smartwatches. In this study, we use two forms of recurrent neural networks (RNNs) to detect sleep apnoea events from single-lead ECG signals.

Methods

We use single-lead ECG data from the PhysioNet Apnea-ECG database, which contains data from 70 patients. We train a bidirectional gated recurrent unit (GRU) model and a bidirectional long short-term memory (LSTM) model on labelled ECG signals from 35 patients and test the models on the remaining 35 patients in the dataset.

Results

Both models achieved 97.1% accuracy, sensitivity and specificity to detect whether the ECG recordings belonged to a patient diagnosed with sleep apnoea. This corresponds to 34/35 patients in the dataset. At detecting individual apnoea events, the GRU and LSTM models achieved 90.4% and 91.7% accuracies respectively.

Discussion

The models achieved high levels of accuracy, specificity and sensitivity. Bidirectional RNNs are strengthened by the ability of the models to be informed by both past and future states when analysing sequential data, such as ECGs. The models also require minimal human intervention as they automatically extract features from the data. If single-lead ECGs prove a suitable tool for sleep apnoea detection, this may enhance the diagnosis of sleep apnoea and potentially allow widespread screening for the condition.

Conclusions

We note that using models such as bidirectional RNNs has the potential to augment model performance. However, more research and validation is required in order to test whether these may be applicable to other datasets and in clinical practice.
Blood transcriptomes of anti-SARS-CoV2 antibody positive healthy individuals with prior asymptomatic versus clinical infection
Authors: Sfikakis Petros P. , Verrou Kleio-Maria , Tsitsilonis Ourania , Paraskevis Dimitrios , Kastritis Efstathios , Lianidou Evi , Moutsatsou Paraskevi , Terpos Evangelos , Trougakos Ioannis , Chini Vasiliki , Manoloukos Menelaos , Moulos Panagiotis , Pavlopoulos Georgios A. , Kollias George , Ampatziadis-Michailidis Giannis , Hatzis Pantelis , Dimopoulos Meletios A
Published: April 2021

Despite tremendous efforts by the international research community to understand the pathophysiology of SARS-CoV-2 infection, the reasons behind the clinical variability, ranging from asymptomatic infection to lethal disease, are still unclear. Existing inter-individual variations of the immune responses, due to environmental exposures and genetic factors, may be critical to the development or not of symptomatic disease after infection with SARS-CoV-2, and transcriptomic differences marking such responses may be observed even later, after convalescence. Herein, we performed genome-wide transcriptional whole-blood profiling to test the hypothesis that immune response-related gene signatures may differ between healthy individuals with prior entirely asymptomatic versus clinical SARS-CoV-2 infection, all of which developed an equally robust antibody response. Among 12.789 protein-coding genes analyzed, there were only six and nine genes with significantly decreased or increased expression, respectively, in those with prior asymptomatic infection (n=17, mean age 34 years) relatively to those with clinical infection (n=15, mean age 37 years). All six genes with decreased expression (IFIT3, IFI44L, RSAD2, FOLR3, PI3, ALOX15), are involved in innate immune response while the first two are interferon-induced proteins. Among genes with increased expression six are involved in immune response (GZMH, CLEC1B, CLEC12A), viral mRNA translation (GCAT), energy metabolism (CACNA2D2) and oxidative stress response (ENC1). Notably, 8/15 differentially expressed genes are regulated by interferons. Our results suggest that an intrinsically weaker expression of some innate immunity-related genes may be associated with an asymptomatic disease course in SARS-CoV-2 infection. Whether a certain gene signature predicts, or not, those who will develop a more efficient immune response upon exposure to SARS-CoV-2, with implications for prioritization for vaccination, warrant further study.
Episodic memory deficits are associated with impaired insight in traumatic encephalopathy syndrome: Initial findings of the SNAP-CTE study
Authors: Mobbs Rowena , Batchelor Jennifer , Teunisse Alessandra , Erskine Ellen , Brown Eamon , Hood Joshua , Mobbs Anthony , Fraser Clare , Pearce Alan J , Stevenson Richard , Beran Roy , Miskovic-Wheatley Anna , Chan Karina , Ching Mun Foo Alicia , Lystad Reidar
Published: April 2021

Chronic traumatic encephalopathy (CTE) has been identified at post-mortem in Australian football codes players. Detailed and objective clinical and radiological characterization of patients at-risk of sporting and non-sporting repetitive concussive and subconcussive traumatic brain injury (RC/SCI) is important to our understanding of traumatic encephalopathy syndrome (TES) and CTE. This paper presents the initial findings of the symptomatology, neurocognitive, and pathophysiological changes in CTE (SNAP-CTE) study. A preliminary, retrospective, cohort study of 28 patients (25 males and 3 females) presenting with complaints of mood, behavioral, and cognitive decline, comprising TES, aged 24 to 78 years (M = 53, SD = 15.3) with at least 10 years of exposure to RC/SCI (mostly through contact sport) and cognitive decline were examined including: demographics; duration of play; age of first exposure to RC/SCI; and neuropsychology. Participants performed significantly worse in tests of auditory, visual, immediate, and delayed memory compared to a normative sample. Those with absent insight, compared to those with preserved insight, had a larger discrepancy between predicted and actual auditory memory scores, and had more severe mood disturbances. Insight, a hallmark sign of dementia, was either absent or impaired in a significant proportion (M = 36.4%, 95% CI =17.2% - 59.3%) of the sample aged under 65, compared with normative epidemiological data. This indicates that RC/SCI may be associated with risk of an early onset dementia syndrome representing probably TES/CTE. CTE is increasingly of concern to the Australian community, and further research in this area is necessary. This retrospective preliminary study will form the basis of large, prospective, longitudinal cohort studies, assessing the natural history of TES/CTE in Australian athletes.
A novel artificial lung organoid for simulating a patient derived adenocarcinoma of lung for personalized oncology
Authors: Esmail Sally , Danter Wayne R
Published: April 2021

Optimizing patient care based on precision oncology will inevitably become the standard of care. If we accept the principle that every persons’ cancer is different then the most effective therapies will have to be designed for the individual patient and for their tumors genetic profile. Access to tumor mutational profiling is now widely available but continues to be limited by cost and actionable information. For example, novel combinations of approved drugs are rarely considered. These considerations lead us to hypothesize that artificially induced Lung Adenocarcinoma (LUAD) derived lung organoids could provide a novel, alternate approach for LUAD disease modeling and large-scale targeted drug screening.

In this project, we used data from a commercially available tumor mutation profile to generate and then validate the artificially induced LUAD-derived lung organoid simulations (aiLUNG-LUAD) to model LUAD and identify several drug combinations that effectively reverse the tumors’ genotypic and phenotypic features when compared with placebo. These results complement previous LUAD-derived lung organoids research and provide a novel and widely applicable cancer drug-screening approach for precision/individualized oncology.
Transdiagnostic neurocognitive deficits in patients with type 2 diabetes mellitus, major depressive disorder, bipolar disorder, and schizophrenia: A 1-year follow-up study
Authors: Correa-Ghisays Patricia , Sánchez-Ortí Joan Vicent , Balanzá-Martínez Vicent , Selva-Vera Gabriel , Vila-Francés Joan , Magdalena-Benedito Rafael , Victor Victor M , Lopez Irene Escribano , Hernández-Mijares Antonio , Vivas-Lalinde Juliana , San-Martín Constanza , Crespo-Facorro Benedicto , Tabarés-Seisdedos Rafael
Published: April 2021

Background

Impairments in neurocognition are critical factors in patients with major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), and also in those with somatic diseases such as type 2 diabetes mellitus (T2DM). Intriguingly, these severe mental illnesses are associated with an increased co-occurrence of diabetes (direct comorbidity). This study sought to investigate the neurocognition and social functioning across T2DM, MDD, BD, and SZ using a transdiagnostic and longitudinal approach.

Methods

A total of 165 subjects, including 30 with SZ, 42 with BD, 35 with MDD, 30 with T2DM, and 28 healthy controls (HC), were assessed twice at a 1-year interval using a comprehensive, integrated test battery on neuropsychological and social functioning.

Results

Common neurocognitive impairments in somatic and psychiatric disorders were identified, including deficits in short-term memory and cognitive reserve (p < 0.01; η2p = 0.08-0.31). Social functioning impairments were observed in almost all the disorders (p < 0.0001; η2p = 0.29-0.49). Transdiagnostic deficits remained stable across the 1-year follow-up (p < 0.001; η2p = 0.13-0.43) and could accurately differentiate individuals with somatic and psychiatric disorders (χ2 = 48.0, p < 0.0001).

Conclusions

This longitudinal study provides evidence of the overlap in neurocognition deficits across somatic and psychiatric diagnostic categories, such as T2DM, MDD, BD, and SZ, which have high comorbidity. This overlap may be a result of shared genetic and environmental etiological factors. The findings further lay forth promising avenues for research on transdiagnostic phenotypes of neurocognition in these disorders, in addition to their biological bases.
EVIDENCE FOR BIOLOGICAL AGE ACCELERATION AND TELOMERE SHORTENING IN COVID19 SURVIVORS
Authors: Mongelli Alessia , Barbi Veronica , Zamperla Michela Gottardi , Atlante Sandra , Forleo Luana , Nesta Marialisa , Massetti Massimo , Pontecorvi Alfredo , Nanni Simona , Farsetti Antonella , Catalano Oronzo , Bussotti Maurizio , Vecchia Laura Dalla , Bachetti Tiziana , Martelli Fabio , La Rovere Maria Teresa , Gaetano Carlo
Published: April 2021

Introduction & Background

the SARS-CoV-2 infection determines the COVID19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokines release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID19 syndrome (PPCS) is a common finding. In patients who survived the SARS-CoV-2 infection, overt PPCS presents one or more symptoms such as fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. The pathophysiology of PPCS is currently poorly understood, and whether epigenetic mechanisms are involved in this process is unexplored.

Methods & Results

In this study, a cohort of 117 COVID19 survivors (post-COVID19) and 144 non-infected volunteers (COVID19-free) were analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. Besides, telomere length (TL) and ACE2 and DPP-4 receptor expression were determined. The results show a consistent biological age increase in the post-COVID19 population (58,44 ± 14,66 ChronoAge Vs. 67,18 ± 10,86 BioAge, P<0,0001), determining a DeltaAge acceleration of 10,45 ± 7,29 years (+5.25 years above range of normality) compared to 3,68 ± 8,17 years for the COVID19-free population (P<0,0001). A significant telomere shortening parallels this finding in the post-COVID19 cohort compared to COVID19-free subjects (post-COVID19 TL: 3,03 ± 2,39 Kb vs. COVID19-free: 10,67 ± 11,69 Kb; P<0,0001). Additionally, ACE2 expression was decreased in post-COVID19 patients compare to COVID19-free, while DPP-4 did not change.

Conclusion

In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID19 condition, particularly in the youngers (<60 years). Although the consequences of such modifications on the long-term clinical outcome remain unclear, this finding might help indicating a direction to investigate the pathophysiology at the onset of the persistent post-COVID19 syndrome.
Mortality of Care Home Residents and Community-Dwelling Controls During the COVID-19 Pandemic in 2020: Matched Cohort Study
Authors: Gulliford Martin C , Prevost A. Toby , Clegg Andrew , Rezel-Potts Emma
Published: April 2021

Objective

To estimate mortality of care home (CH) residents, and matched community-dwelling controls, during the Covid-19 pandemic from primary care electronic health records.

Design

Matched cohort study

Setting

General practices contributing to the Clinical Practice Research Datalink Aurum Database in England.

Participants

There were 83,627 CH residents contributing data in 2020, with 26,923 deaths; 80,730 (97%) were matched on age, gender and general practice with 300,445 community-dwelling adults.

Main outcome measures

All-cause mortality. Adjusted rate ratios (RR) by negative binomial regression were adjusted for age, gender, number of long-term conditions (LTCs), frailty category, region, calendar month or week, and clustering by general practice.

Results

During April 2020, the mortality rate of CH residents was 27.2 deaths per 1,000 patients per week, compared with 2.31 per 1,000 for controls, RR 11.1 (95% confidence interval 10.1 to 12.2). Compared with CH residents, LTCs and frailty were differentially associated with greater mortality in community-dwelling controls. During April 2020, mortality rates per 1,000 patients per week for persons with 9+ LTCs were: CH, 37.9; controls 17.7; RR 2.14 (1.18 to 3.89). In severe frailty, mortality rates were: CH, 29.6; controls 5.1; RR 6.17 (5.74 to 6.62).

Conclusions

Individual-patient data from primary care electronic health records may be used to estimate mortality in care home residents. Mortality is substantially higher than for community-dwelling comparators and showed a disproportionate increase in the first wave of the Covid-19 pandemic. Multiple morbidity and frailty were associated with greater absolute risks but lower relative risks because community-dwelling frail or multi-morbid patients also experienced high mortality.
High-sensitivity detection of facial features on MRI brain scans with a convolutional network
Authors: Bansal Shashank , Kori Avinash , Zulfikar Wazeer , Wexler Joseph , Markiewicz Christopher J. , Feingold Franklin F. , Poldrack Russell A. , Esteban Oscar
Published: April 2021

Platforms and institutions that support MRI data sharing need to ensure that identifiable facial features are not present in shared images. Currently, this assessment requires manual effect as no auto-mated tools exist that can efficiently and accurately detect if an image has been “defaced”. The scarcity of publicly available data with pre-served facial features, as well as the meager incentives to create such a cohort privately, have averted the development of face-detection models. Here, we introduce a framework to detect whether an input MRI brain scan has been defaced, with the ultimate goal of streamlining it within the submission protocols of MRI data archiving and sharing platforms. We present a binary (defaced/”nondefaced”) classifier based on a custom convolutional neural network architecture. We train the model on 980 de-faced MRI scans from 36 different studies that are publicly available at OpenNeuro.org. To overcome the unavailability of nondefaced examples, we augment the dataset by inpainting synthetic faces into each training image. We show the adequacy of such a data augmentation in a cross-validation evaluation. We demonstrate the performance estimated with cross-validation matches that of an evaluation on a held-out dataset (N=581) preserving real faces, and obtain accuracy/sensitivity/speci-ficity scores of 0.978/0.983/0.972, respectively. Data augmentations are key to boosting the performance of models bounded by limited sample sizes and insufficient diversity. Our model contributes towards developing classifiers with∼100% sensitivity detecting faces, which is crucial to ensure that no identifiable data are inadvertently made public.
Osteophyte size and location on hip DXA scans are associated with hip pain: findings from a cross sectional study in UK Biobank
Authors: Faber Benjamin G , Ebsim Raja , Saunders Fiona R , Frysz Monika , Lindner Claudia , Gregory Jennifer S , Aspden Richard M , Harvey Nicholas C , Davey Smith George , Cootes Timothy , Tobias Jonathan H
Published: April 2021

Objective
It remains unclear how the different features of radiographic hip osteoarthritis (rHOA) contribute to hip pain. We examined the relationship between rHOA, including its individual components, and hip pain using a novel dual-energy x-ray absorptiometry (DXA)-based method.

Methods
Hip DXAs were obtained from UK Biobank. An automated method was developed to obtain minimum joint space width (mJSW) from points placed around the femoral head and acetabulum. Osteophyte areas at the lateral acetabulum, superior and inferior femoral head were derived manually. Semi-quantitative measures of osteophytes and joint space narrowing (JSN) were combined to provide a measure of rHOA. Logistic regression was used to examine the relationships between these variables and hip pain, obtained via questionnaires.

Results
6,807 hip DXAs were examined. rHOA was present in 353 [5.2%] individuals and was associated with hip pain [OR 2.07 (95% CI 1.54-2.80)] and hospital diagnosed OA [5.73 (2.89-11.36)]. Total osteophyte area and mJSW were associated with hip pain [1.29 (1.21-1.36), 0.84 (0.77-0.92) respectively] in unadjusted models. After mutually adjusting and adding demographic covariates, total osteophyte area continued to have strong evidence of association with hip pain [1.31 (1.23-1.39)] but mJSW did not [0.95 (0.87-1.04)]. Acetabular, superior and inferior femoral osteophyte areas were all independently associated with hip pain [1.19 (1.13-1.26), 1.22 (1.15-1.29), 1.21 (1.14-1.28) respectively].

Conclusion
The relationship between DXA-derived rHOA and prevalent hip pain is explained by osteophyte area rather than mJSW. Osteophytes at different locations showed important, potentially independent, associations with hip pain, possibly reflecting the contribution of distinct biomechanical pathways.
Therapeutic targeting of SLC6A8 creatine transporter inhibits KRAS mutant and wildtype colon cancer and modulates human creatine levels
Authors: Kurth Isabel , Yamaguchi Norihiro , Andreu-Agullo Celia , Tian Helen S. , Sridhar Subhasree , Takeda Shugaku , Gonsalves Foster C. , Loo Jia Min , Barlas Afsar , Manova-Todorova Katia , Busby Robert , Bendell Johanna C. , Strauss James , Fakih Marwan , McRee Autumn J. , Hendifar Andrew E. , Rosen Lee S. , Cercek Andrea , Wasserman Robert , Spector Scott L. , Raza Syed , Tavazoie Masoud F. , Tavazoie Sohail F.
Published: April 2021

Colorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 creatine transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels and induces tumor cell apoptosis in CRC. RGX-202 suppressed tumor growth across KRAS wild-type and KRAS mutant xenograft, syngeneic and patient-derived xenograft colorectal cancers. Anti-tumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5- fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in metastatic CRC patients enrolled in a Phase-1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of pre-clinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, revealing a critical target for CRC.
Premovement inhibition protects motor actions from interference
Authors: McInnes Aaron N. , Lipp Ottmar V. , Tresilian James R. , Vallence Ann-Maree , Marinovic Welber
Published: April 2021

Shortly before movement initiation, the corticospinal system undergoes a transient suppression. This phenomenon has been observed across a range of motor tasks, suggesting that it may be a obligatory component of movement preparation. We probed whether this was also the case when the urgency to perform a motor action was high, in a situation where little time was available to engage in preparatory processes. We controlled the urgency of an impending motor action by increasing or decreasing the foreperiod duration in an anticipatory timing task. Transcranial magnetic stimulation (TMS; experiment one) or a loud acoustic stimulus (LAS; experiment two) were used to examine how corticospinal and subcortical excitability were modulated during motor preparation. Preparatory inhibition of the corticospinal tract was absent when movement urgency was high, though motor actions were initiated on time. In contrast, subcortical circuits were progressively inhibited as the time to prepare increased. Interestingly, movement force and vigour were reduced by both TMS and the LAS when movement urgency was high, and enhanced when movement urgency was low. Our findings indicate that preparatory inhibition may not be a obligatory component of motor preparation. The behavioural effects we observed in the absence of preparatory inhibition were induced by both TMS and the LAS, suggesting that accessory sensory stimulation may disrupt motor output when such stimulation is presented in the absence of preparatory inhibition. We conclude that preparatory inhibition may be an adaptive strategy which can serve to protect the prepared motor action from external interference.
Isolation and characterization of barley (Hordeum vulgare) extracellular vesicles and their role in RNAi-based crop protection
Authors: Schlemmer T , Weipert L , Preußer C , Hardt M , Möbus A , Barth P , Busche T , Koch A
Published: April 2021

The demonstration that spray-induced gene silencing (SIGS) can confer strong disease resistance bypassing the laborious and time-consuming transgenic expression of double-stranded (ds)RNA to induce gene silencing of pathogenic targets was groundbreaking. However, future field applications will require fundamental mechanistic knowledge on dsRNA uptake, processing, and its transfer. There is increasing evidence that extracellular vesicles (EVs) mediate the transfer of transgene-derived small interfering (si)RNAs in host-induced gene silencing (HIGS) applications. Here, we examined the role of EVs regarding the translocation of sprayed dsRNA from barley (Hordeum vulgare) to the target fungusFusarium graminearum. We found barley EVs with 156 nm in size containing predominantly 21 and 19 nucleotide (nt) siRNAs starting with a 5’-terminal Adenine. Notably, barley EVs contain less siRNA compared to EVs isolated from transgenic HIGS Arabidopsis plants. Together our results further underpin mechanistic differences between HIGS and SIGS applications and a minor role of EVs in SIGS.
An ALE meta-analytic review of top-down and bottom-up processing of music in the brain
Authors: Pando-Naude Victor , Patyczek Agata , Bonetti Leonardo , Vuust Peter
Published: April 2021

A remarkable feature of the human brain is its ability to integrate information from the environment with internally generated content. The integration of top-down and bottom-up processes during complex multi-modal human activities, however, is yet to be fully understood. Music provides an excellent model for understanding this since music listening leads to the urge to move, and music making entails both playing and listening at the same time (i.e. audio-motor coupling). Here, we conducted activation likelihood estimation (ALE) meta-analyses of 130 neuroimaging studies of music perception, production and imagery, with 2660 foci, 139 experiments, and 2516 participants. We found that music perception and production rely on auditory cortices and sensorimotor cortices, while music imagery recruits distinct parietal regions. This indicates that the brain requires different structures to process similar information which is made available either by an interaction with the environment (i.e. bottom-up) or by internally generated content (i.e. top-down).
Changes in Cellular Crosstalk between Skeletal Muscle Myoblasts and Bone Osteoblasts with Aging
Authors: Doering Jonathan A. , Britt Carly E. , Sawicki Gregory S. , Cole Jacqueline H.
Published: April 2021

Musculoskeletal function declines with aging, resulting in an increased incidence of trips and falls. Both bone and muscle experience age-related losses in tissue mass that alter their mechanical interactions in a well characterized manner, but changes in the biochemical interactions between bone and muscle with aging are not well understood. Of note, insulin-like growth factor 1 (IGF-1), a potent growth factor for bone and muscle, can be negatively altered with aging and may help explain losses in these tissues. We recently developed a co-culture system for simultaneous growth of bone mesenchymal stem cells (MSCs) and muscle satellite cells (SCs) to investigate the biochemical crosstalk between the two cell types. Here, we utilized an aging rat model to study cellular changes between young and old rat MSCs and SCs, in particular whether 1) young MSCs and SCs have increased proliferation and differentiation compared to old MSCs and SCs; 2) young cells have increased IGF-1 and collagen expression as a measure of crosstalk compared to old cells; and 3) young cells can mitigate the aging phenotype of old cells in co-culture. Rat MSCs and SCs were either mono- or co-cultured in Transwell®plates, grown to confluence, and allowed to differentiate for 14 days. Across the 14 days, cell proliferation was measured, with differentiation and crosstalk measurements evaluated at 14 days. The results suggest that in both young and old, proliferation is greater in mono-cultures compared to co-cultures, yet age and cell type did not have a significant effect. Differentiation did not differ between young and old cells, yet MSCs and SCs demonstrated the greatest amount of differentiation in co-culture. Finally, age, cell type, and culture type did not have a significant effect on collagen or IGF-1 expression. These results suggest co-culture may have a controlling effect, with the two cell types acting together to promote differentiation more than in mono-cultures, yet this response was not altered by age. In general, results for old cells had higher variability, suggesting a wider variety in the aging phenotypes demonstrated in these animals. This study was the first to use this rat aging model to investigate changes between bone and skeletal muscle cells, however further investigations are required to determine what signaling changes occur in response to age. Determining these signaling changes could lead to new targets for mitigating the progression of aging.
A pro-metastatic tRNA fragment drives Nucleolin oligomerization and stabilization of bound metabolic mRNAs
Authors: Liu Xuhang , Alwaseem Hanan , Molina Henrik , Tavora Bernardo , Tavazoie Sohail F.
Published: April 2021

Stress-induced cleavage of transfer RNAs (tRNAs) into tRNA-derived fragments (tRFs) occurs across organisms from yeast to human, yet its mechanistic bases and pathological consequences remain poorly defined. By performing genome-wide small RNA profiling, we detected increased abundance of a Cysteine tRNA fragment (5’-tRFCys) during breast cancer metastatic progression. 5’’-tRFCys is required for efficient breast cancer metastatic lung colonization and metastatic cell survival. We identified Nucleolin as the direct binding partner of 5’-tRFCys. 5’-tRFCys binding enhanced the stability of Nucleolin’s associated pro-metastatic transcripts encoding metabolic enzymes Mthfd1l and Pafah1b1. 5’-tRFCys stabilized these transcripts by promoting Nucleolin oligomerization and the assembly of Nucleolin and its bound transcripts into a higher-order ribonucleoprotein complex. Our findings reveal that a tRF can promote oligomerization of an RNA binding protein into a stabilizing ribonucleoprotein complex containing specific target transcripts, thereby driving specific metabolic pathways underlying cancer progression.
Fitness estimation for viral variants in the context of cellular coinfection
Authors: Zhu Huisheng , Allman Brent E , Koelle Katia
Published: April 2021

Animal models are frequently used to characterize the within-host dynamics of emerging zoonotic viruses. More recent studies have also deep-sequenced longitudinal viral samples originating from experimental challenges to gain a better understanding of how these viruses may evolvein vivoand between transmission events. These studies have often identified nucleotide variants that can replicate more efficiently within hosts and also transmit more effectively between hosts. Quantifying the degree to which a mutation impacts viral fitness within a host can improve identification of variants that are of particular epidemiological concern and our ability to anticipate viral adaptation at the population level. While methods have been developed to quantify the fitness effects of mutations using observed changes in allele frequencies over the course of a host’s infection, none of the existing methods account for the possibility of cellular coinfection. Here, we develop mathematical models to project variant allele frequency changes in the context of cellular coinfection and, further, integrate these models with statistical inference approaches to demonstrate how variant fitness can be estimated alongside cellular multiplicity of infection. We apply our approaches to empirical longitudinally-sampled H5N1 sequence data from ferrets. Our results indicate that previous studies may have significantly underestimated the within-host fitness advantage of viral variants. These findings underscore the importance of considering the process of cellular coinfection when studying within-host viral evolutionary dynamics.
New phylogenetic Markov models for inapplicable morphological characters
Authors: Tarasov Sergei
Published: April 2021

Abstract

This paper proposes new Markov models for phylogenetic inference with anatomically dependent (inapplicable) morphological characters. The proposed models can explicitly model an anatomical dependency in which one or several characters are allowed to evolve only within a specific state of the hierarchically upstream character. The new models come up in two main types depending on the type of character hierarchy. The functions for constructing custom character hierarchies are provided in the R packagerphenoscate. The performance of the new models is assessed using theory and simulations. This paper provides practical recommendations for using the new models in Bayesian phylogenetic inference withRevBayes.
Mapping and modeling the genomic basis of differential RNA isoform expression at single-cell resolution with LR-Split-seq
Authors: Rebboah Elisabeth , Reese Fairlie , Williams Katherine , Balderrama-Gutierrez Gabriela , McGill Cassandra , Trout Diane , Rodriguez Isaryhia , Liang Heidi , Wold Barbara J. , Mortazavi Ali
Published: April 2021

Alternative RNA isoforms are defined by promoter choice, alternative splicing, and polyA site selection. Although differential isoform expression is known to play a large regulatory role in eukaryotes, it has proved challenging to study with standard short-read RNA-seq because of the uncertainties it leaves about the full-length structure and precise termini of transcripts. The rise in throughput and quality of long-read sequencing now makes it possible, in principle, to unambiguously identify most transcript isoforms from beginning to end. However, its application to single-cell RNA-seq has been limited by throughput and expense. Here, we develop and characterize long-read Split-seq (LR-Split-seq), which uses a combinatorial barcoding-based method for sequencing single cells and nuclei with long reads. We show that LR-Split-seq can associate isoforms with cell types with relative economy and design flexibility. We characterize LR-Split-seq for whole cells and nuclei by using the well-studied mouse C2C12 system in which mononucleated myoblast cells differentiate and fuse into multinucleated myotubes. We show that the overall results are reproducible when comparing long- and short-read data from the same cell or nucleus. We find substantial evidence of differential isoform expression during differentiation including alternative transcription start site (TSS) usage. We integrate the resulting isoform expression dynamics with snATAC-seq chromatin accessibility to validate TSS-driven isoform choices. LR-Split-seq provides an affordable method for identifying cluster-specific isoforms in single cells that can be further quantified with companion deep short-read scRNA-seq from the same cell populations.
Force-dependent interactions between talin and full-length vinculin
Authors: Wang Yinan , Yao Mingxi , Baker Karen B. , Gough Rosemarie E. , Le Shimin , Goult Benjamin T. , Yan Jie
Published: April 2021

Talin and vinculin are part of a multi-component system involved in mechanosensing in cell-matrix adhesions. Both exist in auto-inhibited forms, and activation of vinculin requires binding to mechanically activated talin, yet how forces affect talin’s interaction with vinculin has not been investigated. Here by quantifying the force-dependent talin-vinculin interactions and kinetics using single-molecule analysis, we show that mechanical exposure of a single vinculin binding site (VBS) in talin is sufficient to relieve the autoinhibition of vinculin resulting in high-affinity binding. We provide evidence that the vinculin undergoes dynamic fluctuations between an auto-inhibited closed conformation and an open conformation that is stabilized upon binding to the VBS. Furthermore, we discover an additional level of regulation in which the mechanically exposed VBS binds vinculin significantly more tightly than the isolated VBS alone. Molecular dynamics simulations reveal the basis of this new regulatory mechanism, identifying a sensitive force-dependent change in the conformation of an exposed VBS that modulates binding. Together, these results provide a comprehensive understanding of how the interplay between force and autoinhibition provides exquisite complexity within this major mechanosensing axis.