bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing Drivers of Gender Balance and Racial Makeup of Editorial Board Members in Biomedical Engineering
Authors: Ahmad Fariha , Jackson Hannah , Kuhn Matthew , Danko Katherine , Grande-Allen Jane
Published: April 2024

Scientific journal editors serve as gatekeepers with the decision-making power of assigning reviewers to manuscripts. Serving as an editor is also an important stage in a young academic’s career progression, and an indicator of high regard/acceptance within one’s academic field. For both of these reasons, it is important to have representation with members of underrepresented groups serving in these roles. In this paper, we explore the gender and racial distribution among editorial boards for peer-reviewed scientific journals that are relevant to the field of biomedical engineering (BME). Further, we examine changes in these distributions from 2016 to 2021, amidst societal shifts catalyzed by movements such as #metoo and Black Lives Matter (BLM). Despite BME’s reputation for a relatively high percentage of female degree-earners, this study reveals stark disparities in gender and racial representation among editorial leadership positions. Through meticulous data collection and analysis of 75 BME journals— including 44 for which data from both 2016 and 2021 were analyzed—it was found that while the proportion of female editors increased over time, this proportion consistently fell short of the expected standard, which was based on current BME degree awardee values. Moreover, the percentage of Black editors remained stagnant. Correlation analyses between gender, race, and changes in journal impact factor (ΔJIF) revealed nuanced trends, in some cases showing that increasing ΔJIFs were associated with decreasing proportions of female editors. The study underscores the urgent need for changes in social and policy standards to address gender and racial inequities in BME [editorial] leadership, both of which will be necessary to foster greater diversity and inclusivity throughout the field.
Cardiac Cycle Modulates Alpha and Beta Suppression during Motor Imagery.
Authors: Lai Giuseppe , Landi David , Vidaurre Carmen , Bhattacharya Joydeep , Ruiz Maria Herrojo
Published: April 2024

Introduction The baroreceptor hypothesis posits that baroreceptors, located on the cardiac walls, are most active during systole, translating cardiac contraction information to the brain. Studies within this context have suggested that the systolic phase, characterised by increased noise, may compromise the processing of sensory stimuli. Although the effect of systolic and diastolic cardiac cycle phases on cognition, perception, and action has been widely documented, there remains a gap in applying these interoceptive insights to enhance assistive technologies such as brain-computer interfaces (BCIs). In the context of BCIs, motor imagery (MI), the mental rehearsal of movement, serves as a widely used control paradigm, yet its modulation through the cardiac cycle has not been empirically tested. Bridging this gap, this study examined how the cardiac cycle phases influence MI by assessing their effect on contralateral suppression of alpha (8-13 Hz) and beta (14-30 Hz) activity in primary sensorimotor cortices. Materials & Methods Twenty-nine participants performed left/right thumb abductions based on the direction of an arrow presented on the screen to get familiarised with kinesthetic sensations. They then completed a MI task of the same movements. We recorded both electroencephalography (EEG) and electrocardiography (ECG), focusing our analysis on data epochs aligned with the experimental cue, based on whether it occurred during the systolic or diastolic phase of the cardiac cycle. Time-frequency analysis of source-reconstructed data assessed cue-induced changes in power spectral density (PSD) within the alpha and beta bands in the postcentral and precentral gyrus. Results We found that alpha and beta suppression in the contralateral primary motor and somatosensory cortex was more pronounced when the cue fell during the diastolic phase of the cardiac cycle than during the systolic phase. Validating the main results, an analysis with circular statistics revealed that trials with particularly pronounced contralateral alpha and beta suppression featured cues with latencies clustering during diastole, the quietest time of the cardiac cycle. Accompanying the EEG effects, EMG activity on the side of the movement was enhanced during diastole. Conclusion These findings provide evidence that MI performance can be enhanced by considering the cardiac cycle phases, offering promising implications for BCI-based applications.
Rating Pome Fruit Quality Traits Using Deep Learning and Image Processing
Authors: Nguyen Nhan H. , Michaud Joseph , Mogollon Rene , Zhang Huiting , Hargarten Heidi , Leisso Rachel , Torres Carolina A. , Honaas Loren , Ficklin Stephen
Published: April 2024

Quality assessment of pome fruits (i.e.apples and pears) is used not only crucial for determining the optimal harvest time, but also the progression of fruit-quality attributes during storage. Therefore, it is typical to repeatedly evaluate fruits during the course of a postharvest experiment. This evaluation often includes careful visual assessments of fruit for apparent defects and physiological symptoms. A general best practice for quality assessment is to rate fruit using the same individual rater or group of individuals raters to reduce bias. However, such consistency across labs, facilities, and experiments is often not feasible or attainable. Moreover, while these visual assessments are critical empirical data, they are often coarse-grained and lack consistent objective criteria. Granny, is a tool designed for rating fruit using machine-learning and image-processing to address rater bias and improve resolution. Additionally, Granny supports backwards compatibility by providing ratings compatible with long-established standards and references, promoting research program continuity. Current Granny ratings include starch content assessment, rating levels of peel defects, and peel color analyses. Integrative analyses enhanced by Granny’s improved resolution and reduced bias, such as linking fruit outcomes to global scale-omics data, environmental changes, and other quantitative fruit quality metrics like soluble solids content and flesh firmness, will further enrich our understanding of fruit quality dynamics. Lastly, Granny is open-source and freely available.
Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice
Authors: Russo Ilaria , Dun Wen , Mehta Swasti , Ahmed Sowda , Tzimas Christos , Fukuma Nobuaki , Tsai Emily J.
Published: April 2024

Background

Right ventricular dysfunction (RVD) portends increased death risk for heart failure (HF) and pulmonary arterial hypertension (PAH) patients, regardless of left ventricular function or etiology. In both, RVD arises from the chronic RV pressure overload, and represents advanced cardiopulmonary disease. RV remodeling responses and survival rates of HF and PAH patients, however, differ by sex. Men develop more severe RVD and die at younger ages than do women. Mechanistic details of this sexual dimorphism in RV remodeling are incompletely understood. We sought to elucidate the cardiac pathophysiology underlying the sex-specific RV remodeling phenotypes, RV failure (RVF) versus compensated RVD.

Methods

We subjected male (M-) and female (F-) adult mice to moderate pulmonary artery banding (PAB) for 9wks. Mice underwent serial echocardiography, cardiac MRI, RV pressure-volume loop recordings, histologic and molecular analyses.

Results

M-PAB developed severe RVD with RVF, increased RV collagen deposition and degradation, extracellular matrix (ECM) instability, and activation and recruitment of macrophages. Despite the same severity and chronicity of RV pressure overload, F-PAB had more stable ECM, lacked chronic inflammation, and developed mild RVD without RVF.

Conclusions

ECM destabilization and chronic activation of recruited macrophages are associated with maladaptive RV remodeling and RVF in male PAB mice. Adaptive RV remodeling of female PAB mice lacked these histopathologic changes. Our findings suggest that these two pathophysiologic processes likely contribute to the sexual dimorphism of RV pressure overload remodeling. Further mechanistic studies are needed to assess their pathogenic roles and potential as targets for RVD therapy and RVF prevention.

CLINICAL PERSPECTIVE

What is new?

In a mouse model of pure PH, males but not females showed an association between ECM instability, chronic inflammation with activation of recruited macrophages, and severe RV dysfunction and failure.

What are the clinical implications?

In male HF and PH patients, enhancing ECM stability and countering the recruitment and activation of macrophages may help preserve RV function such that RVF can be prevented or delayed. Further preclinical mechanistic studies are needed to assess the therapeutic potential of such approaches.

RESEARCH PERSPECTIVE

What new question does this study raise? What question should be addressed next?

What mechanisms regulate RV ECM stability and macrophage recruitment and activation in response to chronic RV pressure overload? Are these regulatory mechanisms dependent upon or independent of sex hormone signaling?
Opposites attract: Multiple evidence of sexual antagonistic coevolution driving extreme male-biased sexual size dimorphism inPanopeus meridionalis
Authors: Farias N.E. , Ribeiro P. , Lancia J.P. , Luppi T.
Published: April 2024

Explanations for the evolution of male-biased size dimorphism (MBSSD) traditionally focus on male competition and female choice, overlooking the alternative that larger males may be better at coercing females into mating. While displaying considerable diversity, ‘true crabs’ (Eubrachyura) share common traits that theoretically should promote the evolution of coercive mating strategies. Despite this, there is a conspicuous lack of studies investigating this aspect. We investigated several reproductive and life history traits ofPanopeus meridionalis(a mud crab that exhibits extreme MBSSD) to assess whether the specific set of characters is consistent with the hypothesis of sexual antagonistic coevolution at place. We found that the high MBSSD is likely driven by sexual conflict, where males use their size to coerce females into mating. Experimental matings involved male aggression towards females. Females first resist male attempts, but are ultimately subdued. Mating is relatively brief and there is no evident pre or post copulatory guarding. The female reproductive tract lacks complex structures for long-term sperm storage or manipulation, and given the small size of seminal receptacles related to male sperm load capacity, it is unlikely for females to store sperm from multiple partners. All considered, the evidence suggests that females have limited control over paternity and support the existence of an intrinsically coercive mating system inP. meridionalis. We propose this species as an interesting model for studying the resolution of sexual conflict through antagonistic coevolution and selection in the highly diverse group of true crabs.
Linking brain networks to cognition with magnetoencephalography in paediatric autoimmune encephalitis
Authors: Billaud Charly , Wood Amanda G , Griffiths-King Daniel J. , Kessler Klaus , Wassmer Evangeline , Foley Elaine , Wright Sukhvir K
Published: April 2024

Paediatric autoimmune encephalitis (e.g., acute disseminated encephalomyelitis, N-methyl-D-aspartate receptor antibody encephalitis) is an inflammatory brain disease that causes cognitive deficits, psychiatric symptoms, seizures, MRI, and EEG abnormalities. Patients can continue to experience residual cognitive difficulties months to years after the acute illness. Magnetoencephalography (MEG) can examine neural changes in the absence of frank structural abnormalities and may help identify factors predicting children at risk of long-term cognitive deficits. We predicted that theta and delta brain functional connectivity networks would be associated with processing speed and working memory in children with autoimmune encephalitis. Participants were children diagnosed with autoimmune encephalitis at least 18 months before testing and typically developing children. All completed MEG recording (Elekta Neuromag Triux) at rest, eyes open with a fixation cross during six minutes; T1 MRI scans; and cognitive evaluation using the primary subtests of the Weschler Intelligence Scale for Children, fifth edition. Brain connectivity, specifically in delta and theta brain activity, was estimated with amplitude envelope correlation, and network efficiency was measured using graph measures (global efficiency, local efficiency, modularity). The measures were compared across the two groups with permutation correction for multiple thresholds. Finally, statistical associations with processing speed and working memory scores were tested in the autoimmune encephalitis group. Age and sex-matched cohorts of 12 children with AE (11.2+/-3.5y, IQR 9y; 5M:7F) and 12 typically developing controls (10.6+/-3.2y, IQR 7y; 8M:4F) participated in this study. On average, children with autoimmune encephalitis did not differ from controls in working memory (t(21)= 1.449; p = .162; d = 0.605) but had a significantly lower processing speed (t(21) = 2.463; p = .023; Cohens d = 1.028). The groups did not differ in theta network topology measures but the autoimmune encephalitis group had a significantly lower delta local efficiency across all thresholds tested (d = -1.60 at network threshold 14%). Theta modularity was associated with lower working memory (β = -.781; t(8) = -2.588, p = .032) but this effect did not survive correction for multiple comparisons (p(corr) = .224). No other graph measure was significantly associated with psychometric scores in the autoimmune encephalitis group. MEG was able to capture network alterations in paediatric autoimmune encephalitis patients, specifically in the topological organisation of delta brain activity. This preliminary study demonstrates that MEG is an appropriate tool for assessing children with autoimmune encephalitis; future studies should focus on confirming which functional networks can predict cognitive performance.
Intensive Versus Conservative Blood Pressure Lowering after Endovascular Therapy in Stroke: a meta-analysis of randomized controlled trials
Authors: Mansoor Ahmed Naji , Choudhary Vatsalya , Nasser Zain Mohammad , Jain Muskan , Sharma Dhruvikumari Dayanand , Villegas Mateo Jaramillo , Janarthanam Sujaritha , Ayyan Muhammad , Nimal Simran Ravindra , Cheema Huzaifa Ahmad , Ehsan Muhammad , Rehman Muhammad Aemaz Ur , Dani Sourbha S.
Published: April 2024

Background

The optimum systolic blood pressure after endovascular thrombectomy for acute ischemic stroke is uncertain. We aimed to perform an updated meta-analysis of randomized controlled trials to evaluate the safety and efficacy of more intensive blood pressure management as compared to less intensive blood pressure management.

Methods

We searched various electronic databases including Embase, MEDLINE (via PubMed), and CENTRAL to retrieve relevant randomized controlled trials (RCTs) on the clinical effects of more intensive blood pressure management after endovascular thrombectomy as compared to the less intensive management. We assessed the risk of bias using the revised Cochrane “Risk of bias” tool for randomized trials (RoB 2.0), calculated risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) with 95% CI for continuous outcomes.

Results

Our meta-analysis included 4 RCTs with a total of 1560 patients. According to our analysis, more intensive blood pressure management was associated with a statistically significant decrease in the number of patients showing functional independence (modified Rankin scale mRS score=0-2) at 90 days (RR 0.81; CI = 0.72-0.91; I2= 12%). Regarding 90-day mortality, our pooled results from three RCTs showed no statistically significant difference between the more intensive blood pressure management group and the less intensive blood pressure management group (RR 1.17; CI = 0.90-1.52; I2= 0%). There was no statistically significant difference between the two groups regarding the incidence of intracerebral hemorrhage (ICH) (RR 1.05; CI = 0.90-1.23; I2= 0%) and the incidence of symptomatic intracerebral hemorrhage (sICH) (RR 1.10; CI = 0.76-1.60; I2= 0%).

Conclusion

According to our meta-analysis, no benefit of intensive lowering of blood pressure was observed in terms of functional independence at 90 days, mortality rates, and incidence of intracerebral hemorrhage. Future large-scale trials should focus on other interventions to improve prognosis in these patients.
Can self-testing be enhanced to hasten safe return of healthcare workers in pandemics? Random order, open label trial using two manufacturers’ SARS-CoV-2 lateral flow devices concurrently
Authors: Zhang Xingna , Cheyne Christopher P , Jones Christopher , Humann Michael , Leeming Gary , Smith Claire , Hughes David M , Burnside Girvan , Dodd Susanna , Penrice-Randal Rebekah , Dong Xiaofeng , Semple Malcolm G , Neal Tim , Tunkel Sarah , Fowler Tom , Turtle Lance , Garcia-Finana Marta , Buchan Iain E
Published: April 2024

Background

Covid-19 healthcare worker testing, isolation and quarantine policies had to balance risks to patients from the virus and from staff absence. The emergence of the Omicron variant led to dangerous levels of key-worker absence globally.

We evaluated whether using two manufacturers’ lateral flow tests (LFTs) concurrently improved SARS-CoV-2 Omicron detection and was acceptable to hospital staff. In a nested study, to understand risks of return to work after a 5-day isolation/quarantine period, we examined virus culture 5-7 days after positive test or significant exposure.

Methods

Fully-vaccinated Liverpool (UK) University Hospitals staff participated (February-May 2022) in a random-order, open-label trial testing whether dual LFTs improved SARS-CoV2 detection, and whether dual swabbing was acceptable to users. Participants used nose-throat swab Innova and nose-only swab Orient Gene LFTs in daily randomised order for 10 days. A user-experience questionnaire was administered on exit. Selected participants gave swabs for viral culture on Days 5-7. Cultures were considered positive if cytopathic effect was apparent or SARs-COV2 N gene sub-genomic RNA was detected.

Results

226 individuals reported 1466 pairs of LFT results. Tests disagreed in 127 cases (8.7%). Orient Gene was more likely (78 cf. 49, P=0.03) to be positive. Orient Gene positive Innova negative result-pairs became more frequent over time (P<0.001). If Innova was swabbed second, it was less likely to agree with a positive Orient Gene result (P=0.005); swabbing first with Innova made no significant difference (P=0.85).

Of 311 individuals completing the exit questionnaire, 90.7% reported dual swabbing was easy, 57.1% said it was no barrier to their daily routine and 65.6% preferred dual testing. Respondents had more confidence in dual c.f. single test results (P<0.001).

Viral cultures from Days 5-7 were positive for 6/31 (19.4%, 7.5%-37.5%) and indeterminate for 11/31 (35.5%, 19.2%-54.6%) LFT-positive participants, indicating they were likely still infectious.

Conclusions

Dual brand testing increased LFT detection of SARS-CoV-2 antigen by a small but meaningful margin and was acceptable to hospital workers. Viral cultures demonstrated that policies recommending safe return to work ∼5 days after Omicron infection/exposure were flawed. Key-workers should be prepared for dynamic self-testing protocols in future pandemics.

Trial registration

https://www.isrctn.com/ISRCTN47058442(IRAS:311842)
When should lockdown be implemented? Devising cost-effective strategies for managing epidemics amid vaccine uncertainty
Authors: Doyle Nathan J. , Cumming Fergus , Thompson Robin N. , Tildesley Michael J.
Published: April 2024

During an infectious disease outbreak, public health policy makers are tasked with strategically implementing control interventions whilst balancing competing objectives. To provide a quantitative framework that can be used to guide these decisions, it is helpful to devise a clear and specific objective function that can be evaluated to determine the optimal outbreak response. In this study, we have developed a mathematical modelling framework representing outbreaks of a novel emerging pathogen for which non-pharmaceutical interventions (NPIs) are imposed or removed based on thresholds for hospital occupancy. These thresholds are set at different levels to define four unique control strategies. We illustrate that the optimal intervention strategy is contingent on the choice of objective function. Specifically, the optimal strategy depends on the extent to which policy makers prioritise reducing health costs due to infection over the costs associated with control interventions. Motivated by the scenario early in the COVID-19 pandemic, we incorporate the development of a vaccine into our modelling framework and demonstrate that a policy maker's belief about when a vaccine will become available in future, and its eventual coverage (and/or effectiveness), affects the optimal control strategy to adopt early in the outbreak. Furthermore, we show how uncertainty in these quantities can be accounted for when deciding which interventions to introduce. This research highlights the benefits of policy makers being explicit about the precise objectives of introducing interventions.
Measurement of changes to the menstrual cycle: A transdisciplinary systematic review evaluating measure quality and utility for clinical trials
Authors: Mackenzie Amelia C.L. , Chung Stephanie , Hoppes Emily , Mickler Alexandria K. , Cartwright Alice F.
Published: April 2024

Despite the importance of menstruation and the menstrual cycle to health, human rights, and sociocultural and economic wellbeing, the study of menstrual health suffers from a lack of funding, and research remains fractured across many disciplines. We sought to systematically review validated approaches to measure four aspects of changes to the menstrual cycle—bleeding, blood, pain, and perceptions—caus ed by any source and used within any field. We then evaluated the measure quality and utility for clinical trials of the identified instruments. We searched MEDLINE, Embase, and four instrument databases and included peer-reviewed articles published between 2006 and 2023 that reported on the development or validation of instruments assessing menstrual changes using quantitative or mixed-methods methodology. From a total of 8,490 articles, 8,316 were excluded, yielding 174 articles reporting on 94 instruments. Almost half of articles were from the United States or United Kingdom and over half of instruments were only in English, Spanish, French, or Portuguese. Most instruments measured bleeding parameters, uterine pain, or perceptions, but few assessed characteristics of blood. Nearly 60% of instruments were developed for populations with menstrual or gynecologic disorders or symptoms. Most instruments had fair or good measure quality or clinical trial utility; however, most instruments lacked evidence on responsiveness, question sensitivity and/or transferability, and only three instruments had good scores of both quality and utility. Although we took a novel, transdisciplinary approach, our systematic review found important gaps in the literature and instrument landscape, pointing towards a need to examine the menstrual cycle in a more comprehensive, inclusive, and standardized way. Our findings can inform the development of new or modified instruments, which—if used across the many fields that study menstrual health and within clinical trials—can contribute to a more systemic and holistic understanding of menstruation and the menstrual cycle.
Consensus recommendations for measuring the impact of contraception on the menstrual cycle in contraceptive clinical trials
Authors: Mackenzie Amelia C. L. , Chung Stephanie , Hoppes Emily , Miller Nora , Burke Anne E. , Achilles Sharon L. , Allen C. Leigh , Bahamondes Luis , Blithe Diana L. , Brache Vivian , Callahan Rebecca L. , Cartwright Alice F. , Clancy Kathryn B. H. , Colli Enrico , Cordova-Gomez Amanda , Costenbader Elizabeth E. , Creinin Mitchell D. , Critchley Hilary O. D. , Doncel Gustavo F. , Dorflinger Laneta J. , Edelman Alison , Faustmann Thomas , Gerlinger Christoph , Haddad Lisa B. , Hennegan Julie , Juliato Cássia Raquel Teatin , Kibira Simon P. S. , Mansour Diana , Martinez Andres , Matteson Kristen A. , Maybin Jacqueline A. , Mickler Alexandria K. , Nanda Kavita , Nwachukwu Chukwuemeka E. , OlaOlorun Funmilola M. , Peine Kevin J. , Polis Chelsea B. , Vieira Carolina Sales , Sitruk-Ware Regine , Smit Jennifer A. , Solomon Marsden , Soule Lisa M. , Taylor Douglas , Tolley Elizabeth E. , Vandeputte Olivia
Published: April 2024

Objective

We sought to develop consensus recommendations for improved measurement of contraceptive-induced menstrual changes (CIMCs) in contraceptive clinical trials to build upon previous standardization efforts.

Study Design

We undertook a virtual consensus-building process using a modified Delphi approach, incorporating aspects of Nominal Group Technique and the Jandhyala method. The process consisted of four half-day meetings, developing recommendations within five topical working groups, a series of consensus questionnaires to assess recommendation agreement on a 4-point Likert-like scale, and opportunities for input and feedback throughout the process. Recommendations required at least 75% consensus to be included.

Results

Our interdisciplinary group—from 26 organizations and 13 countries in five global regions across academia, nonprofit research organizations, the pharmaceutical industry, and funding agencies— developed 44 consensus recommendations. These included recommendations on standardization, patient-reported outcome measure development aligned with current regulatory guidance, trial design, protocol development, participant recruitment, data collection, data analysis, and areas for exploratory research. Seven recommendations were deemed a priority by over 85% of our group.

Conclusion

Using a formal consensus-building process, we reached high levels of agreement around recommendations for more standardized and patient-centered measurement of CIMCs in contraceptive clinical trials, now and in the future.

Implications statement

Consensus recommendations on measuring bleeding changes and related outcomes in contraceptive clinical trials can improve reporting of standardized, patient-centered outcomes in future product labeling. These improvements can enable providers to offer more relevant counseling on contraceptives and permit greater comparability and data synthesis across trials to inform clinical guidance.
Integrity of dopaminergic terminals in the caudate nucleus is relevant for rest tremor in Parkinson’s disease
Authors: Mendonça Marcelo D. , Ferreira Pedro , Oliveira Francisco , Barbosa Raquel , Meira Bruna , Costa Durval , Oliveira-Maia Albino , Alves da Silva Joaquim
Published: April 2024

Resting tremor (RT) is a Parkinson’s disease (PD) symptom whose relationship with the dopaminergic system remains puzzling. To clarify this relation, we analysed data from 432 subjects from the PPMI (Parkinson’s Progression Markers Initiative) database, a second cohort of 57 PD patients and controls and a third cohort of 86 subjects referred for dopamine transporter single-photon emission computed tomography (DaT-SPECT). Caudate, but not putamen binding potential (CBP, PBP) was higher in patients with RT. The presence of a higher CBP at the baseline and a relative sparing of CBP were related to the development of RT in the 2ndyear. In the smaller cohorts, a 4-6 Hz oscillation-based metric extracted from inertial sensors correlated with RT amplitude and distinguished groups with DA denervation from controls. The same metric was correlated with CBP, but not PBP in subjects with a denervated DaT-SPECT.In silicomodelling uncovered that higher CBP in patients with RT was fundamental to explain the associations and correlations between RT and DaT-SPECT described in our and other datasets. These results support that the integrity of caudate dopaminergic terminals could be relevant for RT pathophysiology. Unbiased assessment methods, such as inertial sensors, can be important to understand PD pathophysiology.
Dysregulation of lncRNA MALAT1 Contributes to Lung Cancer in African Americans by modulating the tumor immune microenvironment
Authors: Li Jin , Dhilipkannah Pushpa , Holden Van K , Sachdeva Ashutosh , Todd Nevins W , Jiang Feng
Published: April 2024

African American (AA) populations present with notably higher incidence and mortality rates from lung cancer in comparison to other racial groups. Here, we elucidate the contribution of long non-coding RNAs (lncRNAs) in the racial disparities and their potential clinical applications in both diagnosis and therapeutic strategies. AA patients had elevated plasma levels of MALAT1 and PVT1 compared with cancer-free smokers. Incorporating these lncRNAs as plasma biomarkers, along with smoking history, achieved 81% accuracy in diagnosis of lung cancer in AA patients. We observed a rise in MALAT1 expression, correlating with increased levels of monocyte chemoattractant protein-1 (MCP-1) and CD68, CD163, CD206, indicative of tumor-associated macrophages in lung tumors of AA patients. Forced MALAT1 expression led to enhanced growth and invasiveness of lung cancer cells, both in vitro and in vivo, accompanied by elevated levels of MCP-1, CD68, CD163, CD206, and KI67. Mechanistically, MALAT1 acted as a competing endogenous RNA to directly interact with miR-206, subsequently affecting MCP-1 expression and macrophage activity, and enhanced the tumorigenesis. Targeting MALAT1 significantly reduced tumor sizes in animal models. Therefore, dysregulated MALAT1 contributes to lung cancer disparities in AAs by modulating the tumor immune microenvironment through its interaction with miR-206, thereby presenting novel diagnostic and therapeutic targets.
TCR clustering by contrastive learning on antigen specificity
Authors: Pertseva Margarita , Follonier Oceane , Scarcella Daniele , Reddy Sai T.
Published: April 2024

Effective clustering of T-cell receptor (TCR) sequences could be used to predict their antigen-specificities. TCRs with highly dissimilar sequences can bind to the same antigen, thus making their clustering into a common antigen group a central challenge. Here, we develop TouCAN, a method that relies on contrastive learning and pre-trained protein language models to perform TCR sequence clustering and antigen-specificity predictions. Following training, TouCAN demonstrates the ability to cluster highly dissimilar TCRs into common antigen groups. Additionally, TouCAN demonstrates TCR clustering performance and antigen-specificity predictions comparable to other leading methods in the field.
Flow zoometry ofDrosophila
Authors: Peterson Walker , Arenson Joshua , Hata Soichiro , Kacenauskaite Laura , Kobayashi Tsubasa , Otsuka Takuya , Wang Hanqing , Wada Yayoi , Hiramatsu Kotaro , He Zhikai , Clement Jean-Emmanuel , Zhang Chenqi , Hu Chenglang , McCann Phillip , Kanazawa Hayato , Nagasaka Yuzuki , Uechi Hiroyuki , Watanabe Yuh , Yamamura Ryodai , Hayashi Mika , Nakagawa Yuta , Huang Kangrui , Kanno Hiroshi , Zhou Yuqi , Ding Tianben , Herbig Maik , Makino Shimpei , Nonaga Shunta , Takami Ryosuke , Kanca Oguz , Tabata Koji , Amaya Satoshi , Furusawa Kotaro , Ishii Kenichi , Emoto Kazuo , Arai Fumihito , Cagan Ross , Di Carlo Dino , Igaki Tatsushi , Kuranaga Erina , Yamamoto Shinya , Bellen Hugo J , Komatsuzaki Tamiki , Sonoshita Masahiro , Goda Keisuke
Published: April 2024

Drosophilaserves as a highly valuable model organism across numerous fields including genetics, immunology, neuroscience, cancer biology, and developmental biology. Central toDrosophila-based biological research is the ability to perform comprehensive genetic or chemical screens. However, this research is often limited by its dependence on laborious manual handling and analysis, making it prone to human error and difficult to discern statistically significant or rare events amid the noise of individual variations resulting from genetic and environmental factors. In this article we present flow zoometry, a whole-animal equivalent of flow cytometry for large-scale, individual-level, high-content screening ofDrosophila. Our flow zoometer automatically clears the tissues ofDrosophila melanogaster, captures three-dimensional (3D) multi-color fluorescence tomograms of single flies with single-cell volumetric resolution at an unprecedented throughput of over 1,000 animals within 48 hours (24 hr for clearing; 24 hr for imaging), and performs AI-enhanced data-driven analysis – a task that would traditionally take months or years with manual techniques. To demonstrate its broad applications, we employed the flow zoometer in various laborious screening assays, including those in toxicology, genotyping, and tumor screening. Flow zoometry represents a pivotal evolution in high-throughput screening technology: previously from molecules to cells, now from cells to whole animals. This advancement serves as a foundational platform for “statistical spatial biology”, to improve empirical precision and enable serendipitous discoveries across various fields of biology.
PhenoMultiOmics: an enzymatic reaction inferred multi-omics network visualization web server
Authors: Shi Yuying , Xu Botao , Chai Jie , Wang Cheng
Published: April 2024

Enzymatic reactions play a pivotal role in regulating cellular processes with a high degree of specificity to biological functions. When enzymatic reactions are disrupted by gene, protein, or metabolite dysfunctions in diseases, it becomes crucial to visualize the resulting perturbed enzymatic reaction-induced multi-omics network. Multi-omics network visualization aids in gaining a comprehensive understanding of the functionality and regulatory mechanisms within biological systems. In this study, we designed PhenoMultiOmics, an enzymatic reaction-based multi-omics web server designed to explore the scope of the multi-omics network across various cancer types. We first curated the PhenoMultiOmics Database (PMODB), which enables the retrieval of cancer-gene-protein-metabolite relationships based on the enzymatic reactions. We then developed the MultiOmics network visualization module to depict the interplay between genes, proteins, and metabolites in response to specific cancer-related enzymatic reactions. The biomarker discovery module facilitates functional analysis through differential omic feature expression and pathway enrichment analysis. PhenoMultiOmics has been applied to analyze transcriptomics data of gastric cancer and metabolomics data of lung cancer, providing insights into interrupted enzymatic reactions and the associated multi-omics network. PhenoMultiOmics is freely accessed athttps://phenomultiomics.shinyapps.io/cancer/with a user-friendly and interactive web interface.
Revealing the ArabidopsisAtGRP7mRNA binding proteome by specific enhanced RNA interactome capture
Authors: Reichel Marlene , Schmidt Olga , Rettel Mandy , Stein Frank , Köster Tino , Butter Falk , Staiger Dorothee
Published: April 2024

Background

The interaction of proteins with RNA in the cell is crucial to orchestrate all steps of RNA processing. RNA interactome capture (RIC) techniques have been implemented to catalogue RNA-binding proteins in the cell. In RIC, RNA-protein complexes are stabilized by UV crosslinkingin vivo. Polyadenylated RNAs and associated proteins are pulled down from cell lysates using oligo(dT) beads and the RNA-binding proteome is identified by quantitative mass spectrometry. However, insights into the RNA-binding proteome of a single RNA that would yield mechanistic information on how RNA expression patterns are orchestrated, are scarce.

Results

Here, we explored RIC in Arabidopsis to identify proteins interacting with a single mRNA, using the circadian clock-regulatedArabidopsis thalianaGLYCINE-RICH RNA-BINDING PROTEIN 7 (AtGRP7) transcript, one of the most abundant transcripts in Arabidopsis, as a showcase. Seedlings were treated with UV light to covalently crosslink RNA and proteins. TheAtGRP7transcript was captured from cell lysates with antisense oligonucleotides directed against the 5’untranslated region (UTR). The efficiency of RNA capture was greatly enhanced by using locked nucleic acid (LNA)/DNA oligonucleotides, as done in the enhanced RIC protocol. Furthermore, performing a tandem capture with two rounds of pulldown with the 5’UTR oligonucleotide increased the yield. In total, we identified 356 proteins enriched relative to a pulldown fromatgrp7mutant plants. These were benchmarked against proteins pulled down from nuclear lysates byAtGRP7 in vitrotranscripts immobilized on beads. Among the proteins validated byin vitrointeraction we found the family of Acetylation Lowers Binding Affinity (ALBA) proteins. Interaction of ALBA4 with theAtGRP7RNA was independently validated via individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP). The expression of theAtGRP7transcript in analbaloss-of-function mutant was slightly changed compared to wild-type, demonstrating the functional relevance of the interaction.

Conclusion

We adapted specific RNA interactome capture with LNA/DNA oligonucleotides for use in plants usingAtGRP7as a showcase. We anticipate that with further optimization and up-scaling the protocol should be applicable for less abundant transcripts.
Three-photon excited fluorescence microscopy enables imaging of blood flow, neural structure and inflammatory response deep into mouse spinal cordin vivo
Authors: Cheng Yu-Ting , Lett Kawasi M. , Xu Chris , Schaffer Chris B.
Published: April 2024

Nonlinear optical microscopy enables non-invasive imaging in scattering samples with cellular resolution. The spinal cord connects the brain with the periphery and governs fundamental behaviors such as locomotion and somatosensation. Because of dense myelination on the dorsal surface, imaging to the spinal grey matter is challenging, even with two-photon microscopy. Here we show that three-photon excited fluorescence (3PEF) microscopy enables multicolor imaging at depths of up to ~550 μm into the mouse spinal cord,in vivo. We quantified blood flow across vessel types along the spinal vascular network. We then followed the response of neurites and microglia after occlusion of a surface venule, where we observed depth-dependent structural changes in neurites and interactions of perivascular microglia with vessel branches upstream from the clot. This work establishes that 3PEF imaging enables studies of functional dynamics and cell type interactions in the top 550 μm of the murine spinal cord,in vivo.
Proteasome hyperactivation rewires the proteome enhancing stress resistance, proteostasis, lipid metabolism and ERAD inC. elegans
Authors: Salcedo-Tacuma David , Asad Nadeeem , Howells Giovanni , Anderson Raymond , Smith David M.
Published: April 2024

Proteasome dysfunction is implicated in the pathogenesis of neurodegenerative diseases and age-related proteinopathies. Using aC. elegansmodel, we demonstrate that 20S proteasome hyperactivation, facilitated by 20S gate-opening, accelerates the targeting of intrinsically disordered proteins. This leads to increased protein synthesis, extensive rewiring of the proteome and transcriptome, enhanced oxidative stress defense, accelerated lipid metabolism, and peroxisome proliferation. It also promotes ER-associated degradation (ERAD) of aggregation-prone proteins, such as alpha-1 antitrypsin (ATZ) and various lipoproteins. Notably, our results reveal that 20S proteasome hyperactivation suggests a novel role in ERAD with broad implications for proteostasis-related disorders, simultaneously affecting lipid homeostasis and peroxisome proliferation. Furthermore, the enhanced cellular capacity to mitigate proteostasis challenges, alongside unanticipated acceleration of lipid metabolism is expected to contribute to the longevity phenotype of this mutant. Remarkably, the mechanism of longevity induced by 20S gate opening appears unique, independent of known longevity and stress-resistance pathways. These results support the therapeutic potential of 20S proteasome activation in mitigating proteostasis-related disorders broadly and provide new insights into the complex interplay between proteasome activity, cellular health, and aging.
Pervasive loss of regulated necrotic cell death genes in elephants, hyraxes, and sea cows (Paenungualta)
Authors: Birkemeier Meaghan , Swindle Arianna , Bowman Jacob , Lynch Vincent J.
Published: April 2024

Gene loss can promote phenotypic differences between species, for example, if a gene constrains phenotypic variation in a trait, its loss allows for the evolution of a greater range of variation or even new phenotypes. Here, we explore the contribution of gene loss to the evolution of large bodies and augmented cancer resistance in elephants. We used genomes from 17 Afrotherian and Xenarthran species to identify lost genes, i.e., genes that have pseudogenized or been completely lost, and Dollo parsimony to reconstruct the evolutionary history of gene loss across species. We unexpectedly discovered a burst of gene losses in the Afrotherian stem lineage and found that the loss of genes with functions in regulated necrotic cell death modes was pervasive in elephants, hyraxes, and sea cows (Paenungulata). Among the lost genes areMLKLandRIPK3, which mediate necroptosis, and sensors that activate inflammasomes to induce pyroptosis, includingAIM2,MEFV,NLRC4,NLRP1, andNLRP6. These data suggest that the mechanisms that regulate necrosis and pyroptosis are either extremely derived or potentially lost in these lineages, which may contribute to the repeated evolution of large bodies and cancer resistance in Paenungulates as well as susceptibility to pathogen infection.
Circulating, cell-free methylated DNA indicates cellular sources of allograft injury after liver transplant
Authors: McNamara Megan E. , Jain Sidharth S. , Oza Kesha , Muralidaran Vinona , Kiliti Amber J. , McDeed A. Patrick , Patil Digvijay , Cui Yuki , Schmidt Marcel O. , Riegel Anna T. , Kroemer Alexander H.K. , Wellstein Anton
Published: April 2024

Post-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed 130 blood samples collected from 44 patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to patterns established to identify cell types in different organs. For liver cell types DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and regulatory regions functionally important for the respective cell types. We find that multi-tissue cellular damages post-transplant recover in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA beyond the first week indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and timely intervention.
Multiplexed transcriptomic analyses of the plant embryonic hourglass
Authors: Wu Hao , Zhang Ruqiang , Niklas Karl J. , Scanlon Michael J.
Published: April 2024

Zoologists have adduced morphological convergence among embryonic stages of closely related taxa, which has been called the phylotypic stage of embryogenesis. Transcriptomic analyses reveal a phylotypic hourglass pattern of gene expression during plant as well as animal embryogenesis, characterized by the accumulation of evolutionarily older and conserved transcripts during mid-embryogenesis, whereas younger less-conserved transcripts predominate at earlier and later embryonic stages. However, widespread comparisons of embryonic gene expression across animal phyla describe an inverse hourglass pattern, where gene expression is correlated during early and late stages but not during mid-development. Here, multiplexed spatial-transcriptomic analyses is used to investigate embryo ontogeny and homology in maize, which has novel, grass-specific morphology. An embryonic-organ genetic network is identified, replete for ancient/conserved genes manifesting a phylotypic hourglass during mid-embryogenesis. Transcriptomic comparisons of grass embryo ontogeny with that of a mossPhyscomitrium patensidentify a conserved, inverse hourglass pattern across plant phyla, as in animals.

The data indicate that the plant phylotypic stage and that of animals is characterized by ancient gene network expression during early histo– and morphogenesis and polarized embryonic development. The data reveal an ancient, convergent mechanism for the evolution of morphological novelty.
Plk1 inhibition delays mitotic entry revealing prophase-specific changes to the phosphoproteome
Authors: Gobran Monica , Welp Luisa , Jakobi Jasmin , Politi Antonio , Urlaub Henning , Lenart Peter
Published: April 2024

Polo-like kinase 1 (plk1) is a conserved regulator of cell division. During prophase, plk1 phosphorylates direct substrates and is involved in activation of the cyclin-dependent kinase 1 (cdk1). However, the exact functions of plk1 in prophase remain incompletely understood. By testing several cell lines and small-molecule inhibitors, we confirm that plk1 inhibition causes a delay in mitotic entry. We show that cells are delayed in a prophase-like state displaying progressively condensing chromosomes, increased microtubule dynamics, reorganization of the actin cortex, while the nuclear envelope remains intact. We show that during this prolonged prophase cdk1 activity increases gradually over several hours with individual cells stochastically reaching the entry threshold, explaining the highly variable timing of mitotic entry. We then use phosphoproteomics to characterize this prolonged prophase state revealing for the first time phosphosites specific to prophase including several regulators of chromatin organization and the cytoskeleton. Together, we show that plk1 functions as a catalyst of prophase to prometaphase transition, and by using plk1 inhibition as a tool, we identify early changes in the phosphoproteome as the cell prepares for division.