bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term evaluation of E6011, an anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis inadequately responding to biological disease-modifying antirheumatic drugs
Authors: Tanaka Yoshiya , Takeuchi Tsutomu , Yamanaka Hisashi , Nanki Toshihiro , Umehara Hisanori , Yasuda Nobuyuki , Tago Fumitoshi , Kitahara Yasumi , Kawakubo Makoto , Torii Kentaro , Hojo Seiichiro , Kawano Tetsu , Imai Toshio
Published: January 2023

Objectives

The objective of the study is to evaluate the long-term safety and efficacy of E6011, a humanized anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis with an inadequate response to biological disease-modifying antirheumatic drugs.

Methods

In the double-blind treatment phase (24 weeks), placebo or E6011 400 mg was administered until Week 10. Thereafter, E6011 200 mg or 400 mg was administered to Week 22. Subjects who completed the evaluation at Week 24 of the treatment phase were rolled over into the extension phase. The extension phase lasted until Week 104, and all subjects received E6011 400 mg or 200 mg every 2 weeks in an open-label manner until Week 102.

Results

A total of 47 subjects completed the double-blind treatment phase and were rolled over into the extension phase. In total, 46 (97.9%) subjects experienced any adverse events, and the incidence of treatment-related adverse events was 57.4%. No clear efficacy trend in the American College of Rheumatology 20% response rates was observed.

Conclusions

E6011 was well tolerated in active rheumatoid arthritis patients who had shown an inadequate response to biologic disease-modifying antirheumatic drugs, but no clear benefit in the American College of Rheumatology 20% response rates was observed. Further studies are needed to clarify the clinical benefit of E6011.
Factors associated with osteoporosis and fractures in patients with systemic lupus erythematosus: Kyoto Lupus Cohort
Authors: Nakajima Tomoya , Doi Hiroshi , Watanabe Ryu , Murata Koichi , Takase Yudai , Inaba Ryuta , Itaya Takahiro , Iwasaki Takeshi , Shirakashi Mirei , Tsuji Hideaki , Kitagori Koji , Akizuki Shuji , Nakashima Ran , Onishi Akira , Yoshifuji Hajime , Tanaka Masao , Ito Hiromu , Hashimoto Motomu , Ohmura Koichiro , Morinobu Akio
Published: January 2023

Objectives

Osteoporosis and compression fractures of the lumbar spine are some of the major adverse effects of glucocorticoid therapy in patients with systemic lupus erythematosus (SLE). This study examined the association between bone mineral density, bone turnover markers, presence of vertebral fractures, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in SLE patients.

Methods

This was a cross-sectional study of 246 outpatients with SLE at the Kyoto University Hospital. Lumbar and femoral bone mineral density was measured with dual-energy X-ray absorptiometry, and the presence of vertebral fractures was determined using X-ray, computed tomography, or magnetic resonance imaging.

Results

On multiple regression analysis, both high lumbar and femoral T-scores were associated with the concomitant use of hydroxychloroquine (P = .018 and P = .037, respectively), no use of bisphosphonate or denosumab (P = .004 and P = .038, respectively), high body mass index (P < .001), and low bone-specific alkaline phosphatase level (P = .014 and P = .002, respectively). Vertebral fractures showed a significant association with Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score (P < .001) and femoral T-score (P < .001).

Conclusion

Vertebral fracture was associated with SLE-associated organ damage, and serum bone-specific alkaline phosphatase level is a potentially useful marker for osteoporosis monitoring in SLE patients.
GBMdeconvoluteR accurately infers proportions of neoplastic and immune cell populations from bulk glioblastoma transcriptomics data
Authors: Ajaib Shoaib , Lodha Disha , Pollock Steven , Hemmings Gemma , Finetti Martina A , Gusnanto Arief , Chakrabarty Aruna , Ismail Azzam , Wilson Erica , Varn Frederick S , Hunter Bethany , Filby Andrew , Brockman Asa A , McDonald David , Verhaak Roel G W , Ihrie Rebecca A , Stead Lucy F
Published: January 2023

Background

Characterizing and quantifying cell types within glioblastoma (GBM) tumors at scale will facilitate a better understanding of the association between the cellular landscape and tumor phenotypes or clinical correlates. We aimed to develop a tool that deconvolutes immune and neoplastic cells within the GBM tumor microenvironment from bulk RNA sequencing data.

Methods

We developed an IDH wild-type (IDHwt) GBM-specific single immune cell reference consisting of B cells, T-cells, NK-cells, microglia, tumor associated macrophages, monocytes, mast and DC cells. We used this alongside an existing neoplastic single cell-type reference for astrocyte-like, oligodendrocyte- and neuronal progenitor-like and mesenchymal GBM cancer cells to create both marker and gene signature matrix-based deconvolution tools. We applied single-cell resolution imaging mass cytometry (IMC) to ten IDHwt GBM samples, five paired primary and recurrent tumors, to determine which deconvolution approach performed best.

Results

Marker-based deconvolution using GBM-tissue specific markers was most accurate for both immune cells and cancer cells, so we packaged this approach as GBMdeconvoluteR. We applied GBMdeconvoluteR to bulk GBM RNAseq data from The Cancer Genome Atlas and recapitulated recent findings from multi-omics single cell studies with regards associations between mesenchymal GBM cancer cells and both lymphoid and myeloid cells. Furthermore, we expanded upon this to show that these associations are stronger in patients with worse prognosis.

Conclusions

GBMdeconvoluteR accurately quantifies immune and neoplastic cell proportions in IDHwt GBM bulk RNA sequencing data and is accessible here: https://gbmdeconvoluter.leeds.ac.uk.
Phytochrome F mediates red light responsiveness additively with phytochromes B1 and B2 in tomato
Authors: Balderrama Daniel , Barnwell Samantha , Carlson Keisha D , Salido Elsa , Guevara Ruby , Nguyen Christina , Madlung Andreas
Published: January 2023

Phytochromes are red light and far-red light sensitive, plant-specific light receptors that allow plants to orient themselves in space and time. Tomato (Solanum lycopersicum) contains a small family of five phytochrome genes, for which to date stable knockout mutants are only available for three of them. Using CRISPR technology, we created multiple alleles of SlPHYTOCHROME F (phyF) mutants to determine the function of this understudied phytochrome. We report that SlphyF acts as a red/far-red light reversible low fluence sensor, likely through the formation of heterodimers with SlphyB1 and SlphyB2. During photomorphogenesis, phyF functions additively with phyB1 and phyB2. Our data further suggest that phyB2 requires the presence of either phyB1 or phyF during seedling de-etiolation in red light, probably via heterodimerization, while phyB1 homodimers are required and sufficient to suppress hypocotyl elongation in red light. During the end-of-day far-red response, phyF works additively with phyB1 and phyB2. In addition, phyF plays a redundant role with phyB1 in photoperiod detection and acts additively with phyA in root patterning. Taken together, our results demonstrate various roles for SlphyF during seedling establishment, sometimes acting additively, other times acting redundantly with the other phytochromes in tomato.
A systematic review on suicide because of social isolation/and loneliness: does COVID-19 make a difference?
Authors: Blázquez-Fernández Carla , Lanza-León Paloma , Cantarero-Prieto David
Published: January 2023

Background

Suicide is a significant cause of death worldwide. Various purposes can explain why people choose to attempt or commit suicide such as mental-health disorders, income-related-factors, quality of life or issues related to social context. This study aims to identify an updated association between ‘isolation’ and suicides.

Methods

In this regard, we had made a systematic review of the most recent papers, published from January 2016 to March 2022, thought the most acknowledged databases. This review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for systematic reviews. To the best of our knowledge, this issue is very important due to the indirect relationship between COVID-19 and suicides.

Results

Our analysis demonstrates that suicide and -social isolation and loneliness- have a positive and direct relationship although these findings varied slightly by areas. Moreover, most of the attention is focused on the youth during the most recent period and this is a real problem because economies cannot afford losing (young) population.

Conclusions

In order to prevent suicides, public policies should prevent suicidal thoughts that it could induce to terminate the lives of individuals in their most productive years and harmful outcomes to their families and friends.
Primary Cutaneous Peripheral T-Cell Lymphoma With Follicular Helper T-Cell Phenotype: Report of 2 Epstein–Barr Virus–Positive Cases
Authors: Chiang Chien-Ta , Chuang Shih-Sung , Lin Hsuen-Fu , Li Wei-Hsuan , Chiang Ying-Yi , Chen Bo-Jung
Published: January 2023

Primary cutaneous T-cell lymphoma is distinct from nodal T-cell lymphoma clinically and pathologically. Recently, primary cutaneous follicular helper T-cell lymphoma (PC-TFHL) has been described as a peripheral T-cell lymphoma with T-follicular helper (TFH) cell phenotype. PC-TFHL usually presents as multiple plaques and nodules of skin with an indolent clinical course, but without association with Epstein–Barr virus. In this article, we report 2 rare cases of PC-TFHL which are Epstein–Barr virus–positive and with an aggressive clinical course. We discuss the challenges in the differential diagnoses, particularly with primary cutaneous extranodal NK/T-cell lymphoma, and nodal T-cell lymphoma of TFH origin with secondary cutaneous involvement.
Ungual Keratoacanthoma With Features of Regression
Authors: Fernandez-Flores Angel , García-Paíno Luis , Perón Águeda Santos , Cassarino David
Published: January 2023

Ungual keratoacanthoma (UKA) is an infrequent tumor. Different from keratoacanthoma in other parts of the skin, UKA rarely regresses, and grows aggressively with common destruction of the subjacent phalanx. Reported cases of UKA with features of regression are exceptional, and even dermatopathologists with reputed experience in nail pathology admit to having seen very few cases. We herein report a case of a 77-year-old man who presented a painful subungual lesion on the second finger of the right hand. An x-ray showed evidence of erosion of the subjacent distal phalanx. The patient was highly concerned about the lesion and rejected conservative treatment preferring amputation of the distal phalanx. The histopathologic examination revealed a UKA with features of regression.
Injection Site Reaction to Various Insulins as Type III Allergy With Urticarial Vasculitis in a Patient With Type I Diabetes Mellitus
Authors: Müller Cornelia S. L. , Bourg Catherine , Schweitzer Luca Filomena , Friesenhahn-Ochs Bettina , Pföhler Claudia
Published: January 2023

Injection site reactions are defined as skin reactions at the injection site to drugs administered subcutaneously. Pathophysiologically, these reactions are based on different immunological mechanisms. We report the case of a 49-year-old patient with type 1 diabetes mellitus (first diagnosis in 1994 at the age of 23 years). Continuous subcutaneous insulin infusion using an insulin pump has been used for many years. The patient presented to the department of dermatology with progressive symptoms in the area of the insulin injection sites on the lower abdomen, accompanied by pain, burning, erythema, tenderness, and the formation of subcutaneous nodules. Previous attempts to use different insulins and to change the injection sites did not improve his symptoms. Furthermore, the symptoms appeared within hours after the insulin pump was attached, so that the injection site has to be changed as soon as every 48 hours. No anaphylactic shock was reported at any time. Multiple histological specimens were obtained from an older lesion on the abdomen as well as from test sites after standard allergological tests (prick and intradermal tests) of various insulins. Histologically, these biopsies showed the image of an extensive deep-reaching small vessel vasculitis with the aspect of an urticarial vasculitis and confirmed the diagnosis of an injection-site reaction that can be characterized as a type III hypersensitivity reaction.
Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression
Authors: Ma Fengguang , Liu Yuxiao , Hu Zhimin , Xue Yaqian , Liu Zhengshuai , Cai Genxiang , Su Weitong , Zheng Zengpeng , Fang Xia , Yan Xi , Ding Dong , Sun Xiaoyang , Jiang Yang , Wei Shuang , Li Wenjing , Zhao Jiuxiang , Zhang Haibing , Li Hong , Xiao Dongguang , Zhang Cuiying , Ying Hao , Qin Jun , Gao Xin , Dai Xiaozhen , Fu Wenguang , Xu Yong , Li Yu , Cui Aoyuan
Published: January 2023

Background and Aims:

NASH has emerged as a leading cause of chronic liver disease. However, the mechanisms that govern NASH fibrosis remain largely unknown. CREBZF is a CREB/ATF bZIP transcription factor that causes hepatic steatosis and metabolic defects in obesity.

Approach and Results:

Here, we show that CREBZF is a key mechanism of liver fibrosis checkpoint that promotes hepatocyte injury and exacerbates diet-induced NASH in mice. CREBZF deficiency attenuated liver injury, fibrosis, and inflammation in diet-induced mouse models of NASH. CREBZF increases HSC activation and fibrosis in a hepatocyte-autonomous manner by stimulating an extracellular matrix protein osteopontin, a key regulator of fibrosis. The inhibition of miR-6964-3p mediates CREBZF-induced production and secretion of osteopontin in hepatocytes. Adeno-associated virus –mediated rescue of osteopontin restored HSC activation, liver fibrosis, and NASH progression in CREBZF-deficient mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced NASH mouse models and humans with NASH.

Conclusions:

Osteopontin signaling by CREBZF represents a previously unrecognized intrahepatic mechanism that triggers liver fibrosis and contributes to the severity of NASH.
STRICT PRO RE NATA VERSUS TREAT-AND-EXTEND REGIMENS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
Authors: Fang Hwa-Shin , Bai Chyi-Huey , Cheng Cheng-Kuo
Published: January 2023

Purpose:

To compare the visual and anatomical outcomes between strict pro re nata (strict PRN) and treat-and-extend (T&E) anti–vascular endothelial growth factor (anti-VEGF) regimens for neovascular age-related macular degeneration (nAMD).

Methods:

A meta-analysis of 1-year and 2-year changes between strict PRN and T&E anti-VEGF regimens were conducted in both randomized controlled trials (RCTs) and real-world studies (RWSs). The best-corrected visual acuity (BCVA), central retinal thickness (CRT), and weighted mean numbers of visits and injections were evaluated.

Results:

A total of 19 RCTs and 23 RWSs (2,530 eyes in strict PRN and 4,399 eyes in T&E) were included. Mean BCVA change in strict PRN group in both 1-year and 2-year (5.95 and 5.78, respectively) was noninferior to the T&E group (7.85 and 5.96, respectively). Mean CRT changes were also similar in both strict PRN and T&E groups. Mean number of visits were significantly more in the strict PRN group, whereas mean number of injections was significantly more in the T&E group.

Conclusion:

The strict PRN regimen demonstrates a noninferior BCVA improvement to the T&E regimen, achieving fewer injections, and may be both economically and medically beneficial. Both selections should be provided to patients with an overall consideration.
Machine learning augmentation reduces prediction error in collective forecasting: development and validation across prediction markets
Authors: Gruen Alexander , Mattingly Karl R , Morwitch Ellen , Bossaerts Frederik , Clifford Manning , Nash Chad , Ioannidis John P A , Ponsonby Anne-Louise
Published: January 2023

The recent COVID-19 crisis highlighted the inadequacy of human forecasting. We aim to leverage human prediction markets with real-time machine weighting of likely higher accuracy trades to improve performance. The crowd sourced Almanis prediction market longitudinal platform (n=1822) and Next Generation Social Science (NGS2) platform (n=103) were utilised. A 43-feature model predicted top quintile relative Brier accuracy scores in two out-of-sample datasets (pboth<1×10−9). Trades graded as high machine accuracy quality vs. other trades had a greater AUC temporal gain from before to after trade. Hybrid human-machine forecasts had higher accuracy than human forecasts alone, particularly when the two systems disagreed by 5% or more for binary event prediction: the hybrid system demonstrating substantial AUC gains of 13.2%, p=1.35×10−14and 13.8%, p=0.003 in the out-of-sample Almanis B and NGS2 datasets respectively. When discordant, the hybrid model was correct for COVID-19 event occurrence 72.7% of the time vs 27.3% for human-only models, p=0.007. This net classification benefit was replicated in the separate Almanis B dataset, p=2.4×10−7. Real-time machine classification followed by weighting human trades according to likely accuracy improves collective forecasting performance. Implementation may allow improved anticipation of and response to emerging risks and improved human collective efforts generally.

Significance Statement

Human-machine hybrid approaches have been identified as a new frontier for event prediction and decision making in the artificial intelligence and collective human intelligence fields. For the first time, we present the successful development and validation of a human-machine hybrid prediction market approach and demonstrate its superior accuracy when compared to prediction markets based on human forecasting alone. The advantages of this new hybrid system are demonstrated in the context of COVID-19-related event prediction.
The ChAMP App: A Scalable mHealth Technology for Detecting Digital Phenotypes of Early Childhood Mental Health
Authors: Loftness Bryn C. , Halvorson-Phelan Julia , O’Leary Aisling , Bradshaw Carter , Prytherch Shania , Berman Isabel , Torous John , Copeland William L. , Cheney Nick , McGinnis Ryan S. , McGinnis Ellen W.
Published: January 2023

Childhood mental health problems are common, impairing, and can become chronic if left untreated. Children are not reliable reporters of their emotional and behavioral health, and caregivers often unintentionally under-or over-report child symptoms, making assessment challenging. Objective physiological and behavioral measures of emotional and behavioral health are emerging. However, these methods typically require specialized equipment and expertise in data and sensor engineering to administer and analyze. To address this challenge, we have developed the ChAMP (Childhood Assessment and Management of digital Phenotypes) System, which includes a mobile application for collecting movement and audio data during a battery of mood induction tasks and an open-source platform for extracting digital biomarkers. As proof of principle, we present ChAMP System data from 101 children 4-8 years old, with and without diagnosed mental health disorders. Machine learning models trained on these data detect the presence of specific disorders with 70-73% balanced accuracy, with similar results to clinical thresholds on established parent-report measures (63-82% balanced accuracy). Features favored in model architectures are described using Shapley Additive Explanations (SHAP). Canonical Correlation Analysis reveals moderate to strong associations between predictors of each disorder and associated symptom severity (r = .51-.83). The open-source ChAMP System provides clinically-relevant digital biomarkers that may later complement parent-report measures of emotional and behavioral health for detecting kids with underlying mental health conditions and lowers the barrier to entry for researchers interested in exploring digital phenotyping of childhood mental health.
Comparison of gene set scoring methods for reproducible evaluation of multiple tuberculosis gene signatures
Authors: Wang Xutao , VanValkenberg Arthur , Odom-Mabey Aubrey R. , Ellner Jerrold J. , Hochberg Natasha S. , Salgame Padmini , Patil Prasad , Johnson W. Evan
Published: January 2023

Rationale

Many blood-based transcriptional gene signatures for tuberculosis (TB) have been developed with potential use to diagnose disease, predict risk of progression from infection to disease, and monitor TB treatment outcomes. However, an unresolved issue is whether gene set enrichment analysis (GSEA) of the signature transcripts alone is sufficient for prediction and differentiation, or whether it is necessary to use the original statistical model created when the signature was derived. Intra-method comparison is complicated by the unavailability of original training data, missing details about the original trained model, and inadequate publicly-available software tools or source code implementing models. To facilitate these signatures’ replicability and appropriate utilization in TB research, comprehensive comparisons between gene set scoring methods with cross-data validation of original model implementations are needed.

Objectives

We compared the performance of 19 TB gene signatures across 24 transcriptomic datasets using both re-rebuilt original models and gene set scoring methods to evaluate whether gene set scoring is a reasonable proxy to the performance of the original trained model. We have provided an open-access software implementation of the original models for all 19 signatures for future use.

Methods

We considered existing gene set scoring and machine learning methods, including ssGSEA, GSVA, PLAGE, Singscore, and Zscore, as alternative approaches to profile gene signature performance. The sample-size-weighted mean area under the curve (AUC) value was computed to measure each signature’s performance across datasets. Correlation analysis and Wilcoxon paired tests were used to analyze the performance of enrichment methods with the original models.

Measurement and Main Results

For many signatures, the predictions from gene set scoring methods were highly correlated and statistically equivalent to the results given by the original diagnostic models. PLAGE outperformed all other gene scoring methods. In some cases, PLAGE outperformed the original models when considering signatures’ weighted mean AUC values and the AUC results within individual studies.

Conclusion

Gene set enrichment scoring of existing blood-based biomarker gene sets can distinguish patients with active TB disease from latent TB infection and other clinical conditions with equivalent or improved accuracy compared to the original methods and models. These data justify using gene set scoring methods of published TB gene signatures for predicting TB risk and treatment outcomes, especially when original models are difficult to apply or implement.
FcyRIIB is a novel immune checkpoint in the tumor microenvironment limiting activity of Treg-targeting antibodies
Authors: Knorr David , Leidner Rom , Jensen Shawn , Meng Ryan , Jones Andrew , Ballesteros-Merino Carmen , Bell R. Bryan , Baez Maria , Sprott David , Bifulco Carlo , Piening Brian , Dahan Rony , Fox Bernard A. , Ravetch Jeffrey
Published: January 2023

Despite pre-clinical murine data supporting T regulatory (Treg) cell depletion as a major mechanism by which anti-CTLA-4 antibodies function in vivo, the two main antibodies tested in patients (ipilimumab and tremelimumab) have failed to demonstrate similar effects. We report analogous findings in an immunocompetent murine model humanized for CTLA-4 and Fcy receptors (hCTLA-4/hFcyR mice), where both ipilimumab and tremelimumab fail to show appreciable Treg depletion. Immune profiling of the tumor microenvironment (TME) in both mice and human samples revealed upregulation of the inhibitory Fcy receptor, FcyRIIB, which limits the ability of the antibody Fc fragment of human anti-CTLA-4 antibodies to induce effective antibody dependent cellular cytotoxicty/phagocytosis (ADCC/ADCP). Blocking FcyRIIB in humanized mice rescues Treg depleting capacity and anti-tumor activity of ipilimumab. For another target, CC motif chemokine receptor 8 (CCR8), which is selectively expressed on tumor infiltrating Tregs, we show that Fc engineering to enhance binding to activating Fc receptors, while limiting binding to the inhibitory Fc receptor, leads to consistent Treg depletion and single-agent activity across multiple tumor models, including B16, MC38 and MB49. These data reveal the importance of reducing engagement to the inhibitory Fc receptor to optimize Treg depletion by TME targeting antibodies. Our results define the inhibitory FcyRIIB receptor as a novel immune checkpoint limiting antibody-mediated Treg depletion in tumors, and demonstrate Fc variant engineering as a means to overcome this limitation and augment efficacy for a repertoire of antibodies currently in use or under clinical evaluation in oncology.

Highlights

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Fully human anti-CTLA-4 antibodies are limited in their capacity to deplete T regulatory cells and drive durable anti-tumor immunity in humanized FcyR/hCTLA-4 mice

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The inhibitory Fcy receptor, FcyRIIB, is upregulated in the tumor microenvironment in patients and in humanized FcyR/hCTLA-4 mice

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Blocking FcyRIIB leads to rescue of Treg depletion in humanized murine models

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Fc engineering can improve the depleting capacity and in vivo anti-tumor activity of anti-CTLA and anti-CCR8 antibodies targeting tumor infiltrating Tregs
T helper cells exhibit a dynamic and reversible 3’UTR landscape
Authors: Seyres Denis , Gorka Oliver , Schmidt Ralf , Marone Romina , Zavolan Mihaela , Jeker Lukas T.
Published: January 2023

3’ untranslated regions (3’UTRs) are critical elements of messenger RNAs, as they contain binding sites for RNA-binding proteins (RBP) and microRNAs that affect various aspects of the RNA life cycle including transcript stability and cellular localisation. In response to T cell receptor activation, T cells undergo massive expansion during the effector phase of the immune response and dynamically modify their 3’UTRs. Whether this serves to directly regulate the abundance of specific mRNAs or is a secondary effect of proliferation remains unclear. To study 3’UTR dynamics in T helper cells we investigated division-dependent alternative polyadenylation (APA). We generated 3’ end UTR sequencing data from naïve, activated, memory and regulatory CD4+ T cells. 3’UTR length changes were estimated using a non-negative matrix factorization approach and were compared with those inferred from long-read PacBio sequencing. We found that APA events were transient and reverted after effector phase expansion. Using an orthogonal bulk RNAseq dataset, we did not find evidence of APA association with differential gene expression or transcript usage, indicating that APA has only a marginal effect on transcript abundance. 3’UTR sequence analysis revealed conserved binding sites for T cell-relevant microRNAs and RBPs in the alternative 3’UTRs. These results indicate that polyA site usage could play an important role in the control of cell fate decisions and homeostasis.
Functional synapses between small cell lung cancer and glutamatergic neurons
Authors: Schmitt Anna , Sakthivelu Vignesh , Ndoci Kristiano , Wani Gulzar A , Touet Marian , Pintelon Isabel , Kisis Ilmars , Ibruli Olta , Weber Julia , Maresch Roman , Bebber Christina M , Goergens Jonas , Jevtic Milica , Odenthal Franka , Placzek Aleksandra , Hennrich Alexandru A , Conzelmann Karl-Klaus , Boecker Maike , Heimsoeth Alena , Gülcüler Gülce S , Jachimowicz Ron D , George Julie , Brägelmann Johannes , von Karstedt Silvia , Peifer Martin , Persigehl Thorsten , Grüll Holger , Sos Martin L , Brüning Jens , Reifenberger Guido , Fischer Matthias , Adriaensen Dirk , Büttner Reinhard , Brouns Inge , Rad Roland , Thomas Roman K , Bergami Matteo , Motori Elisa , Reinhardt Hans Christian , Beleggia Filippo
Published: January 2023

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, clinical recurrence and high rate of mortality. Usingin vivoinsertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified a strong and consistent signal for neuronal, synaptic, and glutamatergic signaling gene sets in murine and human SCLC. We show that SCLC cells have the ability to develop intimate contacts with neuronal glutamatergic terminalsin vitro, in autochthonous primary lung tumors and in brain-engrafted tumors. These contacts can develop intobona fidesynapses, allowing SCLC cells to receive glutamatergic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we show that SCLC cells derive a robust proliferation advantage when co-cultured with neurons. Moreover, the repression of glutamate release and the stimulation of the inhibitory glutamate receptor GRM8 displayed therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells appear to hijack glutamatergic signaling to sustain tumor growth, thereby exposing a novel entry route for therapeutic intervention.
A novel method for characterising the inter- and intra-lake variability of CH4emissions: validation and application across a latitudinal transect in the Alpine region
Authors: Tomelleri Enrico , Scholz Katharina , Pighini Sylvie , Carotenuto Federico , Gioli Beniamino , Miglietta Franco , Sommaruga Ruben , Tonon Giustino , Zaldei Alessandro , Wohlfahrt Georg
Published: January 2023

Lakes in the Alpine region are recognised as critical CH4 emitters, but a robust characterisation of the magnitude and variability of CH4 fluxes is still needed. We developed a mobile platform for CH4 eddy covariance (EC) flux measurements to tackle this gap. Our approach was shown to be well suited to catch all CH4 emission pathways and overcome the limitations of other methods (e.g., gradient-based). This is by surpassing their local nature and thus being suited for characterising the variability of the within-lake emissions, primarily because of CH4 emissions by ebullition stochasticity. The mobile system was deployed at nine lakes across a latitudinal transect in the Alps and validated by comparing the measured fluxes with a fixed EC station and to chambers and boundary layer estimates. Methane fluxes were explained by water turbidity, dissolved organic carbon, dissolved nitrogen, elevation, particulate organic carbon, and total phosphorus. The highest fluxes and most substantial seasonal variability were found in a shallow low-altitude lake in the Southern Alps. Additionally, the mobile EC permitted to resolve the spatial structure of fluxes at the selected lakes. Finally, we demonstrated the usability of our novel mobile system to characterise intra- and inter-lake variability of fluxes. We suggest that characterising the intra-lake emission heterogeneity and a deeper understanding of inter-lake emission magnitude differences is fundamental for a solid estimate of freshwater CH4 budgets.

Key Points

CH4 emissions from alpine lakes are recognised to be an important component to the global methane budget but they are poorly characterized

We developed and validated a mobile eddy covariance platform for capturing CH4 fluxes across lakes in the alpine region for two years

A robust statistical model based on a fewin-situphysicochemical and biological parameters can be generally used to predict CH4 fluxes
Candidate gene length polymorphisms are linked to dispersive behaviour: searching for a mechanism behind the “paradox of the great speciators”
Authors: Estandía Andrea , Sendell-Price Ashley T. , Oatley Graeme , Robertson Fiona , Potvin Dominique , Massaro Melanie , Robertson Bruce C. , Clegg Sonya M.
Published: January 2023

The “paradox of the great speciators” has puzzled evolutionary biologists for over half a century. A great speciator requires excellent dispersal ability to explain its occurrence on multiple islands, but reduced dispersal ability to explain its high number of subspecies. A rapid reduction in dispersal ability is often invoked to solve this apparent paradox, but a proximate mechanism has not been identified. Here, we explore the role of six genes linked to migration and animal personality differences (CREB1, CLOCK, ADCYAP1, NPAS2, DRD4, andSERT) in 20 South Pacific populations of silvereye (Zosterops lateralis) that range from highly sedentary to partially migratory, to determine if genetic variation is associated with dispersal propensity. We detected genetic associations in three of the six genes: i) in a partial migrant population, migrant individuals had longer microsatellite alleles at theCLOCKgene compared to resident individuals from the same population; ii)CREB1displayed longer average microsatellite allele lengths in recently colonised island populations (< 200 years), compared to evolutionarily older populations. Bayesian broken stick regression models supported a reduction inCREB1length with time since colonisation and decreasing dispersal propensity; and iii) likeCREB1, DRD4showed differences in polymorphisms between recent and old colonisations but a further sample size is needed to confirm.ADCYAP1, SERT, andNPAS2were variable but that variation was not associated with dispersal propensity. The association of genetic variants at three genes with migration and dispersal ability in silvereyes provides the impetus for further exploration of genetic mechanisms underlying dispersal shifts, and the prospect of resolving a long-running evolutionary paradox through a genetic lens.
Extracellular matrices of bone marrow stroma regulate cell phenotype and contribute to distinct stromal nichesin vivo
Authors: Stone Andrew , Rand Emma , Thornes Gabriel , Kay Alasdair , Barnes Amanda , Hitchcock Ian , Genever Paul
Published: January 2023

The heterogeneity of bone marrow stromal cells (BMSCs) has been revealed more in recent years through the advent of single cell RNA sequencing. However, protein level characterisation is likely to provide a deeper understanding of the functions of individual subsets and may reveal insights into the co-ordination of the cell phenotype maintaining niche.

Here, by analysing heterogeneity in BMSC populations using human stromal cell lines to model extremes of cell morphology and migration characteristics, we identified plastic cell phenotypes that can be modified through secreted proteins. Transfer of secreted signals from a differentiation-competent stem cell phenotype was able to stimulate migration in a slow-moving stromal cell, observed via label-free ptychography. Subsequent untargeted proteomic interrogation of the secreted factors from these cell lines identified a highly significant enrichment of extracellular matrix (ECM) protein production by the differentiation-competent cells compared to non-stem cells. The most highly enriched proteins, aggrecan and periostin, were identified on the endosteal surfaces of mouse and human bone, underlying CD271+ stromal cells in the latter, indicating that they may represent key non-cellular niche-components important for cell maintenance and phenotype. ECM from stem cells was further capable of enhancing migration in non-stem cells in a focal adhesion kinase-dependent manner.

Overall, we demonstrate the importance of the ECM in co-ordination of cellular phenotype and highlight how non-cellular components of the BMSC niche may provide insights into the role of BMSCs in health and disease.
Automatic analysis of skull thickness, scalp-to-cortex distance and association with age and sex in cognitively normal elderly
Authors: Zhang Junhao , Treyer Valerie , Sun Junfeng , Zhang Chencheng , Gietl Anton , Hock Christoph , Razansky Daniel , Nitsch Roger M. , Ni Ruiqing ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2023

Personalized neurostimulation has been a potential treatment for many brain diseases, which requires insights into brain/skull geometry. Here, we developed an open source efficient pipeline BrainCalculator for automatically computing the skull thickness map, scalp-to-cortex distance (SCD), and brain volume based on T1-weighted magnetic resonance imaging (MRI) data. We examined the influence of age and sex cross-sectionally in 407 cognitively normal older adults (71.9±8.0 years, 60.2% female) from the ADNI. We demonstrated the compatibility of our pipeline with commonly used preprocessing packages and found that BrainSuite Skullfinder was better suited for such automatic analysis compared to FSL Brain Extraction Tool 2 and SPM12- based unified segmentation using ground truth. We found that the sphenoid bone and temporal bone were thinnest among the skull regions in both females and males. There was no increase in regional minimum skull thickness with age except in the female sphenoid bone. No sex difference in minimum skull thickness or SCD was observed. Positive correlations between age and SCD were observed, faster in females (0.307%/y) than males (0.216%/y) in temporal SCD. A negative correlation was observed between age and whole brain volume computed based on brain surface (females -1.031%/y, males -0.998%/y). In conclusion, we developed an automatic pipeline for MR-based skull thickness map, SCD, and brain volume analysis and demonstrated the sex-dependent association between minimum regional skull thickness, SCD and brain volume with age. This pipeline might be useful for personalized neurostimulation planning.
Profiling extracellular vesicles in circulation enables the early detection of ovarian cancer
Authors: Jo Ala , Green Allen , Medina Jamie E. , Iyer Sonia , Ohman Anders W. , McCarthy Eric T. , Reinhardt Ferenc , Gerton Thomas , Demehin Daniel , Mishra Ranjan , Kolin David L. , Zheng Hui , Crum Christopher P. , Weinberg Robert A. , Rueda Bo R. , Castro Cesar M. , Dinulescu Daniela M. , Lee Hahko
Published: January 2023

Ovarian cancer is a heterogeneous group of tumors in both cell type and natural history. While outcomes are generally favorable when detected early, the most common subtype, high-grade serous carcinoma (HGSOC), typically presents at an advanced stage and portends less favorable prognoses. Its aggressive nature has thwarted early detection efforts through conventional detection methods such as serum CA125 and ultrasound screening and thus inspired the investigation of novel biomarkers. Here, we report the systematic development of an extracellular-vesicle (EV)-based test to detect early-stage HGSOC. Our study is based on emerging insights into HGSOC biology, notably that it arises from precursor lesions within the fallopian tube before traveling to ovarian and/or peritoneal surfaces. To identify HGSOC marker candidates, we established murine fallopian tube (mFT) cells with oncogenic mutations inBrca1/2, Tp53, andPtengenes, and performed proteomic analyses on mFT EVs. The identified markers were then evaluated with an orthotopic HGSOC animal model. In serially-drawn blood samples of tumor-bearing mice, mFT-EV markers increased with tumor initiation, supporting their potential use in early cancer detection. A pilot human clinical study (n= 51) further narrowed EV markers to five candidates, EpCAM, CD24, VCAN, HE4, and TNC. Combined expression of these markers achieved high OvCa diagnostic accuracy (cancer vs. non-cancer) with a sensitivity of 0.89 and specificity of 0.93. The same five markers were also effective in a three-group classification: non-cancer, early-stage (I & II) HGSOC, and late-stage (III & IV) HGSOC. In particular, they differentiated early-stage HGSOC from the rest with a specificity of 0.91. Minimally invasive and repeatable, this EV-based testing could be a versatile and serial tool for informing patient care and monitoring women at high risk for ovarian cancer.
Aging reduces motivation through decreasedBdnfexpression in the ventral tegmental area
Authors: Lei Hanyue Cecilia , Parker Kyle E. , Yuede Carla M. , McCall Jordan G. , Imai Shin-ichiro
Published: January 2023

Age-associated reduced motivation is a hallmark of neuropsychiatric disorders in the elderly. In our rapidly aging societies, it is critical to keep motivation levels high enough to promote healthspan and lifespan. However, how motivation is reduced during aging remains unknown. Here, we used multiple mouse models to evaluate motivation and related affective states in young and old mice. We also compared the effect of social isolation, a common stressor, to those of aging. We found that both social isolation and aging decreased motivation in mice, but thatBdnfexpression in the ventral tegmental area (VTA) was selectively decreased during aging. Furthermore, VTA-specificBdnfknockdown in young mice recapitulated reduced motivation observed in old mice. These results demonstrate that maintainingBdnfexpression in the VTA could promote motivation to engage in effortful activities and potentially prevent age-associated neuropsychiatric disorders.
A scalable platform for functional interrogation of peptide hormones in fish
Authors: Moses Eitan , Harel Itamar
Published: January 2023

Fish display a remarkable diversity of life-history traits, including body size, age at maturity, and longevity. Although pituitary hormones are conserved mediators of life-history transitions, regulatory networks are less understood in fish. However, the relatively long life-cycles and germline-dependent maturation of classical fish models are less compatible with rapid exploration of adult physiology, particularly in females. Here, we describe a high-throughput platform that combines, for the first time, loss- and gain-of-function of peptide hormones in a naturally short-lived fish. As a proof-of-principle, we first manipulate growth by mutating growth hormone (gh1) in the turquoise killifish (N. furzeri). Next, to rescue growth defects, we designed a vector in which hormones are tagged by a self-cleavable fluorescent reporter, and are ectopically expressed using intramuscular electroporation. A single injection of agh1-T2A-GFPplasmid was sufficient to produce a stable expression of tag-free hormone and rescue growth phenotypes. This, in contrast to current practice for which multiple injections of recombinant hormones are required. We demonstrate the versatility of our platform by rescuing female sterility, which is induced by manipulating the follicle stimulating hormone (fshb). As killifish maturation is germline-independent, both sexes can be explored in genetic models with germline defects. Finally, we describe a doxycycline-inducible system for tunable expression control. Together, this platform significantly advances the state-of-the-art by allowing high-throughput functional dissection of distinct life-history strategies in fish. This method could be multiplexed to facilitate various applications, including optimizing commercially valuable traits in aquaculture, or screening pro-longevity hormonal interventions in aging.
Gentrius: identifying equally scoring trees in phylogenomics with incomplete data
Authors: Chernomor Olga , Elgert Christiane , von Haeseler Arndt
Published: January 2023

Phylogenetic trees are routinely built from huge and yet incomplete multi-locus datasets often leading to phylogenetic terraces – topologically distinct equally scoring trees, which induce the same set of per locus subtrees. As typical tree inference software outputs only a single tree, identifying all trees with identical score challenges phylogenomics. Generating all trees from a terrace requires constructing a so-called stand for the corresponding set of induced locus subtrees. Here, we introduce Gentrius – an efficient algorithm that tackles this problem for unrooted trees. Despite stand generation being computationally intractable, we showed on simulated and biological datasets that Gentrius generates stands with millions of trees in feasible time. Depending on the distribution of missing data across species and loci and the inferred phylogeny, the number of equally optimal terrace trees varies tremendously. The strict consensus tree computed from them displays all the branches unaffected by the pattern of missing data. Thus, Gentrius provides an important systematic assessment of phylogenetic trees inferred from incomplete data. Furthermore, Gentrius can aid theoretical research by fostering understanding of tree space structure imposed by missing data.

One-Sentence Summary

Gentrius - the algorithm to generate a complete stand, i.e. all binary unrooted trees compatible with the same set of subtrees.
3D printed magneto-active microfiber scaffolds for remote stimulation of 3Din vitroskeletal muscle models
Authors: Cedillo-Servin Gerardo , Dahri Ouafa , Meneses João , van Duijn Joost , Sage Fanny , Silva Joana , Pereira André , Magalhães Fernão D. , Malda Jos , Geijsen Niels , Pinto Artur M. , Castilho Miguel
Published: January 2023

Tunable culture platforms that guide cellular organization and mechanically stimulate skeletal muscle development are still unavailable due to limitations in biocompatibility and actuation triggered without contact. This study reports the rational design and fabrication of magneto-active microfiber meshes with controlled hexagonal microstructures via melt electrowriting (MEW) of a thermoplastic/graphene/iron oxide composite.In situdeposition of iron oxide nanoparticles on oxidized graphene yielded homogeneously dispersed magnetic particles with sizes above 0.5 μm and low aspect ratio, preventing cellular internalization and toxicity. With these fillers, homogeneous magnetic composites with very high magnetic filler content (up to 10 wt.%) were obtained and successfully processed in a solvent-free manner for the first time. MEW of magnetic composites enabled the skeletal muscle-inspired design of hexagonal scaffolds with tunable fiber diameter, reconfigurable modularity, and zonal distribution of magneto-active and nonactive material. Importantly, the hexagonal microstructures displayed elastic deformability under tension, mitigating the mechanical limitations due to high filler content. External magnetic fields below 300 mT were sufficient to trigger out-of-plane reversible deformation leading to effective end-to-end length decrease up to 17%. Moreover, C2C12 myoblast culture on 3D Matrigel/collagen/MEW scaffolds showed that the presence of magnetic particles in the scaffolds did not significantly affect viability after 8 days with respect to scaffolds without magnetic filler. Importantly,in vitroculture demonstrated that myoblasts underwent differentiation at similar rates regardless of the presence of magnetic filler. Overall, these innovative microfiber scaffolds were proven as a magnetically deformable platform suitable for dynamic culture of skeletal muscle with potential forin vitrodisease modeling.