bluuebunny/crossref_metadata_2025 huggingface dataset:
Ribonanza: deep learning of RNA structure through dual crowdsourcing
Authors: He Shujun , Huang Rui , Townley Jill , Kretsch Rachael C. , Karagianes Thomas G. , Cox David B.T. , Blair Hamish , Penzar Dmitry , Vyaltsev Valeriy , Aristova Elizaveta , Zinkevich Arsenii , Bakulin Artemy , Sohn Hoyeol , Krstevski Daniel , Fukui Takaaki , Tatematsu Fumiya , Uchida Yusuke , Jang Donghoon , Lee Jun Seong , Shieh Roger , Ma Tom , Martynov Eduard , Shugaev Maxim V. , Bukhari Habib S.T. , Fujikawa Kazuki , Onodera Kazuki , Henkel Christof , Ron Shlomo , Romano Jonathan , Nicol John J. , Nye Grace P. , Wu Yuan , Choe Christian , Reade Walter ,   Eterna participants, Das Rhiju
Published: February 2024

Prediction of RNA structure from sequence remains an unsolved problem, and progress has been slowed by a paucity of experimental data. Here, we present Ribonanza, a dataset of chemical mapping measurements on two million diverse RNA sequences collected through Eterna and other crowdsourced initiatives. Ribonanza measurements enabled solicitation, training, and prospective evaluation of diverse deep neural networks through a Kaggle challenge, followed by distillation into a single, self-contained model called RibonanzaNet. When fine tuned on auxiliary datasets, RibonanzaNet achieves state-of-the-art performance in modeling experimental sequence dropout, RNA hydrolytic degradation, and RNA secondary structure, with implications for modeling RNA tertiary structure.
Enhanced microbiota profiling in patients with quiescent Crohn’s disease through comparison with paired healthy first-degree relatives using fecal metagenomics and metabolomics
Authors: Chen Wanning , Li Yichen , Wang Wenxia , Gao Sheng , Wu Dingfeng , Jiao Na , Xu Tao , Zhi Min , Zhu Lixin , Zhu Ruixin
Published: February 2024

Prior studies indicate no correlation between gut microbiota of healthy first-degree relatives (HFDRs) of Crohn’s disease (CD) patients and development of CD. Here, we utilized HFDRs as controls to examine the microbiota and metabolome in individuals with active (CD-A) and quiescent (CD-R) CD, thereby minimizing the influence of genetic and environmental factors. Compared to non-relative controls, the use of HFDR controls identified fewer differential taxa.Faecalibacterium, Dorea,andFusicatenibactershowed decreased abundances in CD-R, independent of inflammation, and correlated with fecal SCFAs. Validation with a large multi-center cohort confirmed decreased abundances inFaecalibacteriumand other SCFA-producing genera in CD-R. Classification models based on these genera distinguished CD-R and CD-A from healthy individuals, in both the discovery and validation cohorts. Thus, the decreased presence ofFaecalibacterium, Dorea,andFusicatenibacterin CD-R likely contributed to disease relapse through reduced SCFA production, highlighting their potential as diagnostic markers and therapeutic targets for CD.
Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2
Authors: Wortham Matthew , Ramms Bastian , Zeng Chun , Benthuysen Jacqueline R. , Sai Somesh , Pollow Dennis P. , Liu Fenfen , Schlichting Michael , Harrington Austin R. , Liu Bradley , Prakash Thazha P. , Pirie Elaine C , Zhu Han , Baghdasarian Siyouneh , Auwerx Johan , Shirihai Orian S. , Sander Maike
Published: February 2024

Selective and controlled expansion of endogenous β-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of β-cell proliferation to avoid excessive β-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of β-cell proliferation whose inactivation results in controlled β-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2).Sirt2deletion in β-cells of mice increased β-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of β-cell mass. SIRT2 restrains proliferation of human islet β-cells cultured in glucose concentrations above the glycemic set point, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level,Sirt2inactivation has context-dependent effects on β-cells, withSirt2controlling how β-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupledSirt2-targeting antisense oligonucleotide achieves β-cell selectiveSirt2inactivation and stimulates β-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing β-cell mass in diabetes without circumventing feedback control of β-cell proliferation.
Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR-T cells
Authors: Kasap Corynn , Izgutdina Adila , Patiño-Escobar Bonell , Kang Amrik , Chilakapati Nikhil , Akagi Naomi , Johnson Haley , Rashid Tasfia , Werner Juwita , Barpanda Abhilash , Geng Huimin , Lin Yu-Hsiu T. , Rampersaud Sham , Gil-Alós Daniel , Sobh Amin , Dupéré-Richer Daphné , Wicaksono Gianina , Kawehi Kelii K.M. , Dalal Radhika , Ramos Emilio , Vijayanarayanan Anjanaa , Salangsang Fernando , Phojanakong Paul , Serrano Juan Antonio Camara , Zakraoui Ons , Tariq Isa , Steri Veronica , Shanmugam Mala , Boise Lawrence H. , Kortemme Tanja , Stieglitz Elliot , Licht Jonathan D. , Karlon William J. , Barwick Benjamin G. , Wiita Arun P.
Published: February 2024

Despite the success of BCMA-targeting CAR-Ts in multiple myeloma, patients with high-risk cytogenetic features still relapse most quickly and are in urgent need of additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target in other cancers, as a specifically upregulated cell surface antigen in high risk myeloma tumors. We use a structure-guided design to define a CD27-based anti-CD70 CAR-T design that outperforms all tested scFv-based CARs, leading to >80-fold improved CAR-T expansion in vivo. Epigenetic analysis via machine learning predicts key transcription factors and transcriptional networks driving CD70 upregulation in high risk myeloma. Dual-targeting CAR-Ts against either CD70 or BCMA demonstrate a potential strategy to avoid antigen escape-mediated resistance. Together, these findings support the promise of targeting CD70 with optimized CAR-Ts in myeloma as well as future clinical translation of this approach.

One sentence summary

Structure-optimized CD27-based CAR-T cells targeting CD70 are a promising therapeutic option for high-risk multiple myeloma patients who are most likely to relapse on current BCMA-targeting cellular therapies.
Wake EEG oscillation dynamics reflect both sleep need and brain maturation across childhood and adolescence
Authors: Snipes Sophia , Krugliakova Elena , Jaramillo Valeria , Volk Carina , Furrer Melanie , Studler Mirjam , LeBourgeois Monique , Kurth Salome , Jenni Oskar G. , Huber Reto
Published: February 2024

An objective measure of brain maturation is highly insightful for monitoring both typical and atypical development. Slow wave activity, recorded in the sleep electroencephalogram (EEG), reliably indexes changes in brain plasticity with age, as well as deficits related to developmental disorders such as attention-deficit hyperactivity disorder (ADHD). Unfortunately, measuring sleep EEG is resource-intensive and burdensome for participants. We therefore aimed to determine whether wake EEG could likewise index developmental changes in brain plasticity. We analyzed high-density wake EEG collected from 163 participants 3-25 years old, before and after a night of sleep. We compared two measures of oscillatory EEG activity, amplitudes and density, as well as two measures of aperiodic activity, intercepts and slopes. Furthermore, we compared these measures in patients with ADHD (8-17 y.o., N=58) to neurotypical controls. We found that wake oscillation amplitudes behaved the same as sleep slow wave activity: amplitudes decreased with age, decreased after sleep, and this overnight decrease decreased with age. Oscillation densities were also substantially age-dependent, decreasing overnight in children and increasing overnight in adolescents and adults. While both aperiodic intercepts and slopes decreased linearly with age, intercepts decreased overnight, and slopes increased overnight. Overall, our results indicate that wake oscillation amplitudes track both development and sleep need, and overnight changes in oscillation density reflect some yet-unknown shift in neural activity around puberty. No wake measure showed significant effects of ADHD, thus indicating that wake EEG measures, while easier to record, are not as sensitive as those during sleep.
Recurrent cortical networks encode natural sensory statistics via sequence filtering
Authors: Deveau Ciana E. , Zhou Zhishang , LaFosse Paul K. , Deng Yanting , Mirbagheri Saghar , Steinmetz Nicholas , Histed Mark H.
Published: February 2024

Recurrent neural networks can generate dynamics, but in sensory cortex it has been unclear if any dynamic processing is supported by the dense recurrent excitatory-excitatory network. Here we show a new role for recurrent connections in mouse visual cortex: they support powerful dynamical computations, but by filtering sequences of input instead of generating sequences. Using two-photon optogenetics, we measure neural responses to natural images and play them back, finding inputs are amplified when played back during the correct movie dynamic context— when the preceding sequence corresponds to natural vision. This sequence selectivity depends on a network mechanism: earlier input patterns produce responses in other local neurons, which interact with later input patterns. We confirm this mechanism by designing sequences of inputs that are amplified or suppressed by the network. These data suggest recurrent cortical connections perform predictive processing, encoding the statistics of the natural world in input-output transformations.
ScISOr-ATAC reveals convergent and divergent splicing and chromatin specificities between matched cell types across cortical regions, evolution, and in Alzheimer’s Disease
Authors: Hu Wen , Foord Careen , Hsu Justine , Fan Li , Corley Michael J , Bhatia Tarun N , Xu Siwei , Belchikov Natan , He Yi , Pang Alina PS , Lanjewar Samantha N , Jarroux Julien , Joglekar Anoushka , Milner Teresa A , Ndhlovu Lishomwa C , Zhang Jing , Butelman Eduardo , Sloan Steven A , Lee Virginia MY , Gan Li , Tilgner Hagen U
Published: February 2024

Multimodal measurements have become widespread in genomics, however measuring open chromatin accessibility and splicing simultaneously in frozen brain tissues remains unconquered. Hence, we devised Single-Cell-ISOform-RNA sequencing coupled with the Assay-for-Transposase-Accessible-Chromatin (ScISOr-ATAC). We utilized ScISOr-ATAC to assess whether chromatin and splicing alterations in the brain convergently affect the same cell types or divergently different ones. We applied ScISOr-ATAC to three major conditions: comparing (i) the Rhesus macaque (Macaca mulatta) prefrontal cortex (PFC) and visual cortex (VIS), (ii) cross species divergence of Rhesus macaque versus human PFC, as well as (iii) dysregulation in Alzheimer’s disease in human PFC. We found that among cortical-layer biased excitatory neuron subtypes, splicing is highly brain-region specific for L3-5/L6 IT_RORBneurons, moderately specific in L2-3 IT_CUX2.RORBneurons and unspecific in L2-3 IT_CUX2neurons. In contrast, at the chromatin level, L2-3 IT_CUX2.RORBneurons show the highest brain-region specificity compared to other subtypes. Likewise, when comparing human and macaque PFC, strong evolutionary divergence on one molecular modality does not necessarily imply strong such divergence on another molecular level in the same cell type. Finally, in Alzheimer’s disease, oligodendrocytes show convergently high dysregulation in both chromatin and splicing. However, chromatin and splicing dysregulation most strongly affect distinct oligodendrocyte subtypes. Overall, these results indicate that chromatin and splicing can show convergent or divergent results depending on the performed comparison, justifying the need for their concurrent measurement to investigate complex systems. Taken together, ScISOr-ATAC allows for the characterization of single-cell splicing and chromatin patterns and the comparison of sample groups in frozen brain samples.
Dietary bacteria controlC. elegansfat content through pathways converging at phosphatidylcholine
Authors: Han Hsiao-Fen , Nien Shao-Fu , Jiang Hang-Shiang , Wu Jui-Ching , Chiang Chia-Yi , Li Man-Tzu , Huang Leng-Jie , Chiang Sufeng , Lin Lien-Chieh , Chuang Yi-Ting , Lin Yu-Ho , Wang Chao-Wen , Wu Yi-Chun
Published: February 2024

Dietary factors play a pivotal role in regulating metabolism in both health and disease. Lipid metabolism is particularly important for organismal health and longevity. However, the mechanisms by which dietary factors influence lipid metabolism remain poorly understood. Here, using the nematodeC. elegansas a model system, we investigated the influence of distinct bacterial diets on fat metabolism. We found that dietary vitamin B12 activates the S-adenosyl methionine (SAM) and phosphatidylcholine (PC) biosynthetic pathways. This activation leads to elevated levels of PC, which in turn suppresses the expression of the genefat-7and modulates lipid droplet dynamics through the regulatory proteins SBP-1/SREBP1 and SEIP-1/SEIPIN, respectively. Additionally, we identified a feedback loop involving SBP-1-mediated regulation of acid sphingomyelinase ASM-3, which enhances the production of phospho-choline and further stimulates PC synthesis. Our localization studies further suggest that ASM-3 may act as a signaling mediator between the intestine and coelomocytes, coordinating their roles in vitamin B12-mediated fat regulation. Overall, our findings shed new light on the complex interplay between diet and metabolic regulation, with a particular emphasis on the central role of phosphatidylcholine.

Highlights

Animals govern PC level to regulate lipid homeostasis in response to diets

B12 regulates SAM-PC axis to affect lipogenic genes expression and LD biogenesis

Coelomocytes regulate diets-induced lipid homeostasis throughasm-3

asm-3constructs a positive feedback loop to participate in PC metabolism
Is facultative sex is the best of both worlds in the parasitoid waspLysiphlebus fabarum?
Authors: Boulton Rebecca A
Published: February 2024

The prevalence of sexual reproduction has long puzzled evolutionary biologists. This is because asexual reproduction is a far more efficient way to transmit copies of one’s own genome to the next generation, and, all-else-being-equal, should predominate over sex. Asexual reproduction is not without its disadvantages though, the lack of genetic recombination can render parthenogenetic lineages vulnerable to extinction under environmental change, or compromise fitness due to the buildup of deleterious recessive mutations. Facultative sex, where individuals retain the ability to reproduce sexually and asexually, has been touted as ‘the best of both worlds’, providing the long-term genetic benefits of sex without the short-term costs. In this study I tested whether sex is facultative in the aphid parasitoidLysiphlebus fabarum, and if so whether facultative sex is ‘the best of both worlds’. I found that females from asexual populations mate with males produced by females from an obligately sexual population, and produced offspring with paternal genetic contributions, confirming facultative sex in this species. I then assayed the fitness of these facultatively sexual wasps and found, contrary to predictions that they actually had significantly lower fitness than asexual or obligately sexual females, as their daughters were up to 40% more likely to fail to reproduce entirely. In contrast, obligately sexual females were not at a disadvantage compared to asexual females in this species; they had increased fecundity compared to asexual females which compensated for the costs of sex. InL. fabarumit seems that all is not equal; the fecundity advantage that obligate sex provides, along with the costs of occasional facultative sex by asexuals may balance the scales and allow stable coexistence of the different reproductive modes in nature.
Differential Responses of Dynamic and Entropic Aging Factors to Longevity Interventions
Authors: Perevoshchikova Kristina , Fedichev Peter O.
Published: February 2024

Aging across most species, including mice and humans, is characterized by an exponential acceleration of mortality rates. In search for the molecular basis of this phenomenon, we analyzed DNA methylation (DNAm) changes in aging mice. Utilizing principal component analysis (PCA) on DNAm profiles, we identified a primary aging signature with an exponential age dependency, closely reflecting the Gompertz law’s description of mortality acceleration. This signature is the manifestation of the dynamic instability in the organism’s state that drives the aging process in mice. It aligns closely with regression-based aging clocks and responds to interventions such as caloric restriction and parabiosis. Additionally, we identified a linear DNAm signature, indicative of a global demethylation level. Through single-cell DNAm (scDNAm) data from aging animals, we demonstrate that this signature captures the exponential expansion of the state space volume spanned by individual cells within an aging organism, and thus quantifying linearly increasing configuration entropy, likely an irreversible process. Consistent with this interpretation, we found that neither caloric restriction (CR) nor parabiosis significantly impacts the entropic feature, reinforcing its link to irreversible damage.
Sample preparation methods for volume electron microscopy in molluscBerghia stephanieae
Authors: Drescher Brandon , Sant Harshada H. , Schalek Richard L. , Lichtman Jeff W. , Katz Paul S.
Published: February 2024

Creating a high-resolution brain atlas in diverse species offers crucial insights into general principles underlying brain function and development. A volume electron microscopy approach to generate such neural maps has been gaining importance due to advances in imaging, data storage capabilities, and data analysis protocols. Sample preparation remains challenging and is a crucial step to accelerate the imaging and data processing pipeline. Here, we introduce several replicable methods for processing the brains of the gastropod mollusc,Berghia stephanieaefor volume electron microscopy. Although high-pressure freezing is the most reliable method, the depth of cryopreservation is a severe limitation for large tissue samples. We introduce a BROPA-based method using pyrogallol and methods to rapidly process samples that can save hours at the bench. This is the first report on sample preparation and imaging pipeline for volume electron microscopy in a gastropod mollusc, opening up the potential for connectomic analysis and comparisons with other phyla.
TISSUE-SPECIFIC METABOLOMIC REPROGRAMMING DETERMINES THE DISEASE PATHOPHYSIOLOGY OF SARS-COV-2 VARIANTS IN HAMSTER MODEL
Authors: Sardarni Urvinder Kaur , Ambikan Anoop , Acharya Arpan , Johnson Samuel D , Avedissian Sean N , Vegvari Akos , Neogi Ujjwal , Byrareddy Siddappa
Published: February 2024

Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between organs and specific SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed increased viremia in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection.
Food-associated calls in disc-winged bats
Authors: Chaverri Gloriana , Page Rachel A.
Published: February 2024

Animals that engage in social foraging can produce food-associated calls that elicit two main responses in receivers: the recruitment of other individuals to a foraging site, and an increase in feeding-related behaviors in conspecifics. Spix’s disc-winged bat,Thyroptera tricolor, is a highly gregarious species that lives in stable social groups and relies on group call-and-response vocalizations to find ephemeral roosting sites. Because this bat also is known to feed on resources that are abundant but ephemeral – for example insect swarms – we hypothesized that it likewise emits vocalizations that serve to recruit conspecifics to a foraging site and elicit food consumption. We found that indeed, feeding bats emitted distinct vocalizations exclusively while consuming an abundant prey item, a call type that has not been previously described in the acoustic repertoire of any bat to date. We also observed that these “food calls” prompted responses typically associated with food-calling: they increased both feeding-related behaviors and social recruitment. Specifically, we observed that the onset of the consumption of novel prey items was strongly associated with the emission of food calls but not with other types of sounds. In addition, individuals approached a speaker broadcasting food calls, especially when food calls had not been broadcast before, while other types of sounds did not consistently prompt inspection. Taken together, these results suggest thatT. tricolorcoordinates foraging behavior through the emission of food-associated communication calls.

SUMMARY STATEMENT

This study provides evidence of food-associated calling in Spix’s disc-winged bats (Thyroptera tricolor), revealing its association with feeding contexts and its potential role in prompting social recruitment and feeding-related behaviors.
Machine Learning for COVID-19 Patient Management: Predictive Analytics and Decision Support
Authors: El Hadi Christopher , Saliba Rindala , Maalouly Georges , Riachy Moussa , Sleilaty Ghassan
Published: February 2024

Background

The global impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has profoundly affected economies and healthcare systems around the world, including Lebanon. While numerous meta-analyses have explored the systemic manifestations of COVID-19, few have linked them to patient history. Our study aims to fill this gap by using cluster analysis to identify distinct clinical patterns among patients, which could aid prognosis and guide tailored treatments.

Methods

We conducted a retrospective cohort study at Beirut’s largest teaching hospital on 556 patients with SARS-CoV-2. We performed cluster analyses using K-prototypes, KAMILA and LCM algorithms based on 26 variables, including laboratory results, demographics and imaging findings. Silhouette scores, concordance index and signature variables helped determine the optimal number of clusters. Subsequent comparisons and regression analyses assessed survival rates and treatment efficacy according to clusters.

Results

Our analysis revealed three distinct clusters: “resilient recoverees” with varying disease severity and low mortality rates, “vulnerable veterans” with severe to critical disease and high mortality rates, and “paradoxical patients” with a late presentation but eventual recovery.

Conclusions

These clusters offer insights for prognosis and treatment selection. Future studies should include vaccination data and various COVID-19 strains for a comprehensive understanding of the disease’s dynamics.
CXCL14 suppresses the progression of colon cancer by regulating tumor epithelial-mesenchymal transition and tumor microenvironment
Authors: Zhang Yinjie , Jin Yue , Wang Siyi , Niu Yuchen , Ma Buyong , Li Jingjing
Published: February 2024

Background

The widespread silencing of CXCL14 in advanced colon cancer underscores the association between CXCL14 and the development of colon cancer. Some studies have demonstratedin vitrothat CXCL14 can inhibit the growth and metastasis of colon cancer cell, and it has also been studied in other disease models for its regulation of immune cell infiltration.

Aims

The aim of this study is to clarify the transcriptional regulation of colon cancer cells mediated by CXCL14 and its regulatory role in the tumor microenvironment.

Method

We analyzed the expression characteristics of CXCL14 in clinical databases of colon cancer. CXCL14 overexpression cell lines were established to study its functions on gene transcriptional regulation and cell physiology. Through subcutaneous tumor models, we investigated the effects of CXCL14 on the immune microenvironment.

Result

Firstly, the clinical data revealed that CXCL14 is silenced during cancer progression, and negatively associated with EMT and cell proliferation markers, and positively associated with the abundance of T cells and NK cells in colon tissue. Secondly, RNA-seq reveals that CXCL14 overexpression is negatively associated with cell EMT, and inhibits tumor migration and invasion. Western blot (WB) assay confirmed that CXCL14 inhibits the Erk/MAPK and Akt signaling pathways. Finally, subcutaneous tumor models demonstrate that CXCL14 overexpression inhibited tumor growth, increased the infiltration of tumor-associated T cells and DC cells, activated the anti-tumor immune response, antigen processing and presentation, and T helper differentiation in the tumor microenvironment.

Conclusion

CXCL14 becomes silenced in late-stage colon cancer samples.In vivoandin vitroexperiments demonstrate that CXCL14 inhibits tumor EMT, proliferation, and metastasis through autocrine signaling. It also enhances the infiltration of T and NK lymphocytes through paracrine signaling and inhibits the proliferation of subcutaneous tumors.
Antiandrogen Flutamide-Induced Restoration of miR-449 Expression Mitigates Functional Biomarkers Associated with Ovarian Cancer Risk
Authors: Wang Xia , Woo Ho-Hyung , Wei Michele , Gibson Steven , Miranda Mitzi , Rush Demaretta , Cragun Janiel , Zheng Wenxin , Yao Guang , Chambers Setsuko K
Published: February 2024

Background

The involvement of the androgen and androgen receptor (AR) pathway in the development of epithelial ovarian cancer is increasingly recognized. However, the specific mechanisms by which anti-androgen agents, such as flutamide, may prevent ovarian cancer and their efficacy remain unknown. We examined the effects of flutamide on the miRNA expression profile found in women at high risk (HR) for ovarian cancer.

Methods

Ovarian and tubal tissues, free from ovarian, tubal, peritoneal cancers, and serous tubal intraepithelial carcinoma (STIC), were collected from untreated and flutamide-treated HR women. Low-risk (LR) women served as controls. Transcriptomic miRNA sequencing was performed on these 3 sample cohorts. The miRNAs that showed the most notable differential expression were subjected to functional assays in primary ovarian epithelial cells and ovarian cancer cells.

Results

Flutamide treatment demonstrated a normalization effect on diminished miRNA levels in HR tissues compared to LR tissues. Particularly, the miR-449 family was significantly upregulated in HR ovarian tissues following flutamide treatment, reaching levels comparable to those in LR tissues. MiR-449a and miR-449b-5p, members of the miR-449 family, were computationally predicted to target the mRNAs of AR and colony-stimulating factor 1 receptor (CSF1R, also known asc-fms), both of which are known contributors to ovarian cancer progression, with emerging evidence also supporting their roles in ovarian cancer initiation. These findings were experimentally validated in primary ovarian epithelial cells and ovarian cancer cell lines (SKOV3 and Hey): flutamide treatment resulted in elevated levels of miR-449a and miR-449b-5p, and introducing mimics of these miRNAs reduced the mRNA and protein levels of CSF1R and AR. Furthermore, introducing miR-449a and miR-449b-5p mimics showed inhibitory effects on the migration and proliferation of ovarian cancer cells.

Conclusion

Flutamide treatment restored the reduced expression of miR-449a and miR-449b-5p in HR tissues, thereby decreasing the expression of CSF1R and AR, functional biomarkers associated with an increased risk of ovarian cancer. In addition to the known direct binding of flutamide to the AR, we found that flutamide also suppresses AR expression via miR-449a and miR-449b-5p upregulation, revealing a novel dual-inhibitory mechanism on the AR pathway. Taken together, our study highlights mechanisms supporting the chemopreventive potential of flutamide in ovarian cancer, particularly in HR patients with reduced miR-449 expression.
A pilot study to investigate the safety and feasibility of antiretroviral therapy for Alzheimer’s disease (ART-AD)
Authors: Sullivan A. Campbell , Zuniga Gabrielle , Ramirez Paulino , Fernandez Roman , Wang Chen-Pin , Li Ji , Davila Lisa , Pelton Kristine , Gomez Sandra , Sohn Claira , Gonzalez Elias , Lopez-Cruzan Marisa , Gonzalez David A. , Parker Alicia , Zilli Eduardo , de Erausquin Gabriel A. , Seshadri Sudha , Espinoza Sara , Musi Nicolas , Frost Bess
Published: February 2024

Retrotransposons are viral-like DNA sequences that constitute approximately 41% of the human genome. Studies inDrosophila,mice, cultured cells, and human brain indicate that retrotransposons are activated in settings of tauopathy, including Alzheimer’s disease, and causally drive neurodegeneration. The anti-retroviral medication 3TC (lamivudine), a nucleoside analog reverse transcriptase inhibitor, limits retrotransposon activation and suppresses neurodegeneration in tau transgenicDrosophila,two mouse models of tauopathy, and in brain assembloids derived from patients with sporadic Alzheimer’s disease. We performed a 24-week phase 2a open-label clinical trial of 300 mg daily oral 3TC (NCT04552795) in 12 participants aged 52-83 years with a diagnosis of mild cognitive impairment due to suspected Alzheimer’s disease. Primary outcomes included feasibility, blood brain barrier penetration, effects of 3TC on reverse transcriptase activity in the periphery, and safety. Secondary outcomes included changes in cognition and fluid-based biomarkers of neurodegeneration and neuroinflammation. All participants completed the six-month trial; one event of gastrointestinal bleeding due to a peptic ulcer was reported. 3TC was detected in blood and cerebrospinal fluid (CSF) of all participants, suggestive of adherence to study drug and effective brain penetration. Cognitive measures remained stable throughout the study. Glial fibrillary acidic protein (GFAP) (P=0.03) and Flt1 (P=0.05) were significantly reduced in CSF over the treatment period; Aβ42/40 (P=0.009) and IL-15 (P=0.006) were significantly elevated in plasma. While this is an open label study of small sample size, the significant decrease of some neurodegeneration- and neuroinflammation-related biomarkers in CSF, significantly elevated levels of plasma Aβ42/40, and a trending decrease of CSF NfL after six months of 3TC exposure suggest a beneficial effect on subjects with mild cognitive impairment due to suspected Alzheimer’s disease. Feasibility, safety, tolerability, and central nervous system (CNS) penetration assessments further support clinical evaluation of 3TC in a larger placebo-controlled, multi-dose clinical trial.
Curating genomic disease-gene relationships with Gene2Phenotype
Authors: Yates T Michael , Ansari Morad , Thompson Louise , Hunt Sarah E , Uhalte Elena Cibrian , Hobson Rachel J , Marsh Joseph A , Wright Caroline F , Firth Helen V
Published: February 2024

Genetically determined disorders are highly heterogenous in clinical presentation and underlying molecular mechanism. The evidence underpinning these conditions in the peer-reviewed literature is variable and requires robust critical evaluation for diagnostic use. Here, we present a structured curation process for the Gene2Phenotype (G2P) project. This draws on multiple lines of clinical, bioinformatic and functional evidence. The process utilises and extends existing terminologies, allows for precise definition of the molecular basis of disease, and confidence levels to be attributed to a given gene-disease assertion. In-depth disease curation using this process will prove useful in applications including in diagnostics, research and the development of targeted therapeutics.
Multidimensional vulnerability and financial risk protection in health in contexts of protracted conflict: Evidence from the Occupied Palestinian Territory
Authors: Hatamyar Julia , Shayeb Sally , Hussain Akseer , Hammoudeh Weeam , Mazumdar Sumit , Moreno-Serra Rodrigo
Published: February 2024

This paper proposes a multidimensional vulnerability index for a setting of protracted conflict, which is applied to study the relationship between financial vulnerability and catastrophic healthcare expenditure (CHE) incidence in the Occupied Palestinian Territory in 2018. We find that our index better captures the extent of financial risk protection (FRP) compared to conventional measures of financial welfare. Results indicate that the most vulnerable groups experience a significantly higher likelihood of incurring CHE, and this likelihood is increased for those living in the West Bank compared to the Gaza Strip. We also find a lack of protection from existing insurance types against the risk of CHE. Our analysis provides valuable insights about key aspects, such as health financing and insurance bottlenecks, that will deserve careful policy attention in efforts to rebuild the Palestinian health system, following the Israel-Hamas war.

KEY MESSAGES

What is already known on this topic

•

In settings of protracted conflict, conventional welfare measures, such as household consumption expenditure, may not adequately capture the multifaceted nature of financial risk protection (FRP) in health.

•

There is a need for more comprehensive approaches to assess household vulnerability and FRP in such settings.

What this study adds

•

We propose a novel multidimensional index of household vulnerability for populations in protracted conflict areas, applied to 2018 data from the Occupied Palestinian Territory.

•

Assessing FRP through this multidimensional lens reveals different patterns of exposure to financially catastrophic health expenditure (CHE) across sub-populations, which are not evident through traditional measures.

•

We find a positive association between CHE risk and greater vulnerability in both the West Bank and the Gaza Strip, with the most vulnerable groups likely to incur CHE regardless of insurance status.

How this study might affect research, practice, or policy

•

Our vulnerability index predicts the risk of CHE across population sub-groups in a protracted conflict setting more effectively than traditional metrics, thereby offering better insights for health policy.

•

The analysis highlights particular policy aspects, such as health insurance arrangements, that will require addressing to “build back better” the Palestinian heath system following escalation of violent conflicts, damages caused to critical health service and social infrastructure, and different constraints on available policy options.
Incidence, prevalence, and survival of lung cancer in the United Kingdom from 2000-2021: a population-based cohort study
Authors: Corby George , Barclay Nicola L , Tan Eng Hooi , Burn Edward , Delmestri Antonella , Duarte-Salles Talita , Golozar Asieh , Man Wai Yi , Tietzova Ilona ,   OPTIMA Consortium, Prieto-Alhambra Daniel , Newby Danielle
Published: February 2024

Background

Lung cancer is the leading cause of cancer-associated mortality worldwide. In the UK, there has been a major reduction in smoking, the leading risk factor for lung cancer, as well as the introduction of the new screening in 2023. Therefore, an up-to-date assessment of the trends of lung cancer is required in the UK.

Methods

We performed a population-based cohort study using the UK primary care Clinical Practice Research Datalink (CPRD) GOLD database, compared with CPRD Aurum. Participants aged 18+ years, with one-year of prior data availability, were included. We estimated lung cancer incidence rates (IR), period prevalence (PP), and survival at one-, five– and ten years after diagnosis using the Kaplan-Meier method.

Results

Overall, 11,388,117 participants, with 45,563 lung cancer cases were studied. The incidence rate of lung cancer was 52.0 (95% CI 51.5 to 52.5) per 100,000 person-years, with incidence increasing from 2000 to 2021, especially in females aged over 50, and males aged over 80, with the highest incidence rate in people aged 80-89. Period prevalence in 2021 was 0.18%, with the largest rise seen in participants aged over 60. Median survival post-diagnosis increased from 6.6 months in those diagnosed between 2000-2004 to 10 months between 2015-2019. Both short and long-term survival was higher in younger cohorts, with 82.7% one-year survival in those aged 18-29, versus 24.2% in the age 90+ cohort. Throughout the study period, survival was longer in females, with a larger increase in survival over time than in males.

Conclusion

The incidence and prevalence of lung cancer diagnoses in the UK have increased, especially in female and older populations, with a small increase in median survival. With the introduction of the UK lung cancer screening programme, this study will enable future comparisons of overall disease burden, so the overall impact may be seen.
AI Derived Therapeutic Development for the Treatment of Opioid Use Disorder
Authors: Lallai Valeria , Martin A.C. , Fowler J.P. , Bautista Malia , Mogul Allison S. , Cheepluesak Jinjutha E. , Mirzaei Saman , Jenkins Ian , Lakey Jonathan R.T. , Tinder Robert , Fowler Christie D.
Published: February 2024

The opioid epidemic has led to a devastating loss of life nationwide. Of those dependent on opioids, many individuals desire to quit or reduce use, but their efforts are often unsuccessful given the powerful reinforcing properties associated with opioid drugs, especially fentanyl given its high potency and speed of onset. Here, we developed a novel theraputic based on a newly developed artificial intelligence (AI)-based platform, which was rationally designed to identify markers of dysregulation from human drug user postmortem brain tissue. The GATC-021 compound was synthesized and validated within vitroscreening for target specificity. Thereafter, GATC-021 was examined for its effectiveness in modulating opioid dependence with an animal model of addiction. We found that GATC-021 substantially reduced fentanyl intake in both male and female rats, as assessed with intravenous self-administration. However, given drug soluability challenges, additional studies are needed to better develop drug formulations to permit translation into clinical populations more effectively. Taken together, these findings validate our AI-based platform for novel therapeutic development with a polypharmacy approach and further support the effectiveness of such target modulation as a promising therapeutic approach for those suffering from opioid use disorder.
Differential proliferation regulates multi-tissue morphogenesis during embryonic axial extension: Integrating viscous modeling and experimental approaches
Authors: Romanos Michèle , Salisbury Tasha , Stephan Samuel , Lansford Rusty , Degond Pierre , Trescases Ariane , Bénazéraf Bertrand
Published: February 2024

The study of how mechanical interactions and different cellular behaviors affect tissues and embryo shaping has been and remains an important challenge in biology. Axial extension is a morphogenetic process that results in the acquisition of the elongated shape of the vertebrate embryonic body. Several adjacent tissues are involved in the process, including the tissues that form the spinal cord and musculoskeletal system: the neural tube and the paraxial mesoderm, respectively. Although we have a growing understanding of how each of these tissues elongates, we still need to fully understand the morphogenetic consequences of their growth and mechanical interactions. In this study, we develop a 2D multi-tissue continuum-based mathematical model to simulate and study how differential growth, tissue biophysical properties, and mechanical interactions affect the morphogenesis of the embryonic body during axial extension. Our model captures the long-term dynamics of embryonic posterior tissues previously observedin vivoby time-lapse imaging of bird embryos. It reveals the underestimated influence of differential tissue proliferation rates in inter-tissue interaction and shaping by capturing the relative impact of this process on tissue dynamics. We verified the predictions of our model in quail embryos by showing that decreasing the rate of cell proliferation in the paraxial mesoderm affects long-term tissue dynamics and shaping of both the paraxial mesoderm and the neighboring neural tube. Overall, our work provides a new theoretical platform to consider the long-term consequences of tissue differential growth and mechanical interactions on morphogenesis.
Stimulation mapping and whole-brain modeling reveal gradients of excitability and recurrence in cortical networks
Authors: Momi Davide , Wang Zheng , Parmigiani Sara , Mikulan Ezequiel , Bastiaens Sorenza P. , Oveisi Mohammad P. , Kadak Kevin , Gaglioti Gianluca , Waters Allison C. , Hill Sean , Pigorini Andrea , Keller Corey J. , Griffiths John D.
Published: February 2024

The human brain exhibits a modular and hierarchical structure, spanning low-order sensorimotor to high-order cognitive/affective systems. What is the causal significance of this organization for brain dynamics and information processing properties? We investigated this question using rare simultaneous multimodal electrophysiology (stereotactic and scalp EEG) recordings in patients during presurgical intracerebral electrical stimulation (iES). Our analyses revealed an anatomical gradient of excitability across the cortex, with stronger iES-evoked EEG responses in high-order compared to low-order regions. Mathematical modeling further showed that this variation in excitability levels results from a differential dependence of recurrent feedback from non-stimulated regions across the anatomical hierarchy, and could be extinguished by suppressing those connections in-silico. High-order brain regions/networks thus show a more functionally integrated processing style than low-order ones, which manifests as a spatial gradient of excitability that is emergent from, and causally dependent on, the underlying hierarchical network structure.
Human stem cell derived neurons and astrocytes to detect novel auto-reactive IgG signature in immune-mediated neurological diseases
Authors: Mathias Amandine , Perriot Sylvain , Jones Samuel , Canales Mathieu , Bernard-Valnet Raphael , Gimenez Marie , Torcida Nathan , Oberholster Larise , Hottinger Andreas F. , Zekeridou Anastasia , Theaudin Marie , Pot Caroline , Du Pasquier Renaud
Published: February 2024

Background and objectives

Up to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known CNS antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and CSF using neurons and astrocytes derived from human induced pluripotent stem cells (hiPSC).

Methods

Human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients (42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)). The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labelled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout.

Results

Using our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our novel 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15/42) than in NIND patients (4/57) (Fisher test,p=0.0005). Three of three patients with astrocyte- reactive (2 AQP4+ NMO, 1 GFAP astrocytopathy), and 3/4 with intracellular neuron-reactive antibodies (2 Hu+, 1 Ri+ AIE/PNS), as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in 2/6 seronegative NMOSD, 6/12 probable AIE/PNS, and 1/13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC detected antibody binding in 13 versus 0 patients, respectively, establishing the specificity of the detected antibodies for neural tissue.

Discussion

Our unique hiPSC-based CBA allows for the screening of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing early diagnosis of such complex diseases.
Minimally invasive serial collection of cerebrospinal fluid reveals sex-dependent differences in neuroinflammation in a rat model of mild traumatic brain injury
Authors: Karam Josh , Ashfaq Nimrah , Benitez Cynthia , Morales Victor , Partida Elizabeth , Hernandez Michelle , Yokoyama Jordan , Villegas Alyssa , Brown Brielle , Sakthivel Pooja , Anderson Aileen J. , Cummings Brian J.
Published: February 2024

Traumatic brain injuries (TBI) are the seventh leading cause of disability globally with 48.99 million prevalent cases and 7.08 million years lived with diability. Approximately 80% of TBI patients are diagnosed with mild TBI (mTBI), or concussion, caused by nonpenetrating mechanical trauma to the head or body along with sudden rotational motion of the head. Studies investigating the temporal dynamics of neuroinflammation after mTBI are greatly needed. Without longitudinal studies, translating preclinical studies to clinical studies remains challenging as the difference in timing remains poorly understood. In this study, we describe a method of minimally invasive serial cerebrospinal fluid (CSF) collection that enables longitudinal investigation of CSF inflammation. The method described in this study can easily be adapted by any laboratory prepared for animal studies. Multiplex immunoassay of serially collected and singly collected CSF samples show collection frequency does not alter protein expression in the CSF. Further, sex-dependent differences in TBI have been reported, but remain poorly understood. This study establishes a framework for assessing sex difference in neuroinflammation after a concussion. We showed that results vary based on the framing of the statistical test. However, it is evident that males experience a more robust inflammatory response to a single concussion than females.