bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade
Authors: Owaki Takayuki , Iida Tadashi , Miyai Yuki , Kato Katsuhiro , Hase Tetsunari , Ishii Makoto , Ando Ryota , Hinohara Kunihiko , Akashi Tomohiro , Mizutani Yasuyuki , Ishikawa Takuya , Mii Shinji , Shiraki Yukihiro , Esaki Nobutoshi , Yamamoto Masami , Tsukamoto Tetsuya , Nomura Sachiyo , Murakami Takashi , Takahashi Masahide , Yuguchi Yuri , Maeda Motohiro , Sano Tomoyasu , Sassa Naoto , Matsukawa Yoshihisa , Kawashima Hiroki , Akamatsu Shusuke , Enomoto Atsushi 
Published: June 2024

Abstract
Background
The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs.

Methods
We investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models.

Results
High infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs.

Conclusion
Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.
ZBP1 causes inflammation by inducing RIPK3-mediated necroptosis and RIPK1 kinase activity-independent apoptosis
Authors: Koerner Lioba , Wachsmuth Laurens , Kumari Snehlata , Schwarzer Robin , Wagner Theresa , Jiao Huipeng , Pasparakis Manolis 
Published: June 2024

AbstractZ-DNA binding protein 1 (ZBP1) has important functions in anti-viral immunity and in the regulation of inflammatory responses. ZBP1 induces necroptosis by directly engaging and activating RIPK3, however, the mechanisms by which ZBP1 induces inflammation and in particular the role of RIPK1 and the contribution of cell death-independent signaling remain elusive. Here we show that ZBP1 causes skin inflammation by inducing RIPK3-mediated necroptosis and RIPK1-caspase-8-mediated apoptosis in keratinocytes. ZBP1 induced TNFR1-independent skin inflammation in mice with epidermis-specific ablation of FADD by triggering keratinocyte necroptosis. Moreover, transgenic expression of C-terminally truncated constitutively active ZBP1 (ZBP1ca) in mouse epidermis caused skin inflammation that was only partially inhibited by abrogation of RIPK3-MLKL-dependent necroptosis and fully prevented by combined deficiency in MLKL and caspase-8. Importantly, ZBP1ca induced caspase-8-mediated skin inflammation by RHIM-dependent but kinase activity-independent RIPK1 signaling. Furthermore, ZBP1ca-induced inflammatory cytokine production in the skin was completely prevented by combined inhibition of apoptosis and necroptosis arguing against a cell death-independent pro-inflammatory function of ZBP1. Collectively, these results showed that ZBP1 induces inflammation by activating necroptosis and RIPK1 kinase activity-independent apoptosis.
TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway in mice
Authors: Cui Yan , Chen Chao , Tang Zhouqi , Yuan Wenjia , Yue Kaiye , Cui Pengcheng , Qiu Xia , Zhang Hedong , Li Tengfang , Zhu Xuejing , Luo Jiadi , Sun Siyu , Li Yaguang , Feng Chen , Peng Longkai , Xie Xubiao , Guo Yong , Xie Yixin , Jiang Xin , Qi Zhongquan , Thomson Angus W. , Dai Helong 
Published: June 2024

AbstractThe triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting cell survival, and counteracting inflammation. Its role in renal injury, in particular, unilateral ureteral obstruction (UUO) or ischemia-reperfusion injury (IRI)-induced renal injury remains unclear. In our study, WT and Trem2−/− mice were employed to evaluate the role of TREM2 in renal macrophage infiltration and tissue injury after UUO. Bone marrow-derived macrophages (BMDM) from both mouse genotypes were cultured and polarized for in vitro experiments. Next, the effects of TREM2 on renal injury and macrophage polarization in IRI mice were also explored. We found that TREM2 expression was upregulated in the obstructed kidneys. TREM2 deficiency exacerbated renal inflammation and fibrosis 3 and 7 days after UUO, in association with reduced macrophage infiltration. Trem2−/− BMDM exhibited increased apoptosis and poorer survival compared with WT BMDM. Meanwhile, TREM2 deficiency augmented M1 and M2 polarization after UUO. Consistent with the in vivo observations, TREM2 deficiency led to increased polarization of BMDM towards the M1 proinflammatory phenotype. Mechanistically, TREM2 deficiency promoted M1 and M2 polarization via the JAK-STAT pathway in the presence of TGF-β1, thereby affecting cell survival by regulating mTOR signaling. Furthermore, cyclocreatine supplementation alleviated cell death caused by TREM2 deficiency. Additionally, we found that TREM2 deficiency promoted renal injury, fibrosis, and macrophage polarization in IRI mice. The current data suggest that TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway. These findings have implications for the role of TREM2 in the regulation of renal injury that justify further evaluation.
DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson’s disease
Authors: Zhao Yichen , Shen Weiwei , Zhang Minjie , Guo Min , Dou Yunxiao , Han Sida , Yu Jintai , Cui Mei , Zhao Yanxin 
Published: June 2024

AbstractThe loss of dopaminergic neurons in the substantia nigra is a hallmark of pathology in Parkinson’s disease (PD). Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is the critical enzyme responsible for the degradation of asymmetric dimethylarginine (ADMA) which inhibits nitric oxide (NO) synthase and has been implicated in neurodegeneration. Mitochondrial dysfunction, particularly in the mitochondria-associated endoplasmic reticulum membrane (MAM), plays a critical role in this process, although the specific molecular target has not yet been determined. This study aims to examine the involvement of DDAH-1 in the nigrostriatal dopaminergic pathway and PD pathogenesis. The distribution of DDAH-1 in the brain and its colocalization with dopaminergic neurons were observed. The loss of dopaminergic neurons and aggravated locomotor disability after rotenone (ROT) injection were showed in the DDAH-1 knockout rat. l-arginine (ARG) and NO donors were employed to elucidate the role of NO respectively. In vitro, we investigated the effects of DDAH-1 knockdown or overexpression on cell viability and mitochondrial functions, as well as modulation of ADMA/NO levels using ADMA or ARG. MAM formation was assessed by the Mitofusin2 oligomerization and the mitochondrial ubiquitin ligase (MITOL) phosphorylation. We found that DDAH-1 downregulation resulted in enhanced cell death and mitochondrial dysfunctions, accompanied by elevated ADMA and reduced NO levels. However, the recovered NO level after the ARG supplement failed to exhibit a protective effect on mitochondrial functions and partially restored cell viability. DDAH-1 overexpression prevented ROT toxicity, while ADMA treatment attenuated these protective effects. The declines of MAM formation in ROT-treated cells were exacerbated by DDAH-1 downregulation via reduced MITOL phosphorylation, which was reversed by DDAH-1 overexpression. Together, the abundant expression of DDAH-1 in nigral dopaminergic neurons may exert neuroprotective effects by maintaining MAM formation and mitochondrial function probably via ADMA, indicating the therapeutic potential of targeting DDAH-1 for PD.
Prescription and dispensing duration of medicines for hypertension and other chronic conditions: a review of international policies and evidence to inform the Australian setting
Authors: af Geijerstam Peder , Falster Michael O. , Chalmers John , McLachlan Andrew J. , Rodgers Anthony , Schutte Aletta E. 
Published: June 2024

AbstractThe duration of treatment for which a physician may prescribe a medicine, ‘prescription duration’, is often dispensed at the pharmacy on multiple occasions of shorter time periods, ‘dispensing duration’. These durations vary significantly between and within countries. In Australia, the quantity of medication supplied at each dispensing has recently been extended from 30 to 60 days for a selection of medicines used for chronic health conditions, such as diabetes and hypertension. Dispensing durations vary between countries, with 30, 60 or 90 days being the most common—with 90 days aligning with the recommendation of the 2023 Global Report on Hypertension from the World Health Organization. The full impact of shorter vs longer prescription durations on health costs and outcomes is unknown, but current evidence suggests that 90-day dispensing could reduce costs and improve patient convenience and adherence. More rigorous research is needed.
Depth-enhanced high-throughput microscopy by compact PSF engineering
Authors: Opatovski Nadav , Nehme Elias , Zoref Noam , Barzilai Ilana , Orange Kedem Reut , Ferdman Boris , Keselman Paul , Alalouf Onit , Shechtman Yoav 
Published: June 2024

AbstractHigh-throughput microscopy is vital for screening applications, where three-dimensional (3D) cellular models play a key role. However, due to defocus susceptibility, current 3D high-throughput microscopes require axial scanning, which lowers throughput and increases photobleaching and photodamage. Point spread function (PSF) engineering is an optical method that enables various 3D imaging capabilities, yet it has not been implemented in high-throughput microscopy due to the cumbersome optical extension it typically requires. Here we demonstrate compact PSF engineering in the objective lens, which allows us to enhance the imaging depth of field and, combined with deep learning, recover 3D information using single snapshots. Beyond the applications shown here, this work showcases the usefulness of high-throughput microscopy in obtaining training data for deep learning-based algorithms, applicable to a variety of microscopy modalities.
An effective and rapidly degradable disinfectant from disinfection byproducts
Authors: Han Jiarui , Li Wanxin , Zhang Xiangru 
Published: June 2024

AbstractChloroxylenol is a worldwide commonly used disinfectant. The massive consumption and relatively high chemical stability of chloroxylenol have caused eco-toxicological threats in receiving waters. We noticed that chloroxylenol has a chemical structure similar to numerous halo-phenolic disinfection byproducts. Solar detoxification of some halo-phenolic disinfection byproducts intrigued us to select a rapidly degradable chloroxylenol alternative from them. In investigating antimicrobial activities of disinfection byproducts, we found that 2,6-dichlorobenzoquinone was 9.0–22 times more efficient than chloroxylenol in inactivating the tested bacteria, fungi and viruses. Also, the developmental toxicity of 2,6-dichlorobenzoquinone to marine polychaete embryos decreased rapidly due to its rapid degradation via hydrolysis in receiving seawater, even without sunlight. Our work shows that 2,6-dichlorobenzoquinone is a promising disinfectant that well addresses human biosecurity and environmental sustainability. More importantly, our work may enlighten scientists to exploit the slightly alkaline nature of seawater and develop other industrial products that can degrade rapidly via hydrolysis in seawater.
Evolution of connectivity architecture in the Drosophila mushroom body
Authors: Ellis Kaitlyn Elizabeth , Bervoets Sven , Smihula Hayley , Ganguly Ishani , Vigato Eva , Auer Thomas O. , Benton Richard , Litwin-Kumar Ashok , Caron Sophie Jeanne Cécile 
Published: June 2024

AbstractBrain evolution has primarily been studied at the macroscopic level by comparing the relative size of homologous brain centers between species. How neuronal circuits change at the cellular level over evolutionary time remains largely unanswered. Here, using a phylogenetically informed framework, we compare the olfactory circuits of three closely related Drosophila species that differ in their chemical ecology: the generalists Drosophila melanogaster and Drosophila simulans and Drosophila sechellia that specializes on ripe noni fruit. We examine a central part of the olfactory circuit that, to our knowledge, has not been investigated in these species—the connections between projection neurons and the Kenyon cells of the mushroom body—and identify species-specific connectivity patterns. We found that neurons encoding food odors connect more frequently with Kenyon cells, giving rise to species-specific biases in connectivity. These species-specific connectivity differences reflect two distinct neuronal phenotypes: in the number of projection neurons or in the number of presynaptic boutons formed by individual projection neurons. Finally, behavioral analyses suggest that such increased connectivity enhances learning performance in an associative task. Our study shows how fine-grained aspects of connectivity architecture in an associative brain center can change during evolution to reflect the chemical ecology of a species.
Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS
Authors: Mora Santiago , Stuckert Anna , von Huth Friis Rasmus , Pietersz Kimberly , Noes-Holt Gith , Montañana-Rosell Roser , Wang Haoyu , Sørensen Andreas Toft , Selvan Raghavendra , Verhaagen Joost , Allodi Ilary 
Published: June 2024

AbstractLoss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1G93A mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1G93A mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.
Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries
Authors: Misek Sean A. , Fultineer Aaron , Kalfon Jeremie , Noorbakhsh Javad , Boyle Isabella , Roy Priyanka , Dempster Joshua , Petronio Lia , Huang Katherine , Saadat Alham , Green Thomas , Brown Adam , Doench John G. , Root David E. , McFarland James M. , Beroukhim Rameen , Boehm Jesse S. 
Published: June 2024

AbstractReducing disparities is vital for equitable access to precision treatments in cancer. Socioenvironmental factors are a major driver of disparities, but differences in genetic variation likely also contribute. The impact of genetic ancestry on prioritization of cancer targets in drug discovery pipelines has not been systematically explored due to the absence of pre-clinical data at the appropriate scale. Here, we analyze data from 611 genome-scale CRISPR/Cas9 viability experiments in human cell line models to identify ancestry-associated genetic dependencies essential for cell survival. Surprisingly, we find that most putative associations between ancestry and dependency arise from artifacts related to germline variants. Our analysis suggests that for 1.2-2.5% of guides, germline variants in sgRNA targeting sequences reduce cutting by the CRISPR/Cas9 nuclease, disproportionately affecting cell models derived from individuals of recent African descent. We propose three approaches to mitigate this experimental bias, enabling the scientific community to address these disparities.
Optimizing cell therapy by sorting cells with high extracellular vesicle secretion
Authors: Koo Doyeon , Cheng Xiao , Udani Shreya , Baghdasarian Sevana , Zhu Dashuai , Li Junlang , Hall Brian , Tsubamoto Natalie , Hu Shiqi , Ko Jina , Cheng Ke , Di Carlo Dino 
Published: June 2024

AbstractCritical challenges remain in clinical translation of extracellular vesicle (EV)-based therapeutics due to the absence of methods to enrich cells with high EV secretion. Current cell sorting methods are limited to surface markers that are uncorrelated to EV secretion or therapeutic potential. Here, we utilize a nanovial technology for enrichment of millions of single cells based on EV secretion. This approach is applied to select mesenchymal stem cells (MSCs) with high EV secretion as therapeutic cells for improving treatment. The selected MSCs exhibit distinct transcriptional profiles associated with EV biogenesis and vascular regeneration and maintain high levels of EV secretion after sorting and regrowth. In a mouse model of myocardial infarction, treatment with high-secreting MSCs improves heart functions compared to treatment with low-secreting MSCs. These findings highlight the therapeutic importance of EV secretion in regenerative cell therapies and suggest that selecting cells based on EV secretion could enhance therapeutic efficacy.
Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target
Authors: Caldi Gomes Lucas , Hänzelmann Sonja , Hausmann Fabian , Khatri Robin , Oller Sergio , Parvaz Mojan , Tzeplaeff Laura , Pasetto Laura , Gebelin Marie , Ebbing Melanie , Holzapfel Constantin , Columbro Stefano Fabrizio , Scozzari Serena , Knöferle Johanna , Cordts Isabell , Demleitner Antonia F. , Deschauer Marcus , Dufke Claudia , Sturm Marc , Zhou Qihui , Zelina Pavol , Sudria-Lopez Emma , Haack Tobias B. , Streb Sebastian , Kuzma-Kozakiewicz Magdalena , Edbauer Dieter , Pasterkamp R. Jeroen , Laczko Endre , Rehrauer Hubert , Schlapbach Ralph , Carapito Christine , Bonetto Valentina , Bonn Stefan , Lingor Paul 
Published: June 2024

AbstractAmyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.
Protein translation rate determines neocortical neuron fate
Authors: Borisova Ekaterina , Newman Andrew G. , Couce Iglesias Marta , Dannenberg Rike , Schaub Theres , Qin Bo , Rusanova Alexandra , Brockmann Marisa , Koch Janina , Daniels Marieatou , Turko Paul , Jahn Olaf , Kaplan David R. , Rosário Marta , Iwawaki Takao , Spahn Christian M. T. , Rosenmund Christian , Meierhofer David , Kraushar Matthew L. , Tarabykin Victor , Ambrozkiewicz Mateusz C. 
Published: June 2024

AbstractThe mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5’-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development.
Ultrafast light-activated polymeric nanomotors
Authors: Wang Jianhong , Wu Hanglong , Zhu Xiaowei , Zwolsman Robby , Hofstraat Stijn R. J. , Li Yudong , Luo Yingtong , Joosten Rick R. M. , Friedrich Heiner , Cao Shoupeng , Abdelmohsen Loai K. E. A. , Shao Jingxin , van Hest Jan C. M. 
Published: June 2024

AbstractSynthetic micro/nanomotors have been extensively exploited over the past decade to achieve active transportation. This interest is a result of their broad range of potential applications, from environmental remediation to nanomedicine. Nevertheless, it still remains a challenge to build a fast-moving biodegradable polymeric nanomotor. Here we present a light-propelled nanomotor by introducing gold nanoparticles (Au NP) onto biodegradable bowl-shaped polymersomes (stomatocytes) via electrostatic and hydrogen bond interactions. These biodegradable nanomotors show controllable motion and remarkable velocities of up to 125 μm s−1. This unique behavior is explained via a thorough three-dimensional characterization of the nanomotor, particularly the size and the spatial distribution of Au NP, with cryogenic transmission electron microscopy (cryo-TEM) and cryo-electron tomography (cryo-ET). Our in-depth quantitative 3D analysis reveals that the motile features of these nanomotors are caused by the nonuniform distribution of Au NPs on the outer surface of the stomatocyte along the z-axial direction. Their excellent motile features are exploited for active cargo delivery into living cells. This study provides a new approach to develop robust, biodegradable soft nanomotors with application potential in biomedicine.