bluuebunny/crossref_metadata_2025_split huggingface dataset:
MaskGraphene: an advanced framework for interpretable joint representation for multi-slice, multi-condition spatial transcriptomics
Authors: Hu Yunfei , Lin Zhenhan , Xie Manfei , Yuan Weiman , Li Yikang , Rao Mingxing , Liu Yichen Henry , Shen Wenjun , Zhang Lu , Zhou Xin Maizie 
Published: February 2024

AbstractRecent advancements in spatial transcriptomics (ST) have underscored the importance of integrating data from multiple ST slices for joint analysis. A major challenge remains generating interpretable joint embeddings that preserve geometric information for downstream analyses. Here we introduce MaskGraphene, a graph neural network that combines self-supervised and self-contrastive training to integrate gene expression and spatial location into joint embeddings. By employing clusterwise alignment and a graph attention autoencoder with masked self-supervised and triplet loss optimizations, MaskGraphene effectively preserves geometric structures while achieving batch correction. In benchmarks against seven state-of-the-art methods, MaskGraphene consistently demonstrated superior alignment accuracy and geometric fidelity across diverse ST datasets. Its interpretable embeddings significantly enhanced downstream applications, including domain identification, spatial trajectory reconstruction, biomarker discovery, and the creation of topographical maps of brain slices. Notably, MaskGraphene successfully recovered layer-wise brain structures with near-perfect accuracy. MaskGraphene provides a powerful and versatile framework for advancing ST data integration and analysis, unlocking valuable biological insights.
Protein-structure-sensitive mid-infrared optoacoustic microscopy enables label-free assessment of drug therapy in myeloma cells
Authors: Gasparin Francesca , Tietje Marlene R. , Katab Eslam , Nurdinova Aizada , Yuan Tao , Chmyrov Andriy , Uluç Nasire , Jüstel Dominik , Bassermann Florian , Ntziachristos Vasilis , Pleitez Miguel A. 
Published: February 2024

AbstractConventional live-cell optical microscopy lacks sensitivity and specificity for label-free detection of intracellular protein-structure dynamics, such as conformational transition from α-helix to β-sheet. Detecting intermolecular β-sheet formation, for instance, is important because it is a hallmark of misfolded proteins and aggresome formation—which are intrinsic indicators of cell apoptosis in myeloma therapy. Going beyond conventional optical microscopy, we introduce a single-cell imaging technology with label-free sensitivity to intracellular intermolecular β-sheet formation in living cells. This unique ability was attained by exploiting the spectral specificity of the mid-infrared amide I region (1700 – 1600 cm-1) to protein structure and the positive-contrast nature of optoacoustic microscopy. By means of this technology, we were able to monitor the efficiency of proteasome inhibition in a myeloma cell line and—as a first demonstration towards clinical translation—in biopsied myeloma cells from patients. Achieving label-free monitoring of treatment at a single-cell level allows longitudinal assessment of response heterogeneity, which could provide crucial therapeutic information, such as patient-specific sensitivity to treatment, thus facilitating personalized medicine in myeloma therapy.
Blockade of Interleukin-6 (IL-6) Signaling in Dedifferentiated Liposarcoma (DDLPS) Decreases Mouse Double Minute 2 (MDM2) Oncogenicity via Alternative Splicing
Authors: Zewdu Abeba , Braggio Danielle , Lopez Gonzalo , Batte Kara , Khurshid Safiya , Costas de Faria Fernanda , Bid Hemant K. , Koller David , Casadei Lucia , Ladner Katherine J. , Wang David , Grignol Valerie , Iwenofu O. Hans , Chandler Dawn , Guttridge Denis C. , Pollock Raphael E. 
Published: February 2024

AbstractEffective therapies for retroperitoneal (RP) dedifferentiated liposarcoma (DDLPS) remain unavailable. Loco-regional recurrence occurs in >80% of cases; 5-year disease-specific survival is only 20%. DDLPS is especially prevalent in the retroperitoneum and abdomen; evaluation of the DDLPS microenvironment in these high-fat compartments appears pertinent. Adipose is a main supplier of interleukin-6 (IL6); excessive activation of IL6 signal transducer glycoprotein 130 (GP130) underlies the development of some diseases. The role of GP130 pathway activation remains unstudied in DDLPS, so we examined the role of microenvironment fat cell activation of the IL6/GP130 signaling cascade in DDLPS. All DDLPS tumors and cell lines studied expressed elevated levels of the GP130-encoding geneIL6STand GP130 protein compared to normal tissue and cell line controls. IL6 increased DDLPS cell growth and migration, possibly through increased signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) activation, and upregulated mouse double minute 2 (MDM2). GP130 loss conveyed opposite effects; pharmacological blockade of GP130 by SC144 produced the MDM2 splice variant MDM2-ALT1, known to inhibit full length MDM2 (MDM2-FL). Although genomicMDM2amplification is pathognomonic for DDLPS, mechanisms driving MDM2 expression, regulation, and function beyond the MDM2:p53 negative feedback loop are poorly understood. Our findings suggest a novel preadipocyte DDLPS-promoting role due to IL6 release, via upregulation of DDLPS MDM2 expression. Pharmacological GP130 blockade reduced the IL6-induced increase in DDLPS MDM2 mRNA and protein levels, possibly through enhanced expression of MDM2-ALT1, a possibly targetable pathway with potential as future DDLPS patient therapy.
Feature selectivity of corticocortical feedback along the primate dorsal visual pathway
Authors: Korkian Yavar , Nakhla Nardin , Pack Christopher C. 
Published: February 2024

AbstractAnatomical studies have revealed a prominent role for feedback projections in the primate visual cortex. Theoretical models suggest that these projections support important brain functions, like attention, prediction, and learning. However, these models make different predictions about the relationship between feedback connectivity and neuronal stimulus selectivity. We have therefore performed simultaneous recordings in different regions of the primate dorsal visual pathway. Specifically, we recorded neural activity from the medial superior temporal (MST) area, and one of its main feedback targets, the middle temporal (MT) area. We estimated functional connectivity from correlations in the single-neuron spike trains and performed electrical microstimulation in MST to determine its causal influence on MT. Both methods revealed that inhibitory feedback occurred more commonly when the source and target neurons had very different stimulus preferences. At the same time, the strength of feedback suppression was greater for neurons with similar preferences. Excitatory feedback projections, in contrast, showed no consistent relationship with stimulus preferences. These results suggest that corticocortical feedback could play a role in shaping sensory responses according to behavioral or environmental context.
The CryoEM structure of human serum albumin in complex with ligands
Authors: Catalano Claudio , Lucier Kyle W. , To Dennis , Senko Skerdi , Tran Nhi L. , Farwell Ashlyn C. , Silva Sabrina M. , Dip Phat V. , Poweleit Nicole , Scapin Giovanna 
Published: February 2024

AbstractHuman serum albumin (HSA) is the most prevalent plasma protein in the human body, accounting for 60% of the total plasma protein. HSA plays a major pharmacokinetic function, serving as a facilitator in the distribution of endobiotics and xenobiotics within the organism. In this paper we report the cryoEM structures of HSA in the apo form and in complex with two ligands (salicylic acid and teniposide) at a resolution of 3.5, 3.7 and 3.4 Å, respectively. We expand upon previously published work and further demonstrate that sub-4 Å maps of ∼60 kDa proteins can be routinely obtained using a 200 kV microscope, employing standard workflows. Most importantly, these maps allowed for the identification of small molecule ligands, emphasizing the practical applicability of this methodology and providing a starting point for subsequent computational modeling and in silico optimization.
RevealingIn SituMolecular Profiles of Glomerular Cell Types and Substructures with Integrated Imaging Mass Spectrometry and Multiplexed Immunofluorescence Microscopy
Authors: Esselman Allison B. , Moser Felipe A. , Tideman Léonore , Migas Lukasz G. , Djambazova Katerina V. , Colley Madeline E. , Pingry Ellie L. , Patterson Nathan Heath , Farrow Melissa A. , Yang Haichun , Fogo Agnes B. , de Caestecker Mark , Van de Plas Raf , Spraggins Jeffrey M. 
Published: February 2024

AbstractGlomeruli filter blood through the coordination of podocytes, mesangial cells, fenestrated endothelial cells, and the glomerular basement membrane. Cellular changes, such as podocyte loss, are associated with pathologies like diabetic kidney disease (DKD). However, little is known regarding thein situmolecular profiles of specific cell types and how these profiles change with disease. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is well-suited for untargeted tissue mapping of a wide range of molecular classes. Additional imaging modalities can be integrated with MALDI IMS to associate these biomolecular distributions to specific cell types. Herein, we demonstrate an integrated workflow combining MALDI IMS and multiplexed immunofluorescence (MxIF) microscopy. High spatial resolution MALDI IMS (5 µm pixel size) was used to determine lipid distributions within human glomeruli, revealing intra-glomerular lipid heterogeneity. Mass spectrometric data were linked to specific glomerular cell types through new methods that enable MxIF microscopy to be performed on the same tissue section following MALDI IMS without sacrificing signal quality from either modality. A combination of machine-learning approaches was assembled, enabling cell-type segmentation and identification based on MxIF data followed by the mining of cell type or cluster-associated MALDI IMS signatures using classification models and interpretable machine learning. This allowed the automated discovery of spatially specific biomarker candidates for glomerular substructures and cell types. Overall, the work presented here establishes a toolbox for probing molecular signatures of glomerular cell types and substructures within tissue microenvironments and provides a framework that applies to other kidney tissue features and organ systems.
Systematically developing a registry of splice-site creating variants utilizing massive publicly available transcriptome sequence data
Authors: Iida Naoko , Okada Ai , Kobayashi Yoshihisa , Chiba Kenichi , Yatabe Yasushi , Shiraishi Yuichi 
Published: February 2024

AbstractGenomic variants causing abnormal splicing play an important role in genetic disorders and cancer development. Among them, variants that cause formations of novel splice-sites (splice-site creating variants, SSCVs) are particularly difficult to identify and often overlooked in genomic studies. Additionally, these SSCVs, especially those found in deep intronic regions, are frequently considered promising candidates for treatment with splice-switching antisense oligonucleotides (ASOs), offering therapeutic potential for rare disease patients. To leverage massive transcriptome sequence data such as those available from the Sequence Read Archive, we developed a novel framework to screen for SSCVs solely using transcriptome data. We have applied it to 322,072 publicly available transcriptomes and identified 30,130 SSCVs. Utilizing this extensive collection of SSCVs, we have revealed the characteristics of Alu exonization via SSCVs, especially the hotspots of SSCVs within Alu sequences and their evolutionary relationships. Many of the SSCVs affecting disease-causing variants were predicted to generate premature termination codons and are degraded by nonsense-mediated decay. On the other hand, several genes, such asCREBBPandTP53,showed characteristic SSCV profiles indicative of heterogeneous mutational functions beyond simple loss-of-function. Finally, we discovered novel gain-of-function SSCVs in the deep intronic region of theNOTCH1gene and demonstrated that their activation can be suppressed using splice-switching ASOs. Collectively, we provide a systematic approach for automatically acquiring a registry of SSCVs, which can be used for elucidating novel biological mechanisms for splicing and genetic variation, and become a valuable resource for pinpointing critical targets in drug discovery. Catalogs of SSCVs identified in this study are accessible on SSCV DB (https://sscvdb.io/).
Impact of Cervical Lymphatic Obstruction on Brain Pathophysiology in Cervical Lymphedema Animal Models
Authors: Cheon Hwayeong , Woo Dong Cheol , Cha Seungwoo , Chae Yeon Ji , Maeng Inhee , Oh Seung Jae , Jeon Jae Yong 
Published: February 2024

ABSTRACTBackgroundInjury to the cervical lymph nodes can lead to cervical lymphedema and subsequent fluid accumulation in the head and neck region, potentially causing pathophysiological alteration in the brain. This condition is thought to be linked with various neurological diseases, although the direct connection between cervical lymphatic obstruction and its effect on the brain has been difficult to establish.MethodsWe produced the disease animal models through lymph node dissection and radiation in fifteen male Sprague–Dawley rats aged 8 weeks and weighing 280–320 g. The models were specifically designed to induce lymphatic obstruction in the cervical region only, with no direct interventions applied to the brain. We evaluated swelling and lymphatic drainage in the head and neck for follow-up. The size of the lateral ventricles was verified through MRI, and changes in water content in brain tissue were directly measured. At 2 and 8 weeks, we observed immune cell infiltration, ventricular enlargement, and pathohistological changes in the harvested brain tissues.ResultsThe experimental animals exhibited lymphatic obstruction in the cervical region, with swelling, abnormal lymphatic drainage, and immune cell infiltration into the brain’s white matter, reminiscent of extremities lymphedema. MRI revealed lateral ventricular enlargement in these animals, indicative of increased cerebrospinal fluid levels compared to the control group. This increase in cerebrospinal fluid was associated with an increase in brain tissue water content, leading to pathophysiological changes akin to those seen in hydrocephalus and cerebral edema.ConclusionThe outcomes in this study underscore a significant link between lymphatic circulatory dysfunction and the onset of neurophysiological diseases. Cervical lymphedema showed pathophysiological changes similar to those seen in extremities lymphedema. However, these changes in the brain could be more critical than in the extremities. Our finding highlights the importance of understanding lymphatic system health in preventing and managing neurological conditions.
Ubiquitin-mediated stabilization of SlPsbS regulates low night temperature tolerance in tomatoes
Authors: Lu Jiazhi , Yu Junchi , Liu Pengkun , Gu Jiamao , Chen Yu , Zhang Tianyi , Li Jialong , Wang Taotao , Yang Wenqiang , Lin Rongcheng , Wang Feng , Qi Mingfang , Li Tianlai , Liu Yufeng 
Published: February 2024

ABSTRACTNon-photochemical quenching (NPQ) plays a fundamental role in safely operating photosynthesis under low night temperatures (LNT). PsbS protein is essential for the rapid induction of NPQ, and its stability is often affected by adverse environmental conditions. However, the regulatory mechanism for the stability of PsbS or chloroplast proteins remains to be fully characterized. We showed that LNT decreased NPQ levels and SlPsbS protein abundance in tomato leaves. COP9 signalosome subunit 5A (SlCSN5A) facilitated SlPsbS ubiquitination and degradation in the cytosol. Further, tomato chloroplast vesiculation (SlCV) was activated by LNT. Under LNT, SlCV targeted the chloroplasts and induced the formation of CV-containing vesicles (CCVs) containing SlPsbS, which were exported from the chloroplasts. Subsequently, SlCV and SlPsbS contact SlCSN5A in the cytosol and are ubiquitinated and degraded. Genetic evidence demonstrated that overexpression of SlCV aggravated SlPsbS protein degradation, whereas silencing of SlCSN5 and SlCV delayed LNT-induced NPQ reduction and SlPsbS protein turnover. This study provides evidence that CSN5A is associated with chloroplast proteins, and reveals a ubiquitin-dependent degradation pathway of chloroplast proteins co-mediated by CV and CSN5A, thereby providing new insights into the regulation of chloroplast protein stability under stress conditions.
Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer’s disease mouse model
Authors: Penalva Ylauna Christine Megane , Paschkowsky Sandra , Yang Jingyun , Recinto Sherilyn Junelle , Cinkorpumin Jessica , Hernandez Marina Ruelas , Xiao Bin , Nitu Albert , Wu Helen Yee-Li , Munter Hans Markus , Michalski Bernadeta , Fahnestock Margaret , Pastor William , Bennett David A. , Munter Lisa Marie 
Published: February 2024

AbstractCharacteristic cerebral pathological changes of Alzheimer’s disease (AD) such as glucose hypometabolism or the accumulation of cleavage products of the amyloid precursor protein (APP), known as Aβ peptides, lead to sustained endoplasmic reticulum (ER) stress and neurodegeneration. To preserve ER homeostasis, cells activate their unfolded protein response (UPR). The rhomboid-like-protease 4 (RHBDL4) is an enzyme that participates in the UPR by targeting proteins for proteasomal degradation. We demonstrated previously that RHBLD4 cleaves APP in HEK293T cells, leading to decreased total APP and Aβ. More recently, we showed that RHBDL4 processes APP in mouse primary mixed cortical cultures as well. Here, we aim to examine the physiological relevance of RHBDL4 in the brain. We first found that brain samples from AD patients and an AD mouse model (APPtg) showed increased RHBDL4 mRNA and protein expression. To determine the effects of RHBDL4’s absence on APP physiologyin vivo, we crossed APPtg mice to a RHBDL4 knockout (R4-/-) model. RHBDL4 deficiency in APPtg mice led to increased total cerebral APP and amyloidogenic processing when compared to APPtg controls. Contrary to expectations, as assessed by cognitive tests, RHBDL4 absence rescued cognition in 5-month-old female APPtg mice. Informed by unbiased RNAseq data, we demonstratedin vitroandin vivothat RHBDL4 absence leads to greater levels of active β-catenin due to decreased proteasomal clearance. Decreased β-catenin activity is known to underlie cognitive defects in APPtg mice and AD. Our work suggests that RHBDL4’s increased expression in AD, in addition to regulating APP levels, leads to aberrant degradation of β-catenin, contributing to cognitive impairment.
Mimivirus encodes an essential MC1-like non-histone architectural protein involved in DNA condensation
Authors: Sharma Deepti , Coulibaly Fasséli , Kondabagil Kiran 
Published: February 2024

AbstractThe first giant virus discovered,Acanthamoeba polyphagamimivirus (APMV), has a 1.2 Mb dsDNA genome organized as genomic fiber within the capsid. This fiber is comprised of a proteinaceous shell of ∼30 nm diameter that encloses the folded DNA. Surprisingly, for the assembly of the enormous genome of APMV, no DNA condensing protein has been reported to date. Our analysis of the uncharacterized packaged protein complement of Mimivirus led to the identification of a putative DNA-bending archaeal MC1 domain in a hypothetical protein (gp275) coded by the R252 gene. Gene knock-out analysis shows that gp275 is critical for viral multiplication. Biochemical and microscopic characterization further demonstrates the compaction of DNA upon binding to gp275. Together, this study suggests that gp275 is an MC1-like architectural protein involved in the organization of the genomic DNA within the capsid of Mimivirus.
High-throughput screening for Cushing’s disease: therapeutic potential of thiostrepton via cell cycle regulation
Authors: Hakata Takuro , Yamauchi Ichiro , Kosugi Daisuke , Sugawa Taku , Fujita Haruka , Okamoto Kentaro , Ueda Yohei , Fujii Toshihito , Taura Daisuke , Inagaki Nobuya 
Published: February 2024

AbstractCushing’s disease is a life-threatening disorder caused by autonomous secretion of adrenocorticotropic hormone (ACTH) from pituitary neuroendocrine tumors (PitNETs). Few drugs are indicated for inoperative Cushing’s disease, in particular that due to aggressive PitNETs. To explore agents that regulate ACTH-secreting PitNETs, we conducted high-throughput screening (HTS) using AtT-20, a murine pituitary tumor cell line characterized by ACTH secretion. For the HTS, we constructed a live cell– based ACTH reporter assay for high-throughput evaluation of ACTH changes. This assay was based on HEK293T cells overexpressing components of the ACTH receptor and a fluorescent cAMP biosensor, with high-throughput acquisition of fluorescence images at the single-cell level. Of 2480 screened bioactive compounds, over 50% inhibition of ACTH secreted from AtT-20 cells was seen with 84 compounds at 10 μM, and 20 compounds at 1 μM. Among these hit compounds, we focused on thiostrepton (TS) and determined its antitumor effects in bothin vitroandin vivoxenograft models of Cushing’s disease. Transcriptome and flow cytometry analyses revealed that TS administration induced AtT-20 cell cycle arrest at the G2/M phase, which was mediated by FOXM1-independent mechanisms including downregulation of cyclins. Simultaneous TS administration with a CDK 4/6 inhibitor that affected the cell cycle at the G0/1 phase showed cooperative antitumor effects. Thus, TS is a promising therapeutic agent for Cushing’s disease. Our list of hit compounds and new mechanistic insights into TS effects serve as a valuable foundation for future research.
WITHDRAWN: Antibiotic Bacteria Interaction: Dataset and Benchmarking
Authors: Chatterjee Sayantika , Majumdar Angshul , Chouzenoux Emilie 
Published: February 2024

Withdrawal StatementThe authors have withdrawn their manuscript owing to inability to reproduce the results. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.