bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neural signatures for temporal order memory in the macaque medial posterior parietal cortex
Authors: Zuo Shuzhen , Wang Chenyu , Wang Lei , Jin Zhiyong , Zhou Xufeng , Su Ning , Liu Jianhua , McHugh Thomas J. , Kusunoki Makoto , Kwok Sze Chai 
Published: August 2023

ABSTRACTEpisodic memory involves encoding and remembering the order of events experienced over time. Previous work examining the mechanisms of temporal-order memories has focused on the hippocampus and prefrontal cortices but has largely ignored the memory ensembles in the medial posterior parietal cortex (mPPC). Combiningin vivomulti-unit electrophysiology and a temporal-order judgment task with cinematic material in the macaque, we find that mPPC neuronal activity reflects temporal context both during encoding and recall. During learning, mPPC neuronal ensembles encode the temporal information as well as contextual information embedded in the videos, whereas at retrieval these neurons fire in synchrony prior to memory-guided decisions. Moreover, the similarity between encoding and retrieval correlates with the animal’s performance. A control experiment further ruled out eye saccades, fixation, and scan path for their confounding roles in the neural results. Together, these data suggest that neurons in mPPC track the passage of time and contextual changes, thereby orchestrating for successful temporal-order memories at retrieval.SIGNIFICANCERemembering the temporal order of events is a vital function of the brain. This study provides the first evidence for the retrieval of temporal order of episodes at both single neuron and ensemble levels in the primate parietal cortex. The study’s key breakthrough is the revelation that ensembles of time perceptive neurons, acting as “temporal context cells”, can encode a spectrum of time constants and contexts for the experienced past and subsequently utilize this temporal record to discriminate the chronological order of past experiences. These results enhance theoretical frameworks for how encoded temporal past is maintained and reconstructed during memory retrieval.
Targeting CD19-positive lymphomas with the antibody-drug conjugate (ADC) loncastuximab tesirine: preclinical evidence as single agent and as combinatorial approach
Authors: Tarantelli Chiara , Wald David , Munz Nicolas , Spriano Filippo , Bruscaggin Alessio , Cannas Eleonora , Cascione Luciano , Gaudio Eugenio , Arribas Alberto J. , Manjappa Shivaprasad , Golino Gaetanina , Scalise Lorenzo , Zucca Emanuele , Stathis Anastasios , van Berkel Patrick H. , Rossi Davide , Caimi Paolo F. , Zammarchi Francesca , Bertoni Francesco 
Published: August 2023

AbstractPurposeAntibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma.Experimental DesignWe assessed the activity of loncastuximab tesirine inin vitroandin vivomodels of lymphomas, correlated its activity with CD19 expression levels and identified combination partners providing synergy with loncastuximab tesirine.ResultsLoncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine has strong cytotoxic activity in B-cell lymphoma cell lines and thein vitroactivity is correlated with CD19 expression level and with intrinsic sensitivity of cell lines to the ADC’s warhead.Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity also largely correlated with cell line sensitivity to R-CHOP.Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors.ConclusionsOur data support the further development of loncastuximab tesirine as single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression, and the existence of lymphoma populations characterized by resistance to multiple therapies.
Predicting forest damage using relative abundance of multiple deer species and national forest inventory data
Authors: Brock Colin , Morera-Pujol Virginia , Murphy Kilian J. , Nieuwenhuis Maarten , Ciuti Simone 
Published: August 2023

AbstractHuman modification of landscape and natural resources have facilitated deer population irruptions across the world resulting in widespread human-wildlife conflicts. These conflicts occur across the field of natural resource management and negatively affect both the public and vested stakeholders when their livelihoods are placed at risk, for instance, the forestry sector. Deer, both native and non-native, at high densities can damage forest ecosystems impacting biodiversity and ecological functioning at multiple levels and can inflict large ecological and economic costs. The ecological drivers of forest damage and the roles of single and multiple co-occurring deer species is not well understood due to a lack of coordinated high resolution deer distribution, deer abundance and forest damage data. Here, we aim to disentangle the relationship between forest damage, forest characteristics and the roles deer play in damaging forest ecosystems. To achieve this, we adopt a novel approach integrating recent high resolution deer distribution data for multiple deer species (native and non-native) and combining them with forest inventory data collected in 1,681 sampling stations across Ireland to provide risk scenario predictions for practitioners to use on a national scale. Forest characteristics played a key role in the severity and type of damage risk that deer posed. We found all damage types were more prevalent in forests with greater tree densities where deer are more likely to find refuge from human disturbance. Bark stripping damage was more prevalent in mature forests with high tree diversity and ground level flora (e.g., bryophytes, herbs, and shrubs). Similarly, browsing damage was more prevalent in forests with greater tree richness but with understorey vegetation dominated by grass and ferns. Fraying damage was more common in mixed woodlands with understory dominated by bryophytes and grass. Crucially, we found that type and severity of forest damage were shaped by the interaction of multiple deer species occurring simultaneously, particularly at high densities, suggesting subtle inter-species competition and exclusion/partition dynamics that require further investigation to understand the ecological mechanism. Finally, we produce risk scenarios of forest damage by co-occurring deer species and precisely predict where damage is likely to occur on a national scale. We predict high levels of damage in sika and/or red deer hotspots, matching areas of highly concentrated deer distributions. This study highlights the ecological drivers and the role that co-occurring native and non-native deer species have on forest damage within a large spatial scale. By combining reliable species distribution models with the national forest inventory data, we can now provide a useful tool for practitioners to help alleviate and mitigate forest damage and human wildlife conflicts.
Hemopexin Reverses Activation of Lung eIF2a and Decreases Mitochondrial Injury in Chlorine Exposed Mice
Authors: Matalon Sadis , Yu Zhihong , Dubey Shubham , Ahmad Israr , Stephens Emily M. , Alishlash Ammar Saadoon , Meyers Ashley , Cossar Douglas , Stewart Donald , Acosta Edward P. , Kojima Kyoko , Jilling Tamas , Mobley James A. 
Published: August 2023

AbstractWe assessed the mechanisms by which non-encapsulated heme, released in the plasma of mice post exposure to chlorine (Cl2) gas, resulted in the initiation and propagation of acute lung injury. We exposed adult C57BL/6 male and female to Cl2(500 ppm for 30 min) in environmental chambers and returned them to room air and injected them intramuscularly with a single dose of human hemopexin (hHPX; 5 µg/ g BW), the most efficient scavenger of heme, 30-60 min post exposure. Concentrations of hHPX in plasma of air and Cl2exposed mice were 9081±900 vs. 1879± 293 at 6 h and 2966±463 vs. 1555±250 at 50 h post injection (ng/ml; X±1 SEM=3; p<0.01). Cl2exposed mice developed progressive acute lung injury post exposure characterized by increased concentrations of plasma heme, marked inflammatory response, respiratory acidosis and increased concentrations of plasma proteins in the alveolar space. Injection of hHPX decreased the onset of acute lung injury at 24 h post exposure; mean survival, for the saline and hHPX groups were 40 vs. 80% (P<0.001) at 15 d post exposure. Non-supervised global proteomics analysis of mouse lungs at 24 h post exposure, revealed the upregulation of 92 and downregulation of 145 lung proteins. Injection of hHPX at one h post exposure moderated the Cl2induced changes in eighty-three of these 237 lung proteins. System biology analysis of the global proteomics data showed that hHPX reversed changes in mitochondrial dysfunction and elF2 and integrin signaling. Western blot analysis of lung tissue showed significant increase of phosphorylated elF2 at 24 h post exposure in vehicle treated mice but normal levels in those injected with hHPX. Similarly, RT-PCR analysis of lung tissue showed that hHPX reversed the onset of mtDNA lesions. A form of recombinant human hemopexin generated in tobacco plants was equally effective in reversing acute lung and mtDNA injury. The results of this study offer new insights as to the mechanisms by which exposure to Cl2results in acute lung injury and to the therapeutic effects of hemopexin.
Endothelial TMEM16F lipid scramblase regulates angiogenesis
Authors: Shan Ke Zoe , Le Trieu , Liang Pengfei , Dong Ping , Yang Huanghe 
Published: August 2023

AbstractDynamic loss of lipid asymmetry through the activation of TMEM16 Ca2+-activated lipid scramblases (CaPLSases) has been increasingly recognized as an essential membrane event in a wide range of physiological and pathological processes, including blood coagulation, microparticle release, bone development, pain sensation, cell-cell fusion, and viral infection. Despite the recent implications of TMEM16F CaPLSase in vascular development and endothelial cell-mediated coagulation, its signaling role in endothelial biology remains to be established. Here, we show that endothelial TMEM16F regulatesin vitroandin vivoangiogenesis through intracellular signaling. Developmental retinal angiogenesis is significantly impaired in TMEM16F deficient mice, as evidenced by fewer vascular loops and larger loop areas. Consistent with ourin vivoobservation, TMEM16F siRNA knockdown in human umbilical vein endothelial cells compromises angiogenesisin vitro. We further discovered that TMEM16F knockdown enhances VE-cadherin phosphorylation and reduces its expression. Moreover, TMEM16F knockdown also promotes Src kinase phosphorylation at tyrosine 416, which may be responsible for downregulating VE-cadherin expression. Our study thus uncovers a new biological function of TMEM16F in angiogenesis and provides a potential mechanism for how the CaPLSase regulates angiogenesis through intracellular signaling.
Air Pollution Aggravates Renal Ischemia-Reperfusion-Induced Acute Kidney Injury
Authors: Sanches Talita Rojas , Parra Antonio Carlos , Sun Peiqi , Graner Mariana , Itto Lucas Yuji Umesaki , Butter Loes M. , Claessen Nike , Roelofs Joris J.T.H. , Florquin Sandrine , Veras Mariana Matera , Andrade Maria de Fátima , Saldiva Paulo Hilário Nascimento , Kers Jesper , Andrade Lucia , Tammaro Alessandra 
Published: August 2023

ABSTRACTChronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM2.5) and declined renal function. PM2.5 exerts its harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischemia reperfusion injury (IRI) involves similar biological processes involved in PM2.5 toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM2.5 exposure on IRI-induced AKI. Mice were exposed to PM2.5 or filtered air for 12 weeks before IRI, and were euthanized 48h after IRI. Animals exposed to PM2.5 and IRI exhibited reduced glomerular filtration and impaired urine concentration ability. Moreover, they showed elevated tubular damage markers NGAL and KIM-1, along with significant tubular necrosis. PM2.5 exposure exacerbated local innate immune activation, leading to an increased infiltration of Ly6G+ granulocytes and F480+ macrophages in the kidney. This, in turn, contributed to heightened renal senescence markers and myofibroblast infiltration. Collectively, our findings suggest that AKI-induced hampered tubular function is worsened by PM2.5, leading to reduced resilience to stress, activation of aging mechanisms and early hallmarks of fibrosis. Decreasing PM2.5 and implementing preventive strategies can improve AKI patients outcome and prevent AKI progression.
Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells
Authors: Dellorusso Paul V. , Proven Melissa A. , Calero-Nieto Fernando J. , Wang Xiaonan , Mitchell Carl A. , Hartmann Felix , Amouzgar Meelad , Favaro Patricia , DeVilbiss Andrew , Swann James W. , Ho Theodore T. , Zhao Zhiyu , Bendall Sean C. , Morrison Sean , Göttgens Berthold , Passegué Emmanuelle 
Published: August 2023

AbstractAging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction (1). Autophagy is central for the benefits associated with activation of longevity signaling programs (2), and for HSC function and response to nutrient stress (3,4). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional (4). However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown. Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche (5). We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.One-Sentence SummaryAutophagy compensates for chronic inflammation-induced metabolic deregulation in old HSCs, and its transient modulation can reset old HSC glycolytic and regenerative capacity.
Evaluation of the RNA-dependence of PRC2 binding to chromatin in human pluripotent stem cells
Authors: Long Yicheng , Hwang Taeyoung , Gooding Anne R. , Goodrich Karen J. , Hanson Skylar D. , Vallery Tenaya K. , Rinn John L. , Cech Thomas R. 
Published: August 2023

AbstractPolycomb Repressive Complex 2 (PRC2), an important histone modifier and epigenetic repressor, has been known to interact with RNA for almost two decades. In our previous publication (Long, Hwang et al. 2020), we presented data supporting the functional importance of RNA interaction in maintaining PRC2 occupancy on chromatin, using comprehensive approaches including an RNA-binding mutant of PRC2 and an rChIP-seq assay. Recently, concerns have been expressed regarding whether the RNA-binding mutant has impaired histone methyltransferase activity and whether the rChIP-seq assay can potentially generate artifacts. Here we provide new data that support a number of our original findings. First, we found the RNA-binding mutant to be fully capable of maintaining H3K27me3 levels in human induced pluripotent stem cells. The mutant had reduced methyltransferase activity in vitro, but only on some substrates at early time points. Second, we found that our rChIP-seq method gave consistent data across antibodies and cell lines. Third, we further optimized rChIP-seq by using lower concentrations of RNase A and incorporating a catalytically inactive mutant RNase A as a control, as well as using an alternative RNase (RNase T1). The EZH2 rChIP-seq results using the optimized protocols supported our original finding that RNA interaction contributes to the chromatin occupancy of PRC2.
Synthetic Homoserine Lactone Sensors for Gram-PositiveBacillus subtilisusing LuxR-type Regulators
Authors: Zeng Min , Sarker Biprodev , Howitz Nathaniel , Shah Ishita , Andrews Lauren B. 
Published: August 2023

AbstractA universal biochemical signal for bacterial cell-cell communication could facilitate programming dynamic responses in diverse bacterial consortia. However, the classical quorum sensing paradigm is that gram-negative and gram-positive bacteria generally communicate via homoserine lactones (HSL) or oligopeptide molecular signals, respectively, to elicit population responses. Here, we create synthetic HSL sensors for gram-positiveBacillus subtilis168 using allosteric LuxR-type regulators (RpaR, LuxR, RhlR, and CinR) and synthetic promoters. Promoters were combinatorially designed from different sequence elements (–35, –16, –10, and transcriptional start regions). We quantified the effects of these combinatorial promoters on sensor activity and determined how regulator expression affects its activation, achieving up to 293-fold activation. Using statistical design of experiments, we identified significant effects of promoter regions and pairwise interactions on sensor activity, which helped to understand the sequence-function relationships for synthetic promoter design. We present the first known set of functional HSL sensors (≥ 20-fold dynamic range) inB. subtilisfor four different HSL chemical signals:p-coumaroyl-HSL, 3-oxohexanoyl-HSL,n-butyryl-HSL, andn-(3-hydroxytetradecanoyl)-HSL. This set of synthetic HSL sensors for a gram-positive bacterium can pave the way for designable interspecies communication within microbial consortia.
How reliable are estimates of key parameters in viral dynamic models?
Authors: Zitzmann Carolin , Ke Ruian , Ribeiro Ruy M. , Perelson Alan S. 
Published: August 2023

AbstractMathematical models of viral infection have been developed and fit to data to gain insight into disease pathogenesis for a number of agents including HIV, hepatitis C and B virus. However, for acute infections such as influenza and SARS-CoV-2, as well as for infections such as hepatitis C and B that can be acute or progress to being chronic, viral load data are often collected after symptoms develop, usually around or after the peak viral load. Consequently, we frequently lack data in the exponential phase of viral growth, i.e., when most transmission events occur. Missing data may make estimation of the time of infection, the infectious period, and parameters in viral dynamic models, such as the cell infection rate, difficult. Here, we evaluated the reliability of estimates of key model parameters when viral load data prior to the viral load peak is missing. We estimated the time from infection to peak viral load by fitting non-linear mixed models to a dataset with frequent viral RNA measurements, including pre-peak. We quantified the reliability of estimated infection times, key model parameters, and the time to peak viral load. Although estimates of the time of infection are sensitive to the quality and amount of available data, other parameters important in understanding disease pathogenesis, such as the loss rate of infected cells, are less sensitive. We find a lack of data in the exponential growth phase underestimates the time to peak viral load by several days leading to a shorter predicted exponential growth phase. On the other hand, having an idea of the time of infection and fixing it, results in relatively good estimates of dynamical parameters even in the absence of early data.
Acto3D: user- and budget-friendly software for multichannel high-resolution three-dimensional imaging
Authors: Takeshita Naoki , Sakaki Shinichiro , Saba Rie , Inoue Satoshi , Nishikawa Kosuke , Ueyama Atsuko , Matsuo Kazuhiko , Shigeta Masaki , Nakajima Yoshiro , Kobayashi Daisuke , Yamazaki Hideya , Yamada Kei , Iehara Tomoko , Yashiro Kenta 
Published: August 2023

AbstractAdvances in fluorescence microscopy and tissue-clearing technology have revolutionized three-dimensional (3D) imaging of fluorescently labeled tissues, organs, and embryos. However, the complexity and high cost of existing software and computer solutions for such imaging limit its widespread adoption by researchers with limited resources. We here introduce Acto3D as a user- and budget-friendly, open-source computer software application designed to streamline the generation and observation of high-resolution 3D images of targets labeled with multiple fluorescent probes. Acto3D features an intuitive interface that simplifies the importation, visualization, and analysis of data sets, has an associated tool for annotation of vascular lumens, and incorporates multiple fluorescence channels for comprehensive imaging. Underpinned by an integrated graphics processing unit, Acto3D allows accurate image reconstruction and efficient data processing without the need for expensive high-performance computers. We validated the software by imaging mouse embryonic structures. Acto3D thus constitutes a cost-effective and efficient platform to support biological research.
Programmable multi-kilobase RNA editing using CRISPR-mediated trans-splicing
Authors: Borrajo Jacob , Javanmardi Kamyab , Griffin James , Martin Susan J. St. , Yao David , Hill Kaisle , Blainey Paul C. , Al-Shayeb Basem 
Published: August 2023

AbstractCurrent gene editing approaches in eukaryotic cells are limited to single base edits or small DNA insertions and deletions, and remain encumbered by unintended permanent effects and significant challenges in the delivery of large DNA cargo. Here we describe Splice Editing, a generalizable platform to correct gene transcriptsin situby programmable insertion or replacement of large RNA segments. By combining CRISPR-mediated RNA targeting with endogenous cellular RNA-splicing machinery, Splice Editing enables efficient, precise, and programmable large-scale editing of gene targets without DNA cleavage or mutagenesis. RNA sequencing and measurement of spliced protein products confirm that Splice Editing achieves efficient and specific targeted RNA and protein correction. We show that Splice Editors based on novel miniature RNA-targeting CRISPR-Cas systems discovered and characterized in this work can be packaged for effective delivery to human cells and affect different types of edits across multiple targets and cell lines. By editing thousands of bases simultaneously in a single reversible step, Splice Editing could expand the treatable disease population for monogenic diseases with large allelic diversity without the permanent unintended effects of DNA editing.One-sentence summaryCRISPR-guided trans-splicing enables efficient and specific recombination of large RNA molecules in mammalian cells, with broad applications in therapeutic development for genetic diseases and as a research tool for the study of basic RNA biology.