bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proformer: a hybrid macaron transformer model predicts expression values from promoter sequences
Authors: Kwak Il-Youp , Kim Byeong-Chan , Lee Juhyun , Garry Daniel J. , Zhang Jianyi , Gong Wuming 
Published: March 2023

AbstractThe breakthrough high-throughput measurement of the cis-regulatory activity of millions of randomly generated promoters provides an unprecedented opportunity to systematically decode the cis-regulatory logic that determines the expression values. We developed an end-to-end transformer encoder architecture named Proformer to predict the expression values from DNA sequences. Proformer used a Macaron-like Transformer encoder architecture, where two half-step feed forward (FFN) layers were placed at the beginning and the end of each encoder block, and a separable 1D convolution layer was inserted after the first FFN layer and in front of the multi-head attention layer. The slidingk-mers from one-hot encoded sequences were mapped onto a continuous embedding, combined with the learned positional embedding and strand embedding (forward strand vs. reverse complemented strand) as the sequence input. Moreover, Proformer introduced multiple expression heads with mask filling to prevent the transformer models from collapsing when training on relatively small amount of data. We empirically determined that this design had significantly better performance than the conventional design such as using the global pooling layer as the output layer for the regression task. These analyses support the notion that Proformer provides a novel method of learning and enhances our understanding of how cis-regulatory sequences determine the expression values.
The Role of Terminal Uridyl Transferases in the Circadian Rhythm
Authors: Song Wei , Wang Juan , Piao Weilan , Yang Yuening , Son Ahyeon , Chang Hyeshik , Wen Xianghui , Zhang Honglei , Li Chong , Na Daxiang , Lu Yanming , Menet Jerome , Kim V. Narry , Jin Hua 
Published: March 2023

AbstractThe 3’ terminal oligo-uridylation, a post-transcriptional mRNA modification, is conserved among eukaryotes and drives mRNA degradation, thereby affecting several key biological processes such as animal development and viral infection. Our TAIL-seq experiment of mouse liver mRNA collected from six zeitgeber times reveals transcripts with rhythmic poly(A) tail lengths and demonstrates that overall 3’ terminal uridylation frequencies at mRNA poly(A) tail very-ends undergo rhythmic change. Consistently, major terminal uridylyl transferases, TUT4 and TUT7, have cycling protein expression in mouse liver corresponding to 3’ terminal uridylation rhythms, indicating that the cycling expression of TUTases correlates with the rhythmic pattern of uridylation. Furthermore, the double knockdown of TUT4 and TUT7 in U2OS cells lengthens the circadian period and decreases the rhythmic amplitude of clock gene expression. Our work thoroughly profiles the dynamic changes in poly(A) tail lengths and terminal modifications and uncovers uridylation as a post-transcriptional modulator in the mammalian circadian clock.
The Colibactin-ProducingEscherichia colialters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance
Authors: de Oliveira Alves Brito Nilmara , Dalmasso Guillaume , Nikitina Darja , Vaysse Amaury , Ruez Richard , Ledoux Lea , Pedron Thierry , Bergsten Emma , Boulard Olivier , Autier Lora , Allam Sofian , Motreff Laurence , Sauvanet Pierre , Letourneur Diane , Tang Gabriel , Gagnière Johan , Pezet Denis , Godfraind Catherine , Salzet Michel , Lemichez Emmanuel , Bonnet Mathilde , Najjar Imène , Malabat Christophe , Monot Marc , Mestivier Denis , Barnich Nicolas , Fournier Isabelle , Kennedy Sean P. , Mettouchi Amel , Bonnet Richard , Sobhani Iradj , Chamaillard Mathias 
Published: March 2023

ABSTRACTIntratumoral bacteria locally contribute to cellular and molecular tumor heterogeneity that support cancer stemness through poorly understood mechanisms. This study aims to explore how Colibactin-producingEscherichia coli(CoPEC) flexibly alters the tumor microenvironment in right-sided colorectal cancer (CRC). Metabolomic and transcriptomic spatial profiling uncovered that CoPEC colonization establishes a high-glycerophospholipid microenvironment within the tumor that is conducive to exhaustion of infiltrated CD8+T cell and has a lowered prognostic value in right-sided CRC. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress and supply with sufficient energy for sustaining cell survival and lowering tumor immunogenicity. Specifically, a heightened phosphatidylcholine remodeling of CoPEC-infected cancer cells by the enzyme of the Land’s cycle coincided with a lowered accumulation of proapoptotic ceramide and lysophosphatidylcholine. Consequently, a reduced infiltration of CD8+T lymphocytes that produce the cytotoxic cytokines IFN-γ was found where invading bacteria have been geolocated. By contrast, such an immunosuppressive dysmetabolic process was not observed when human colon cancer cells were infected with the mutant strain that did not produce colibactin (11G5δClbQ). This work revealed an unexpected property of CoPEC on lipid overload within tumors that could locally provide an inflammatory environment leading to immunosuppressive mechanisms and tumor expansion. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.
PathogenicLeptospiraare widespread in the urban wildlife of southern California
Authors: Helman Sarah K. , Tokuyama Amanda F.N. , Mummah Riley O. , Gamble Mason W. , Snedden Celine E. , Borremans Benny , Gomez Ana C.R. , Cox Caitlin , Nussbaum Julianne , Tweedt Isobel , Haake David A. , Galloway Renee L. , Monzón Javier , Riley Seth P.D. , Sikich Jeff A. , Brown Justin , Friscia Anthony , Lynch Jessica W. , Prager Katherine C. , Lloyd-Smith James O. 
Published: March 2023

ABSTRACTLeptospirosis is the most widespread zoonotic disease in the world, yet it is broadly understudied in multi-host wildlife systems. Knowledge gaps regardingLeptospiracirculation in wildlife, particularly in densely populated areas, contribute to frequent misdiagnoses in humans and domestic animals. We assessedLeptospiraprevalence levels and risk factors in five target wildlife species across the greater Los Angeles region: striped skunks (Mephitis mephitis), Northern raccoons (Procyon lotor), coyotes (Canis latrans), Virginia opossums (Didelphis virginiana), and fox squirrels (Sciurus niger). We sampled more than 960 individual animals, including over 700 from target species in the greater Los Angeles region, and an additional 260 sampled opportunistically from other regions and species. In the five target species, seroprevalences ranged from 5-60% and active infection prevalences ranged from 0.8-15.2% in all except fox squirrels (0%). Patterns of serologic reactivity suggest that mainland terrestrial wildlife, particularly mesocarnivores, could be the source of repeated observed introductions ofLeptospirainto local marine and island ecosystems. Overall, we found evidence of widespreadLeptospiraexposure in wildlife across Los Angeles and surrounding regions. This indicates exposure risk for humans and domestic animals and highlights that this pathogen can circulate endemically in many wildlife species even in densely populated urban areas.
Loss-of-SIRT7 sensitizes hepatocellular carcinoma to sorafenib through the regulation of ERK Phosphorylation
Authors: Kim Yuna , Jung Kwan-Young , Kim Yun Hak , Xu Pan , Jo Yunju , Kang Baeki E. , Pandit Navin , Kwon Jeongho , Gariani Karim , Gariani Joanna , Lee Junguee , Verbeek Jef , Nam Seungyoon , Bae Sung-Jin , Ha Ki-Tae , Yi Hyon-Seung , Shong Minho , Kim Kyun-Hwan , Kim Doyoun , Lee Chang-Woo , Jung Hee Jung , Kim Kwang Rok , Schoonjans Kristina , Ryu Dongryeol , Auwerx Johan 
Published: March 2023

AbstractThe FDA-approved oral multi-kinase inhibitor, sorafenib (BAY 43-9006, Nexavar), is the first approved systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). Although it has been shown to significantly improve the overall survival of patients with HCC, drug resistance limits the response rate to this therapeutic. Here, we report that acquired sorafenib resistance is associated with overexpression of the deacetylase, SIRT7, and a high level of ERK phosphorylation. Further, we identify that the hyperactivation of ERK is controlled by SIRT7-mediated deacetylation of DDX3X. The inhibition of SIRT7 combined with sorafenib resulted in a marked reduction of cell viability in vitro and of tumor growth in vivo. It seems plausible that SIRT7 is responsible for the acquired sorafenib resistance and its inhibition is most likely beneficial together in conjunction with sorafenib by suppressing ERK signaling.HighlightsSorafenib resistance in HCC is associated with SIRT7 and ERK hyperactivation.Suppression of SIRT7 combined with sorafenib restores sensitivity to sorafenib.SIRT7 controls sorafenib resistance through ERK activation by mediating DDX3X deacetylation.
Molecular signature of domestication in the arboviral vectorAedes aegypti
Authors: Lozada-Chávez A.N. , Lozada-Chávez I. , Alfano N. , Palatini U. , Sogliani D. , Elfekih S. , Degefa T. , Sharakhova M.V. , Badolo A. , Patchara S. , Casas-Martinez M. , Carlos B.C , Carballar-Lejarazú R. , Lambrechts L. , Souza-Neto J.A. , Bonizzoni M. 
Published: March 2023

AbstractBackgroundDomestication is a complex, multi-stage and species-specific process that results in organisms living close to humans. In the arboviral vectorAedes aegyptiadaptation to living in proximity with anthropogenic environments has been recognized as a major evolutionary shift, separating a generalist form,Aedes aegypti formosus(Aaf), from the domestic formAedes aegypti aegypti(Aaa), which tends to deposit eggs artificial containers and bite humans for a blood meal. These behaviors enhance the mosquito vectorial capacity. The extent to which domestication has impacted theAe. aegyptigenome has not been thoroughly investigated yet.ResultsTaking advantage of two forms’ distinct and historically documented geographic distributions, we analyzed the genomes of 634 worldwideAe. aegyptimosquitoes. Using more than 300 million high-confidence SNPs, we found a unique origin for all out-of-AfricaAe. aegyptimosquitoes, with no evidence of admixture events in Africa, apart from Kenya. A group of genes were under positive selection only in out-of-Africa mosquitoes and 236 genes had nonsynonymous mutations, occurring at statistically different frequencies in Aaa and Aaf mosquitoes.ConclusionWe identified a clear signal of genetic differentiation between Aaa and Aaf, circumscribed to a catalogue of candidate genes. These “Aaa molecular signature” genes extend beyond chemosensory genes to genes linked to neuronal and hormonal functions. This suggests that the behavioral shift to domestication may rely on the fine regulation of metabolic and neuronal functions, more than the role of a few significant genes. Our results also provide the foundation to investigate new targets for the control ofAe. aegyptipopulations.
Mechanisms of octopus arm search behavior without visual feedback
Authors: Sivitilli Dominic M. , Strong Terrell , Weertman Willem , Ullmann Joseph , Smith Joshua R. , Gire David H. 
Published: March 2023

AbstractThe octopus coordinates multiple, highly flexible arms with the support of a complex distributed nervous system. The octopus’s suckers, staggered along each arm, are employed in a wide range of behaviors. Many of these behaviors, such as foraging in visually occluded spaces, are executed under conditions of limited or absent visual feedback. In coordinating unseen limbs with seemingly infinite degrees of freedom across a variety of adaptive behaviors, the octopus appears to have solved a significant control problem facing the field of soft-bodied robotics. To study the strategies that the octopus uses to find and capture prey within unseen spaces, we designed and 3D printed visually occluded foraging tasks and tracked arm motion as the octopus attempted to find and retrieve a food reward. By varying the location of the food reward within these tasks, we can characterize how the arms and suckers adapt to their environment to find and capture prey. We compared these results to simulated experimental conditions performed by a model octopus arm to isolate the primary mechanisms driving our experimental observations. We found that the octopus relies on a contact-based search strategy that emerges from local sucker coordination to simplify the control of its soft, highly flexible limbs.
GITR and TIGIT immunotherapy provokes divergent multi-cellular responses in the tumor microenvironment of gastrointestinal cancers
Authors: Sathe Anuja , Ayala Carlos , Bai Xiangqi , Grimes Susan M. , Lee Byrne , Kin Cindy , Shelton Andrew , Poultsides George , Ji Hanlee P. 
Published: March 2023

ABSTRACTUnderstanding the cellular mechanisms of novel immunotherapy agents in the human tumor microenvironment (TME) is critical to their clinical success. We examined GITR and TIGIT immunotherapy in gastric and colon cancer patients usingex vivoslice tumor slice cultures derived from cancer surgical resections. This primary culture system maintains the original TME in a near-native state. We applied paired single-cell RNA and TCR sequencing to identify cell type specific transcriptional reprogramming. The GITR agonist was limited to increasing effector gene expression only in cytotoxic CD8 T cells. The TIGIT antagonist increased TCR signaling and activated both cytotoxic and dysfunctional CD8 T cells, including clonotypes indicative of potential tumor antigen reactivity. The TIGIT antagonist also activated T follicular helper-like cells and dendritic cells, and reduced markers of immunosuppression in regulatory T cells. Overall, we identified cellular mechanisms of action of these two immunotherapy targets in the patients’ TME.
Foxtrot migration and dynamic over-wintering range of an arctic raptor
Authors: Pokrovsky Ivan , Curk Teja , Dietz Andreas , Fufachev Ivan , Kulikova Olga , Rößler Sebastian , Wikelski Martin 
Published: March 2023

ABSTRACTAdvances in tracking technologies have revealed the diverse migration patterns of birds, which are critical for range mapping and population estimation. Population trends are usually estimated in breeding ranges where birds remain stationary, but for species that breed in remote areas like the Arctic, these trends are often assessed in over-wintering ranges. Evaluating population trends during the wintering season is challenging due to the extensive movements of birds in these ranges, which require a deep understanding of the movement dynamics. However, these movements remain understudied, particularly in the mid-latitudes, where many Arctic breeders overwinter, increasing uncertainty in their ranges and numbers. Here, we show that the Arctic breeding raptor Rough-legged buzzard, which overwinters in the mid-latitudes, has a specific wintering strategy. After migrating ca 1,500 km from the Arctic to mid-latitudes, the birds continue to move throughout the entire over-wintering period, covering an additional 1,000 km southwestward and then back northeastward as the snowline advances. This ongoing movement makes their wintering range dynamic over the course of the season. In essence, this movement represents an extension of the quick migration process, albeit at a slower pace, and we have termed this migration pattern ‘foxtrot migration,’ drawing an analogy to the alternating fast and slow movements of the foxtrot dance. These results highlight the potential errors in range mapping from single mid-winter surveys and emphasize the importance of this migration pattern in assessing the conservation status of bird species. Understanding this migration pattern could help to correctly estimate bird populations in over-wintering ranges, which is especially important for species that nest in hard-to-reach regions such as the Arctic.
Tumour Extracellular Vesicles Induce Neutrophil Extracellular Traps To Promote Lymph Node Metastasis
Authors: Su Xin , Brassard Ariane , Bartolomucci Alexandra , Dhoparee-Doomah Iqraa , Qiu Qian , Tsering Thupten , Rohanizadeh Ramin , Koufos Olivia , Giannias Betty , Bourdeau France , Feng Lixuan , Leo Sabrina , Sangwan Veena , Tankel James , Quail Daniela , Spicer Jonathan , Burnier Julia V , Bailey Swneke Donovan , Ferri Lorenzo , Cools-Lartigue Jonathan 
Published: March 2023

AbstractLymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastasis status. However, there is evidence suggesting that LN metastasis is facilitated by a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. We have previously reported that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition abolishes LN metastases in animal mode. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings are the first to reveal the role of EV induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities.Graphic AbstractIllustrative demonstration of the LNs premetastatic niche formation induced by EVs and NETs. Primary tumour constantly secretes EVs, which were actively uptaken by LECs. LECs subsequently secretes CXCL8 or CXCL2 upon EV reception. CXCL8 and CXCL2 are both neutrophil chemoattractants and potent NETs inducers. The following neutrophil recruitment and NETs formation lead to increased LN metastasis burden.
Murine Alveolar Macrophages Rapidly Accumulate Intranasally Administered SARS-CoV-2 Spike Protein leading to Neutrophil Recruitment and Damage
Authors: Park Chung , Hwang Il-Young , Yan Serena Li-Sue , Vimonpatranon Sinmanus , Wei Danlan , Ryk Don Van , Girard Alexandre , Cicala Claudia , Arthos James , Kehrl John H. 
Published: March 2023

AbstractThe trimeric SARS-CoV-2 Spike protein mediates viral attachment facilitating cell entry. Most COVID-19 vaccines direct mammalian cells to express the Spike protein or deliver it directly via inoculation to engender a protective immune response. The trafficking and cellular tropism of the Spike proteinin vivoand its impact on immune cells remains incompletely elucidated. In this study we inoculated mice intranasally, intravenously, and subcutaneously with fluorescently labeled recombinant SARS-CoV-2 Spike protein. Using flow cytometry and imaging techniques we analyzed its localization, immune cell tropism, and acute functional impact. Intranasal administration led to rapid lung alveolar macrophage uptake, pulmonary vascular leakage, and neutrophil recruitment and damage. When injected near the inguinal lymph node medullary, but not subcapsular macrophages, captured the protein, while scrotal injection recruited and fragmented neutrophils. Wide-spread endothelial and liver Kupffer cell uptake followed intravenous administration. Human peripheral blood cells B cells, neutrophils, monocytes, and myeloid dendritic cells all efficiently bound Spike protein. Exposure to the Spike protein enhanced neutrophil NETosis and augmented human macrophage TNF-α and IL-6 production. Human and murine immune cells employed C-type lectin receptors and Siglecs to help capture the Spike protein. This study highlights the potential toxicity of the SARS-CoV-2 Spike protein for mammalian cells and illustrates the central role for alveolar macrophage in pathogenic protein uptake.
Aversive experience drives offline ensemble reactivation to link memories across days
Authors: Zaki Yosif , Pennington Zachary T. , Morales-Rodriguez Denisse , Francisco Taylor R. , LaBanca Alexa R. , Dong Zhe , Lamsifer Sophia , Segura Simón Carrillo , Chen Hung-Tu , Christenson Wick Zoé , Silva Alcino J. , van der Meer Matthijs , Shuman Tristan , Fenton André , Rajan Kanaka , Cai Denise J. 
Published: March 2023

AbstractMemories are encoded in neural ensembles during learning and stabilized by post-learning reactivation. Integrating recent experiences into existing memories ensures that memories contain the most recently available information, but how the brain accomplishes this critical process remains unknown. Here we show that in mice, a strong aversive experience drives the offline ensemble reactivation of not only the recent aversive memory but also a neutral memory formed two days prior, linking the fear from the recent aversive memory to the previous neutral memory. We find that fear specifically links retrospectively, but not prospectively, to neutral memories across days. Consistent with prior studies, we find reactivation of the recent aversive memory ensemble during the offline period following learning. However, a strong aversive experience also increases co-reactivation of the aversive and neutral memory ensembles during the offline period. Finally, the expression of fear in the neutral context is associated with reactivation of the shared ensemble between the aversive and neutral memories. Taken together, these results demonstrate that strong aversive experience can drive retrospective memory-linking through the offline co-reactivation of recent memory ensembles with memory ensembles formed days prior, providing a neural mechanism by which memories can be integrated across days.