bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequence Dependent UV Damage of Complete Pools of Oligonucleotides
Authors: Kufner Corinna L. , Krebs Stefan , Fischaleck Marlis , Philippou-Massier Julia , Blum Helmut , Bucher Dominik B. , Braun Dieter , Zinth Wolfgang , Mast Christof B. 
Published: August 2022

AbstractUnderstanding the sequence-dependent DNA damage formation requires to probe a complete pool of sequences over a wide dose range of the damage causing exposure. We used high throughput sequencing to simultaneously obtain the dose dependence and quantum yields for oligonucleotide damages for all possible 4096 DNA sequences with hexamer length. We exposed the DNA with ultraviolet radiation at 266 nm and doses of up to 500 photons per base. At the dimer level our results confirm existing literature values, whereas we now quantified the susceptibility of sequence motifs to UV irradiation up to previously inaccessible polymer lengths. This revealed the protective effect of the sequence context in preventing the formation of UV-lesions. For example, the rate to form dipyrimidine lesions is strongly reduced by nearby guanine bases. Our results provide a complete picture of the sensitivity of oligonucleotides to UV irradiation and allow to predict their survival chances in high-UV environments.
They call me the wanderer – Neurovascular anatomy of dwarfed dinosaur implies precociality in sauropods
Authors: Schade Marco , Knötschke Nils , Hörnig Marie K. , Paetzel Carina , Stumpf Sebastian 
Published: August 2022

AbstractMacronaria, a group of mostly colossal sauropod dinosaurs, comprised the largest terrestrial vertebrates of Earth’s history. However, some of the smallest sauropods belong to this group as well. The Late Jurassic macronarianEuropasaurus holgeriis one of the best-known sauropods worldwide. So far, the braincase material of this taxon from Germany pended greater attention. With the aid of microCT, we report on the neuroanatomy of the almost complete braincase of an adult individual, as well as the inner ears of one other adult and several juveniles (also containing so far unknown vascular cavities). The presence of large and morphologically adult inner ears in juvenile material suggests precociality. Our findings add to the diversity of neurovascular anatomy in sauropod braincases and buttress the perception of sauropods as fast-growing and autonomous giants with manifold facets of reproductive and social behavior. This suggests that – apart from sheer size – little separated the island dwarfEuropasaurusfrom its large-bodied relatives.
Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity
Authors: Rem Pascal Dominic , Sereikaite Vita , Fernandez-Fernandez Diego , Reinartz Sebastian , Ulrich Daniel , Fritzius Thorsten , Trovò Luca , Roux Salome , Chen Ziyang , Rondard Philippe , Pin Jean-Philippe , Schwenk Jochen , Fakler Bernd , Gassmann Martin , Barkat Tania R. , Strømgaard Kristian , Bettler Bernhard 
Published: August 2022

AbstractAmyloid-β precursor protein (APP) regulates neuronal activity through the release of secreted APP (sAPP) acting at cell-surface receptors. APP and sAPP were reported to bind to the extracellular sushi domain 1 (SD1) of GABAB receptors (GBRs). A 17 amino-acid peptide (APP17) derived from APP was sufficient for SD1 binding and shown to mimic the inhibitory effect of sAPP on neurotransmitter release and neuronal activity. The functional effects of APP17 and sAPP were similar to those of the GBR agonist baclofen and blocked by a GBR antagonist. These experiments led to the proposal that sAPP activates GBRs to exert its neuronal effects. However, whether APP17 and sAPP indeed influence classical GBR signaling pathways in heterologous cells was not analyzed. Here, we confirm that APP17 binds to GBRs with nanomolar affinity. However, biochemical and electrophysiological assays indicate that APP17 does not influence GBR activity in heterologous cells. Moreover, we found no evidence for APP17 regulating K+ currents in cultured neurons, neurotransmitter release in brain slices, or neuronal activity in vivo. Our results show that APP17 is not a functional GBR ligand and indicate that sAPP exerts neuronal effects through receptors other than GBRs.
Alternative promoters in CpG depleted regions pervasively account for epigenetic misregulation of cancer transcriptomes
Authors: Nepal Chirag , Andersen Jesper B. 
Published: August 2022

AbstractEukaryotic genes are regulated by multiple alternative promoters with distinct expression patterns. In cancer, alternative promoters are pervasively utilized, but our understanding of the mechanism of activation and how their regulatory architecture differs from reference promoters remains elusive. We analyzed 100 CAGE-seq libraries from HCC patients and annotated 4083 alternative promoters in 2926 multi-promoter genes that are known genes involved in hepatocarcinogenesis. Many alternative promoters are undetected in the normal liver. We find that multi-promoter genes are enriched among genes downregulated in the tumor, highlighting alternative promoters’ impact in global transcription changes in cancer. Alternative promoters are depleted for CpG islands, have narrow nucleosome depleted regions, and are enriched for sharp promoters as well as tissue-specific transcription factors. Alternative promoters have high DNA methylation levels around transcription start sites. Tumor cells globally lose DNA methylation, but there exists a hierarchical retention of intragenic DNA methylation, which is dictated by the genomic CG content. As such, intragenic CG-poor regions lose methylation, while CG-rich regions retain it, a phenomenon caused by differential binding of H3K36me3,DNMT3B, TET1andSETD2.Thus, the selective loss of DNA methylation in CG-poor regions opens the chromatin and makes these regions accessible for transcription. Upon transcription factors availability, alternative transcription can pervasively occur in cancer. These results provide a framework for understanding the importance of alternative promoters in controlling the tumor transcriptomes, highlighting their architecture and role in regulatory mechanism(s).
Lung Tumor Microphysiological System with 3D Endothelium to Evaluate Modulators of T-Cell Infiltration
Authors: Wisdom Katrina M. , Suijker Johnny , van den Broek Lenie , Sridharan BanuPriya , Grandhi Taraka Sai Pavan , Cheng Aaron , Lamb Mahdi , Titus Steven A. , Gehman Andrew , Poore Derek , Shah Niyant , Cheng Shih-Hsun , Kim Edward , Griffin Sue , Ekert Jason 
Published: August 2022

AbstractLung cancer is a leading cause of death worldwide, with only a fraction of patients responding to immunotherapy. The correlation between increased T-cell infiltration and positive patient outcomes has motivated the search for therapeutics promoting T-cell infiltration. While transwell and spheroid platforms have been employed, these models lack flow and endothelial barriers, and cannot faithfully model T-cell adhesion, extravasation and migration through 3D tissue. Presented here is a 3D chemotaxis assay, in a lung tumor on chip model with 3D endothelium (LToC-Endo), to address this need. The described assay consists of a vascular tubule cultured under rocking flow, through which T-cells are added; a collagenous stromal barrier, through which T-cells infiltrate; and a chemoattractant/tumor compartment. Here, activated T-cells extravasate and infiltrate in response to gradients of rhCXCL11 and rhCXCL12. Adopting a T-cell activation protocol with a rest period enables proliferative burst prior to introducing T-cells into chips, increases T-cell expression of CXCR3 and CXCR4 receptors, and enhances assay sensitivity. In addition, incorporating this rest recovers endothelial activation in response to rhCXCL12. As a final control, we show that blocking ICAM-1 interferes with T-cell adhesion and chemotaxis. This microphysiological system, which mimics in vivo stromal and vascular barriers, can be used to evaluate potentiation of immune chemotaxis into tumors while probing for vascular responses to potential therapeutics. Finally, we propose a translational strategy by which this assay could be linked to preclinical and clinical models to support human dose prediction, personalized medicine, and the reduction, refinement, and replacement of animal models.
MOSQUITO MICROBIOMES OF RWANDA: CHARACTERIZING MOSQUITO HOST AND MICROBIAL COMMUNITIES IN THE LAND OF A THOUSAND HILLS
Authors: Tokash-Peters Amanda G. , Niyonzima Jean Damascene , Kayirangwa Mirielle , Muhayimana Simon , Tokash Ivan W. , Jabon Jaimy D. , Lopez Sergio G. , Woodhams Douglas C. 
Published: August 2022

AbstractMosquitoes are a complex nuisance around the world, and tropical countries bear the greatest brunt of the burden of mosquito-borne diseases. Rwanda has had success in reducing malaria and some arboviral diseases over the last few years, but still faces challenges to elimination. By building our understanding ofin situmosquito communities in Rwanda at a disturbed, human-occupied site and at a natural, preserved site, we can build our understanding of natural mosquito microbiomes toward the goal of implementing novel microbial control methods. Here, we examined the composition of collected mosquitoes and their microbiomes at two diverse sites using Cytochrome c Oxidase I sequencing and 16S V4 barcode sequencing. The majority of mosquitoes captured and characterized in this study are the first-known record of their species for Rwanda but have been characterized in other nations in East Africa. Beta diversity metrics were significantly different between sampling sites, mosquito genera, and mosquito species, but not between mosquito sexes, catch method, or presumed bloodfed status. Bacteria of interest for arbovirus control,Asaia, Serratia, andWolbachia, were found in abundance at both sites, but were more prevalent at the disturbed site and varied greatly by species. Additional studies to build our understanding of naturally-formed microbial communities are essential to safely employing microbial control methods and further reducing the burden of mosquito-borne diseases.
Resource asynchrony and landscape homogenization as drivers of virulence evolution
Authors: Kürschner Tobias , Scherer Cédric , Radchuk Viktoriia , Blaum Niels , Kramer-Schadt Stephanie 
Published: August 2022

AbstractIn the last years, the emergence of zoonotic diseases and the frequency of disease outbreaks have increased substantially, fuelled by habitat encroachment and asynchrony of biological cycles due to global change. The virulence of these diseases is a key aspect for their success. In order to understand the complex processes of pathogen virulence evolution in the global change context, we adapted an established individual-based model of host-pathogen dynamics. Our model simulates a population of social hosts affected by an evolving pathogen in a dynamic landscape. Pathogen virulence evolution is explored by the inclusion of multiple strains in the model that differ in their transmission capability and lethality. Simultaneously, the host’s resource landscape is subjected to spatial and temporal dynamics, emulating effects of global change.We found an increase in pathogenic virulence and a shift in strain dominance with increasing landscape homogenisation. Our model further shows a trend to lower virulence pathogens being dominant in fragmented landscapes, although pulses of highly virulent strains are expected under resource asynchrony. While all landscape scenarios favour coexistence of low and high virulent strains, when host density increases, the high virulence strains capitalize on the high possibility for transmission and are likely to become dominant.Author SummaryDisease outbreaks primarily caused by contact with animals are increasing in recent years, related to habitat destruction and altered biological cycles due to climate change. Pathogens associated with such outbreaks will be more successful the more effectively they can spread in a population. Thus, understanding the conditions over which those pathogens evolve will help us to limit the impact of disease outbreaks in the future. To this end, we used an individual based model that allowed us to study different scenarios. Our model had three main components: a host-pathogen system, a dynamic resource landscape with different degrees of fragmentation and temporal resource mismatches. We used dynamic landscapes with varying resource amounts over the years and consisting of multiple large or smaller habitat clusters. Our simulations showed that homogenous landscapes resulted in higher virulent pathogens and fragmented landscapes in lesser virulent pathogens. However, across all scenarios, high and low virulent pathogen strains were able to coexist.
Persistent Hypersomnia Following Repetitive Mild Experimental Traumatic Brain Injury: Roles of Chronic Stress and Sex Differences
Authors: Portillo Edwin , Zi Xiaomei , Kim Yeonho , Tucker Laura B. , Fu Amanda , Miller Lauren A. , Valenzuela Krystal S. , Sullivan Genevieve M. , Gauff Amina K. , Yu Fengshan , Radomski Kryslaine L. , McCabe Joseph T. , Armstrong Regina C. 
Published: August 2022

ABSTRACTTraumatic brain injury (TBI) is often more complicated than a single head injury. An extreme example of this point may be military service members who experience a spectrum of exposures over a prolonged period under stressful conditions. Understanding the effects of complex exposures can support proper evaluation and care for patients experiencing persistent symptoms. We designed a longitudinal series of non-invasive procedures in adult mice to evaluate the effects of prolonged mild exposures. We assessed anxiety, depression, and sleep-wake dysfunction as symptoms that can impact long term outcomes after mild TBI. Unpredictable chronic mild stress (UCMS) was generated from a variable sequence of environmental stressors distributed within each of 21 days. Subsequently, mice received a mild blast combined with closed-head mild TBI on five days at 24-hour intervals. TBI components were either five linear force impacts, or a novel alternating repetitive mild TBI (Ar-mTBI) model of linear and rotational (CHIMERA) impacts over five days to produce diffuse pathology. In males and females, UCMS induced anxiety without depressive behavior. Persistent hypersomnia, specifically increased sleep during the active dark period, was found through 6-12 month time points in male mice receiving UCMS with repetitive blast plus TBI events, or surprisingly after UCMS alone. Sleep-wake dysfunction was not found with TBI events alone and was not found in females under any conditions. These results identify prolonged stress and sex differences as important considerations for sleep-wake dysfunction. Furthermore, this reproducible hypersomnia is similar to excessive daytime sleepiness reported in patients, which may inform treatments.
Distributed cortical regions for the recall of people, places and objects
Authors: Kidder Alexis , Silson Edward H , Nau Matthias , Baker Chris I 
Published: August 2022

AbstractHuman medial parietal cortex (MPC) is recruited during multiple cognitive processes. Previously, we demonstrated regions specific to recall of people or places and proposed that the functional organization of MPC mirrors the category selectivity defining the medial-lateral axis of ventral temporal cortex (VTC). However, prior work considered recall of people and places only and VTC also shows object-selectivity sandwiched between face- and scene-selective regions. Here, we tested a strong prediction of our proposal: like VTC, MPC should show a region specifically recruited during object recall, and its relative cortical position should mirror the one of VTC. While responses during people and place recall showed a striking replication of prior findings, we did not observe any evidence for object-recall effects within MPC, which differentiates it from the spatial organization in VTC. Importantly, beyond MPC, robust recall-effects were observed for people, places, and objects on the lateral surface of the brain. Place-recall effects were present in the angular gyrus, frontal eye fields and peripheral portions of early visual cortex, whereas people-recall selectively drove response in the right posterior superior temporal sulcus. Object-recall effects were largely restricted to a region posterior to left somatosensory cortex, in the vicinity of the supramarginal gyrus. Taken together, these data demonstrate that while there are distributed regions active during recall of people, places and objects, the functional organization of MPC does not mirror the medial-lateral axis of VTC but reflects only the most salient features of that axis - namely representations of people and places.Significance statementHuman medial parietal cortex (MPC) is recruited during multiple cognitive processes. Recently, we proposed a framework for interpreting the functional organization of MPC by suggesting that it reflects the categorical preferences for people and places that is evident also in ventral temporal cortex (VTC). Because VTC also exhibits selectivity for objects, we here extend this framework to test whether MPC also shows object selectivity during recall. Robust people and place recall effects were evident in MPC, but we found no evidence for object-recall within MPC, suggesting that MPC and VTC are not mirror-copies of each other. Together, these data suggest that the functional organization of MPC reflects the most salient categorical representations within VTC for people and places.
A novel subtype of reactive astrocytes critical for HIV associated pain pathogenesis
Authors: Zheng Junying , Spurgat Michael , Tang Shao-Jun 
Published: August 2022

AbstractPathological pain is common in HIV patients, but the underlying mechanism remains elusive and therapeutic targets for effective treatment have not been identified. Reactive astrocytes are specifically activated in the spinal dorsal horn (SDH) of HIV patients with pathological pain and required for the development of HIV-associated pain in mouse models. These findings suggest a key role of reactive astrocytes in HIV-associated pain pathogenesis. However, due to the heterogeneity of reactive astrocytes, the pathogenic subtype is unknown. Using single-nucleus RNA-seq (snRNA-seq) transcriptomic analysis, we identified a novel subtype of HIV-pain associated astrocytes (HIPAs) in the lumbar spinal cord of the HIV -1 gp120 transgenic model. HIPAs were galectin 3 (Gal3)-positive and had transcriptomic signatures of phagocytosis and inflammation; they were also induced in the spinal cord of HIV patients. We showed HIPAs phagocytosed neuronal and synaptic components and were associated with neuronal degeneration. We found that knockout (KO) of Gal3 in gp120 transgenic mice severely diminished HIPAs. Interestingly, the activation of other astrocytes (e.g., homeostatic astrocytes) were also diminished in the Gla3 KO/gp120 transgenic mice. These results indicate that Gal3 is critical for gp120 to induce HIPAs, and that Gal3 may directly or via HIPAs to control the activation of other subtypes of astrocytes. Finally, we showed that the loss of HIPAs caused by Gal3 KO was associated with attenuated neuronal degeneration, neuroinflammation, and pain in gp120 transgenic mice. Collectively, our data suggest that HIPAs are a Gal3-expressing astrocytic subtype that mediates gp120-induced neurodegeneration and neuroinflammation in the spinal pain neural circuit during pain pathogenesis and is a potential cell target for treating HIV-associated pain.
Crosslinker Structure Modulates Bulk Mechanical Properties and Dictates hMSC Behavior on Hyaluronic Acid Hydrogels
Authors: Morton Logan D. , Castilla-Casadiego David A. , Palmer Ajay C. , Rosales Adrianne M. 
Published: August 2022

AbstractSynthetic hydrogels are attractive platforms due in part to their highly tunable mechanics, which impact cell behavior and secretory profile. These mechanics are often controlled by altering the number of crosslinks or the total polymer concentration in the gel, leading to structure-property relationships that inherently couple network connectivity to the overall modulus. In contrast, the native extracellular matrix (ECM) contains structured biopolymers that enable stiff gels even at low polymer content, facilitating 3D cell culture and permeability of soluble factors. To mimic the hierarchical order of natural ECM, this work describes a synthetic hydrogel system in which mechanics are tuned using the structure of sequence-defined peptoid crosslinkers, while fixing network connectivity. Peptoid crosslinkers with different secondary structures are investigated: 1) a helical, molecularly stiff peptoid, 2) a non-helical, less stiff peptoid, and 3) an unstructured, relatively flexible peptoid. Bulk hydrogel storage modulus increases when crosslinkers of higher chain stiffness are used. In-vitro studies assess the viability, proliferation, cell morphology, and immunomodulatory activity of human mesenchymal stem cells (hMSCs) on each hydrogel substrate. Matrix mechanics regulate the morphology of hMSCs on the developed substrates, and all of the hydrogels studied upregulate IDO production over culture on TCP. Softer substrates further this upregulation to a plateau. Overall, this system offers a biomimetic strategy for decoupling hydrogel storage modulus from network connectivity, enabling systematic study of biomaterial properties on hMSC behavior and enhancement of cellular functionality for therapeutic applications.Graphical Abstract
Genomics highlight an underestimation of the urban heat island effect on red oak phenology
Authors: Blumstein M. , Webster S. , Hopkins R. , Basler D. , Des Marais D. L 
Published: August 2022

AbstractThe phenological timing of leaf-out in temperate forests is a critical transition point each year, altering the global climate system via changes to carbon and hydrologic cycles and land-surface albedo. In turn, climate is impacting phenology by advancing leaf-out an average of 2.8 +/-0.35 days per decade as the planet warms. Thus, understanding the relationship between warming and leaf-out is critical for understanding future global change. Rural-to-urban gradients in temperature, which result in clines over which urban areas are up to 4°C warmer than their surrounding countryside (dubbed the urban heat island – UHI – effect), may be used as a space-for-time substitution in studies of response to climate change. However, studies have recently highlighted that using the UHI effect over space rather than measurements at the same site through time results in consistently weaker relationships between temperature and leaf-out date in spring (i.e., urban-to-rural gradients underpredict the impact of warming on leaf-out). While such studies suggest many potential environmental explanations, the effect of genetic diversity is often neglected. While sensitive to environmental warming, leaf-out phenology is also highly heritable. Given that rural areas are largely natural sites, they likely have higher intraspecific genetic diversity than urban sites, where plants are selected by land managers for a narrow set of resilience traits. Here we measured the environment, genomic background, and phenological timing of northern red oak (Q. rubra) over several years between an urban and rural site to demonstrate how genetic background explains why the UHI effect leads to an underprediction of plant response to warming. Using a space-for-time substitution, we found that the date of leaf-out at our sites is predicted to advance approximately 20 days over the next 80 years. However, if we further account for the genomic background at the two sites, leaf-out, phenology is predicted to advance 22 days; a 10% difference between the two models. We demonstrate that this stronger relationship is because urban trees are largely a monoculture and, moreover, are most closely related to individuals at the rural site that leaf out latest. We highlight the critical need to consider genetic background, particularly in studies examining highly heritable traits, because both environmentandgenetics are changing across rural-to-urban gradients.