bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell RNA Sequencing of Pediatric Ependymoma Unravels Subclonal Heterogeneity Associated with Patient Survival
Authors: Wu Haoda , Fu Ruiqing , Zhang Yu-Hong , Liu Zhiming , Chen Zhenhua , Xu Jingkai , Tian Yongji , Jin Wenfei , Wong Samuel Zheng Hao , Wu Qing-Feng 
Published: March 2022

AbstractEpendymoma (EPN) is a malignant glial tumor occurring throughout central nervous system which commonly presents in children. Although recent studies have characterized EPN samples at both the bulk and single-cell level, intra-tumoral heterogeneity across subclones remains a confounding factor which impedes understanding of EPN biology. In this study, we generated a high-resolution single-cell dataset of pediatric ependymoma with a particular focus on the comparison of subclone differences within tumors, and show upregulation of cilium-associated genes in more highly differentiated subclone populations. As a proxy to traditional pseudotime analysis, we applied a novel trajectory scoring method to reveal cellular compositions associated with poor survival outcomes across primary and relapsed patients. Furthermore, we identified putative cell-cell communication features between relapsed and primary samples and show upregulation of pathways associated with immune cell crosstalk. Our results reveal both inter- and intratumoral gene expression profiles and tumor differentiation and provide a framework for studying transcriptomic signatures of individual subclones in ependymoma at single-cell resolution.
Tissue-specific landscape of protein aggregation and quality control in an aging vertebrate
Authors: Chen Yiwen R. , Harel Itamar , Singh Param Priya , Ziv Inbal , Moses Eitan , Goshtchevsky Uri , Machado Ben E. , Brunet Anne , Jarosz Daniel F. 
Published: March 2022

SUMMARYProtein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate. Age-dependent aggregation is strikingly tissue-specific, and not simply driven by protein expression differences. Experimental interrogation, combined with machine learning, indicates that this specificity is linked to both protein-autonomous biophysical features and tissue-selective alterations in protein quality control. Co-aggregation of protein quality control machinery during aging may further reduce proteostasis capacity, exacerbating aggregate burden. A segmental progeria model with accelerated aging in specific tissues exhibits selectively increased aggregation in these same tissues. Intriguingly, many age-related protein aggregates arise in wild-type proteins that, when mutated, drive human diseases. Our data chart a comprehensive landscape of protein aggregation during aging and reveal strong, tissue-specific associations with dysfunction and disease.HIGHLIGHTSTissue-specific protein aggregation is prevalent during vertebrate agingBoth protein biophysical properties and tissue-specific protein homeostasis patterns impact aggregationA segmental progeria model with accelerated aging exhibits selectively increased protein aggregation in affected tissuesMany aggregates that accumulate during physiological aging are linked to disease
In utero delivery of miRNA induces epigenetic alterations and corrects pulmonary pathology in congenital diaphragmatic hernia
Authors: Ullrich Sarah J , Yung Nicholas K , Bauer-Pisani Tory J , Maassel Nathan L , Guerra Mary Elizabeth , Freedman-Weiss Mollie , Ahle Samantha L , Ricciardi Adele S , Sauler Maor , Saltzman W Mark , Piotrowski-Daspit Alexandra S , Stitelman David H. 
Published: March 2022

AbstractStructural fetal diseases, such as congenital diaphragmatic hernia (CDH) can be diagnosed prenatally. Neonates with CDH are healthy in utero as gas exchange is managed by the placenta, but impaired lung function results in critical illness from the time a baby takes its first breath. During fetal development, lungs are capable of remarkable growth and the fetus does not yet require lung function for gas exchange. MicroRNA (miR) 200b and its downstream targets in the TGFβ pathway are critically involved lung branching morphogenesis. Here we characterize the expression of miR200b and the TGFβ pathway at different gestational times using a rat model of CDH. Fetal rats with CDH are deficient in miR200b at gestational day 18. We demonstrate that NPs loaded with miR200b given systemically to fetal rats result in changes in the TGFβ pathway; these epigenetic changes improve lung size, lung morphology, and lung vascularization. This is the first demonstration of in utero epigenetic therapy to improve lung growth and development in a pre-clinical model. With refinement, this technique could be applied to fetal cases of CDH or other forms of impaired lung development in a minimally invasive fashion.eTOC SynopsisIn utero treatment with NPs loaded with miR200b improves lung development in a rat model of CDH. miR200b treatment epigenetic changes in the TGFβ, leads to larger lungs with more airspace and favorable pulmonary vascular remodeling.
Traditional treatment of HIV and the role of family members as barriers to access to HIV care service or antiretroviral therapy among people living with HIV
Authors: Fauk Nelsensius Klau , Mwanri Lillian , Hawke Karen , Ward Paul Russell 
Published: March 2022

AbstractAccess to HIV care service or antiretroviral therapy (ART) is essential for the improvement of health outcomes of people living with HIV (PLHIV) and in reducing HIV transmission and HIV-related deaths. As a part of a qualitative study in Belu, this paper describes the use of traditional treatment and the role of families in determining traditional treatment for their HIV-positive family member as barriers to access to HIV care service or ART among PLHIV. One-on-one in-depth interviews were employed to collect data from 46 PLHIV (26 women and 20 men) and 10 healthcare professionals recruited using the snowball sampling technique. Data analysis was performed using NVivo 12 software and guided by a qualitative data analysis framework. The findings showed that the use of traditional treatment, a well-known cultural practice in Belu, was a barrier to access to HIV care service or ART among PLHIV. The role of family in determining traditional treatment for HIV, supported by the lack of knowledge of ART, effectiveness of traditional medicines in treating other health issues, and social influence of families, neighbours and friends, were also significant barriers to PLHIV’s access to HIV care service or ART. The findings indicate the need for dissemination of HIV care-related information for PLHIV, family and community members to increase their knowledge on the service, ART and its function, and to support and improve access to ART by PLHIV.
A compartmental Mathematical model of COVID-19 intervention scenarios for Mumbai
Authors: Singh Avaneesh , Bajpai Manish Kumar 
Published: March 2022

AbstractA new mathematical method with an outstanding potential to predict the incidence of COVID-19 diseases has been proposed. The model proposed is an improvement to the SEIR model. In order to improve the basic understanding of disease spread and outcomes, four compartments included presymptomatic, asymptomatic, quarantine hospitalized and hospitalized. We have studied COVID-19 cases in the city of Mumbai. We first gather clinical details and fit it on death cases using the Lavenberg-Marquardt model to approximate the various parameters. The model uses logistic regression to calculate the basic reproduction number over time and the case fatality rate based on the age-category scenario of the city of Mumbai. Two types of case fatality rate are calculated by the model: one is CFR daily, and the other is total CFR. The total case fatality rate is 4.2, which is almost the same as the actual scenario. The proposed model predicts the approximate time when the disease is at its worst and the approximate time when death cases barely arise and determines how many hospital beds in the peak days of infection would be expected. The proposed model outperforms the classic ARX, SARIMAX and the ARIMA model. And It also outperforms the deep learning models LSTM and Seq2Seq model. To validate results, RMSE, MAPE and R squared matrices are used and are represented using Taylor diagrams graphically.
Delirium due to hip fracture is associated with activated immune-inflammatory pathways and a reduction in negative immunoregulatory mechanisms
Authors: Thisayakorn Paul , Thipakorn Yanin , Tantavisut Saran , Sirivichayakul Sunee , Maes Michael 
Published: March 2022

AbstractThe objectives of this study were to delineate whether delirium is associated with activation of the immune-inflammatory response system (IRS) as indicated by activation of M1, Thelper (Th)1, and Th17 profiles, and/or by reduced activities of the compensatory immunoregulatory system (CIRS), including Th2 and Tregulatory profiles. We recruited 65 elderly patients with a low energy impact hip fracture who underwent hip fracture operation. The CAM-ICU and the Delirium Rating Scale, Revised-98-Thai version (DRS-R-98) were assessed pre-operatively and 1, 2 and 3 days after surgery. Blood samples (day 1 and 2) post-surgery were assayed for cytokines/chemokines using a MultiPlex assay and the neutrophil/lymphocyte ratio. We found that delirium and/or the DRS-R-98 score were associated with IRS activation as indicated by activated M1, Th1, Th17 and T cell growth profiles and by attenuated CIRS functions. The most important IRS biomarkers were CXCL8, interleukin (IL)-6, and tumor necrosis factor-α, and the most important CIRS biomarkers were IL-4 and soluble IL-1 receptor antagonist. We found that 42.5% of the variance in the actual changes in the DRS-R-98 score (averaged from day 1 to day 3) was explained by T cell growth factors, baseline DRS-R-98 scores and age. The pain scores during delirium were significantly and positively associated with CXCL8 and CCL3 and negatively with IL-4 and sIL-1RA. An increase in the NLR reflects overall IRS, M1, Th1, Th17, and Th2 activation. In conclusion, post-hip surgery delirium is associated with activated IRS pathways and appears especially in patients with lowered CIRS functions.
The CTP-binding domain is disengaged from the DNA-binding domain in a co-crystal structure of Bacillus subtilis Noc-DNA complex
Authors: Sukhoverkov Kirill V. , Jalal Adam S. B. , Lawson David M. , Le Tung B. K. 
Published: March 2022

ABSTRACTIn Bacillus subtilis, a ParB-like nucleoid occlusion protein (Noc) binds specifically to Noc-binding sites (NBS) around the chromosome to help coordinate chromosome segregation and cell division. Noc does so by binding to cytidine triphosphate (CTP) to form large membrane-associated nucleoprotein complexes to physically inhibit the assembly of the cell division machinery. The site-specific binding of Noc to NBS DNA is a prerequisite for CTP-binding and the subsequent formation of a membrane-active DNA-entrapped protein complex. Here, we solve the structure of a truncated B. subtilis Noc bound to NBS DNA to reveal the conformation of Noc at this crucial step. Our structure reveals the disengagement between the N-terminal CTP-binding domain and the NBS-binding domain of each DNA-bound Noc subunit, this is driven, in part, by the swapping of helices 4 and 5 at the interface of the two domains. Site-specific crosslinking data suggest that this conformation of Noc-NBS exists in solution. Overall, our results lend support to the recent proposal that parS/NBS-binding catalyzes CTP-binding and DNA-entrapment by preventing the re-engagement of the NTD and DBD from the same ParB/Noc subunit.
Separability of Human Motor Memories during Reaching Adaptation with Force Cues
Authors: Crevecoeur F. , Mathew J. , Lefèvre P 
Published: March 2022

AbstractJudging by the breadth of our motor repertoire during daily activities, it is clear that acquiring multiple motor skills is a hallmark of the human motor system. However, for reaching movements the different planning conditions under which this is possible in laboratory settings have remained a challenging question. Considering the sensitivity of limb afferent feedback relative to externally applied forces, we hypothesised that independent cues delivered by means of background loads could support simultaneous formation of different motor memories of various velocity-dependent force fields. We demonstrate in a series of experiments that indeed healthy adults can form internal priors about opposite force fields, independently of the direction of the background force cue. However, when the cue and force field were only related by their magnitude, a separation was still observed but the associated mechanism was subject to interference. Finally, we highlight that this paradigm allows dissociating trial-by-trial acquisition of internal representations from within-trial feedback adaptation, as these two adaptation mechanisms are associated with different time scales that can be measured reliably.Significance StatementThe conditions under which humans can adapt to different contexts in parallel remain the subject of active debates. Mounting evidence highlights that contextual factors linked to movement planning are necessary to form different motor memories. Here we show that background forces indicative of the direction of a force field could play the role of contextual factors, and enable dual adaptation to different force fields. However, we uncovered that when the cue and the force field were in the same direction but of different magnitudes, the motor memories were still distinct but subject to interference. We further show that different timescales of adaptation observed can be explained by offline and online mechanisms in a model of reaching adaptation and control.
A single episode of CMV reactivation initiates long-term expansion and differentiation of the NK cell repertoire
Authors: Hassan Norfarazieda , Eldershaw Suzy , Stephens Christine , Kinsella Francesca , Craddock Charles , Malladi Ram , Zuo Jianmin , Moss Paul 
Published: March 2022

AbstractNK cells play an important role in suppression of viral replication and are critical for effective control of persistent infections such as herpesviruses. Cytomegalovirus infection is associated with expansion of ‘adaptive-memory’ NK cells with a characteristic CD16brightCD56dimNKG2C+ phenotype but the mechanisms by which this population is maintained remain uncertain. We studied NK cell reconstitution in patients undergoing haemopoietic stem cell transplantation and related this to CMV reactivation. NK cells expanded in the early post-transplant period but then remained stable in the absence of viral reactivation. However, a single episode of CMV reactivation led to a rapid and sustained 10-fold increase in NK cell number. NKG2C expression was increased on all NK subsets although the kinetics of expansion peaked at 6 months on immature CD56brightcells whilst continuing to rise on the mature CD56dimpool. Phenotypic maturation was observed by acquisition of CD57 and KIR expression. Transplantation from CMV-seropositive donors was associated with more rapid NK expansion and superior control of viral reactivation. Effective control of viral reactivation was seen when the peripheral NK cell count reached 20,000/ml. These data show that a single episode of CMV reactivation acts to reprogramme hemopoiesis to drive a sustained modulation and expansion of the NK cell pool and reveal further insight into long term regulation of the innate immune repertoire by infectious challenge.Author Summaryim to highlight where your work fits within a broader context; present the significance or possible implications of your work simply and objectively; and avoid the use of acronyms and complex terminology wherever possible. The goal is to make your findings accessible to a wide audience that includes both scientists and non-scientistsInnate immune cells respond rapidly to infectious challenge and it has previously been thought that they were unable to ‘learn’ from specific infecitons but provided only short term control. However, in recent years it has become apparent that some subsets of innate cells, termed adaptive natural killer (NK) cells, are permanently increased in people who have become infected with cytomegalovirus. The mechanism by which this is maintained is not known. We studied the kinetics of adaptive NK cell expansion in patients who had recently undergone stem cell (bone marrow) transplantation as CMV very often ‘reactivates’ in this setting and allows study of how this affects the immune system. We find that one short term episode of viral replication led to a large and prolonged expansion of adaptive NK cells. Indeed, their levls increasd 11-fold over 10 months.
In-vivo phase-dependent enhancement and suppression of brain oscillations by transcranial alternating current stimulation (tACS)
Authors: Haslacher David , Narang Asmita , Cavallo Alessia , Nasr Khaled , Santarnecchi Emiliano , Soekadar Surjo R. 
Published: March 2022

AbstractTranscranial alternating current stimulation (tACS) can influence human perception and behavior, with recent evidence also suggesting its potential impact in clinical settings, but the underlying mechanisms are poorly understood. Behavioral and indirect physiological evidence indicates that phase-dependent constructive and destructive interference between the tACS electric field and ongoing brain oscillations may play an important role, but direct in-vivo validation was infeasible because stimulation artifacts impeded such assessment. Using stimulation artifact source separation (SASS), a real-time compatible artifact suppression approach, we overcame this limitation and provide direct evidence for millisecond-by-millisecond phase-dependent enhancement and suppression of ongoing brain oscillations during amplitude-modulated tACS (AM-tACS) across 29 healthy human volunteers. We found that AM-tACS enhanced and suppressed targeted brain oscillations by 11.7 ± 5.14% and 10.1 ± 4.07% respectively. Millisecond-precise modulation of oscillations predicted modulation of behavior (r = 0.65, p < 0.001). These results not only provide direct evidence for constructive and destructive interference as a key mechanism of AM-tACS but suggest superiority of phase-locked (closed-loop) AM-tACS over conventional (open-loop) AM-tACS to purposefully enhance or suppress brain oscillations.SignificanceThe presented data provide direct evidence for a key mechanism underlying neurophysiological and behavioral effects of transcranial alternating current stimulation (tACS), a broadly used neuromodulation approach that yields promising clinical results but also raised controversies because of its variable effects. Our findings not only elucidate the underlying mechanisms of tACS, but also provide the rationale for closed-loop tACS protocols that will enable targeted enhancement and suppression of brain oscillations related to various brain functions such perception, memory or cognition. Towards this end, we introduce the technical prerequisites to establish millisecond-to-millisecond precise closed-loop tACS protocols that will be important to advance tACS as a neuroscientific and clinical tool, for example in the treatment of neuropsychiatric disorders.
The extracellular matrix fibulin 7 maintains epidermal stem cell heterogeneity during skin aging
Authors: Raja Erna , Changarathil Gopakumar , Oinam Lalhaba , Ngo Yen Xuan , Tsunezumi Jun , Ishii Ryutaro , Sasaki Takako , Imanaka-Yoshida Kyoko , Yanagisawa Hiromi , Sada Aiko 
Published: March 2022

AbstractTissue stem cells divide infrequently as a protective mechanism against internal and external stresses associated with aging. Here, we demonstrate that slow- and fast-cycling interfollicular epidermal stem cells in mouse skin undergo distinct aging processes. Two years of lineage tracing reveals that Dlx1+ slow-cycling clones expanded into the fast-cycling stem cell territory, while the number of Slc1a3+ fast-cycling clones gradually declined. Transcriptome analysis further indicated that the molecular properties of each stem cell population are altered with age. Mice lacking fibulin 7, an extracellular matrix (ECM), show early impairments resembling epidermal stem cell aging, such as the loss of fast-cycling clones, delayed wound healing, and increased expression of inflammation- and differentiation-related genes. Fibulin 7 interacts with structural ECM and matricellular proteins, and the overexpression of fibulin 7 in primary keratinocytes results in slower proliferation in the absence or presence of inflammatory cytokine IL-6. Thus, these results suggest that fibulin 7 plays a crucial role in maintaining tissue resilience and epidermal stem cell heterogeneity during skin aging.
HIF-1α induces glycolytic reprogramming in tissue-resident alveolar macrophages to promote survival during acute lung injury
Authors: Woods Parker S. , Kimmig Lucas M. , Sun Kaitlyn A. , Meliton Angelo Y. , Shamaa Obada R. , Tian Yufeng , Cetin-Atalay Rengül , Sharp Willard W. , Hamanaka Robert B. , Mutlu Gökhan M. 
Published: March 2022

ABSTRACTCellular metabolism is a critical regulator of macrophage effector function. Tissue-resident alveolar macrophages (TR-AMs) inhabit a unique niche marked by high oxygen and low glucose. We have recently shown that in contrast to bone marrow-derived macrophages (BMDMs), TR-AMs cannot utilize glycolysis and predominantly rely on mitochondrial function for their effector response. It is not known how changes in local oxygen concentration that occur during conditions such as acute respiratory distress syndrome (ARDS) might affect TR-AM metabolism and function; however, ARDS is associated with progressive loss of TR-AMs, which correlates with the severity of disease and mortality. Here, we demonstrate that hypoxia robustly stabilizes HIF-1α in TR-AMs to promote a glycolytic phenotype. Hypoxia altered TR-AM metabolite signatures, cytokine production, and decreased their sensitivity to the inhibition of mitochondrial function. By contrast, hypoxia had minimal effects on BMDM metabolism. The effects of hypoxia on TR-AMs were mimicked by FG-4592, a HIF-1α stabilizer. Treatment with FG-4592 decreased TR-AM death and attenuated acute lung injury in mice. These findings reveal the importance of microenvironment in determining macrophage metabolic phenotype, and highlight the therapeutic potential in targeting cellular metabolism to improve outcomes in diseases characterized by acute inflammation.