bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lifecycle dominates the volatilome character of the dimorphic fungusCoccidioidesspp
Authors: Keppler Emily A. Higgins , Mead Heather L. , Barker Bridget M. , Bean Heather D. 
Published: January 2021

ABSTRACTValley fever (coccidioidomycosis) is an endemic fungal pneumonia of the North and South American deserts. The causative agents of Valley fever are the dimorphic fungiCoccidioides immitisandC. posadasii, which grow as mycelia in the environment and spherules within the lungs of vulnerable hosts. The current diagnostics for Valley fever are severely lacking due to poor sensitivity and invasiveness, contributing to a 23-day median time-to-diagnosis, and therefore new diagnostic tools are needed. We are working toward the development of a breath-based diagnostic for coccidioidomycosis, and in this initial study we characterized the volatile metabolomes (or volatilomes) ofin vitrocultures ofCoccidioides. Using solid-phase microextraction and comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC–TOFMS), we characterized the VOCs produced by six strains of each species during mycelial or spherule growth. We detected a total of 353 VOCs that were at least two-fold more abundant in aCoccidioidesculture versus medium controls and found the volatile metabolome ofCoccidioidesis more dependent on growth phase (spherule versus mycelia) than on the species. The volatile profiles ofC. immitisandC. posadasiihave strong similarities, indicating that a single suite of Valley fever breath biomarkers can be developed to detect both species.IMPORTANCECoccidioidomycosis, or Valley fever, causes up to 30% of community-acquired pneumonias in endemic and highly populated areas of the US desert southwest. The infection is difficult to diagnose by standard serological and histopathological methods, which delays an appropriate treatment. Therefore, we are working toward the development of breath-based diagnostics for Valley fever. In this study, we characterized the volatile metabolomes of six strains each ofCoccidioides immitisandC. posadasii, the dimorphic fungal species that cause Valley fever. By analyzing the volatilomes during the two modes of growth for the fungus—mycelia and spherules—we observed that the lifecycle plays a significant role in the volatiles produced byCoccidioides. In contrast, we observed no significant differences in theC. immitisversusC. posadasiivolatilomes. These data suggest that lifecycle, rather than species, should guide the selection of putative biomarkers for a Valley fever breath test.
Compound FC-10696 Inhibits Egress and Spread of Marburg Virus
Authors: Han Ziying , Ye Hong , Liang Jingjing , Shepley-McTaggart Ariel , Wrobel Jay E. , Reitz Allen B. , Whigham Alison , Kavelish Katrina N. , Saporito Michael S. , Freedman Bruce D. , Shtanko Olena , Harty Ronald N. 
Published: January 2021

AbstractMarburg virus (MARV) VP40 protein (mVP40) directs egress and spread of MARV, in part, by recruiting specific host WW-domain containing proteins via its conserved PPxY Late (L) domain motif to facilitate efficient virus-cell separation. We reported previously that small molecule compounds targeting the viral PPxY/host WW-domain interaction inhibited VP40-mediated egress and spread. Here, we report on the antiviral potency of novel compound FC-10696, which emerged from extensive structure activity relationship (SAR) of a previously described series of PPxY inhibitors. We show that FC-10696 inhibits egress of both mVP40 VLPs and egress and spread of authentic MARV from HeLa cells and primary human macrophages. Moreover, FC-10696 treated mice displayed delayed onset of weight loss, clinical signs, and significantly lower viral loads compared to controls, with 14% of animals surviving 21 days following a lethal MARV challenge. Thus, FC-10696 represents a first-in-class, host-oriented inhibitor effectively targeting late stages of the MARV lifecycle.
Cognitive boundary signals in the human medial temporal lobe shape episodic memory representation
Authors: Zheng Jie , Gómez Palacio Schjetnan Andrea , Yebra Mar , Mosher Clayton , Kalia Suneil , Valiante Taufik A. , Mamelak Adam N. , Kreiman Gabriel , Rutishauser Ueli 
Published: January 2021

AbstractWhile experience unfolds continuously, memories are organized as a set of discrete events that bind together the “where”, “when”, and “what” of episodic memory. This segmentation of continuous experience is thought to be facilitated by the detection of salient environmental or cognitive events. However, the underlying neural mechanisms and how such segmentation shapes episodic memory representations remain unclear. We recorded from single neurons in the human medial temporal lobe while subjects watched videos with different types of embedded boundaries and were subsequently evaluated for memories of the video contents. Here we show neurons that signal the presence of cognitive boundaries between subevents from the same episode and neurons that detect the abstract separation between different episodes. The firing rate and spike timing of these boundary-responsive neurons were predictive of later memory retrieval accuracy. At the population level, abrupt neural state changes following boundaries predicted enhanced memory strength but impaired order memory, capturing the behavioral tradeoff subjects exhibited when recalling episodic content versus temporal order. Successful retrieval was associated with reinstatement of the neural state present following boundaries, indicating that boundaries structure memory search. These findings reveal a neuronal substrate for detecting cognitive boundaries and show that cognitive boundary signals facilitate the mnemonic organization of continuous experience as a set of discrete episodic events.
Salt Inducible Kinase activation and IRE1-dependent intracellular ATP depletion to form Sec bodies in Drosophila cells
Authors: Zhang Chujun , van Leeuwen Wessel , Blotenburg Marloes , Aguilera-Gomez Angelica , Brussee Sem , Grond Rianne , Kampinga Harm H. , Rabouille Catherine 
Published: January 2021

AbstractThe phase separation of the non-membrane bound Sec bodies occurs in Drosophila S2 cells by coalescence of components of the ER exit sites under the stress of amino-acid starvation. Here we address which signaling pathways cause Sec body formation. We find that two pathways are critical. The first is a SIK dependent pathway induced by salt (NaCl) stress in a necessary and sufficient manner. The second is the activation of IRE1 (one of the key kinases mediating the Unfolded Protein Response) by absence of amino- acids, which partly leads to the depletion of intracellular ATP. However, IRE1 activation is not sufficient to induce Sec body formation and needs to be combined to salt stress. This works pioneers the role of SIK in phase transition and re-enforces the role of IRE1 as a metabolic sensor for the level of circulating amino-acids.
An early-morning flowering trait in rice helps retain grain yield under heat stress field conditions at flowering stage
Authors: Ishimaru Tsutomu , Hlaing Khin Thandar , Oo Ye Min , Lwin Tin Mg , Sasaki Kazuhiro , Lumanglas Patrick D. , Simon Eliza-Vie M. , Myint Tin Tin , Hairmansis Aris , Susanto Untung , Ayyenar Bharathi , Muthurajan Raveendran , Hirabayashi Hideyuki , Fukuta Yoshimichi , Kobayasi Kazuhiro , Matsui Tsutomu , Yoshimoto Mayumi , Htun Than Myint 
Published: January 2021

AbstractEarly-morning flowering (EMF) trait is supposed to be effective in retaining grain yield due to mitigation of heat-induced spikelet sterility at flowering in rice. This study evaluated (i) phenotypic differences between a near-isogenic line carrying a QTL for EMF trait, designated as IR64+qEMF3, and a recurrent parent, IR64, under wide variation in climates and (ii) whether an EMF trait can retain grain yield under heat stress at flowering. IR64+qEMF3had significant earlier flower opening time (FOT) in diverse environmental conditions including temperate, subtropical, and tropical regions. Under normal temperatures at flowering, IR64+qEMF3had similar grain yield to IR64 with some significant changes in agronomic traits and yield components. Field trials in heat-vulnerable regions of central Myanmar for seven crop seasons showed that higher percentage of filled grains contributed to the significantly higher grain yield in IR64+qEMF3among yield components when plants were exposed to daily maximum air temperatures around 36.5 °C or higher. Lower spikelet sterility in IR64+qEMF3was attributed to the earlier FOT during cooler early morning hours. This is the first field study that clearly demonstrates the advantage of the EMF trait for retaining grain yield by stabilizing percentage of fertile grains under heat stress at flowering.
A conserved role of Parkinson-associated DJ-1 metabolites in sperm motility, mitosis, and embryonic development
Authors: Bour Susanne , Dening Yanina , Balbach Melanie , Poser Ina , Álvarez Inés Ramírez , den Haan Helena , Kluge Christoph , Naumann Ronald , Oertel Reinhard , Alba-Alejandre Irene , Accardi Davide , Stief Christian G. , Dieterich Marianne , Falkai Peter , Böckmann Rainer A. , Pérez-Sánchez Horacio , Hyman Anthony A. , Trottmann Matthias , Pan-Montojo Francisco 
Published: January 2021

AbstractFertility rates in the developing world have dramatically dropped in the last decades. This drop is likely due to a decline in sperm quality and women having children at older ages. Loss of function mutations inDJ-1, a Parkinson’s associated gene, are linked to alterations in multiple cellular processes such as mitochondrial activity, ROS production or sperm motility and lead to an early onset of Parkinson’s disease and male infertility in humans and other species. Glycolate (GA) and D-lactate (DL), products ofDJ-1glyoxalase activity, sustain mitochondrial function and protect against environmental aggressions. We, therefore, tested whether these substances could also have a rescue effect on these phenotypes. Here, we show thatDJ-1loss of function not only affects sperm motility but also leads to defects in mitosis and an age-dependent increase in the abortion rate. Remarkably, whereas DL was only able to rescue embryonic lethality inC. elegans, GA rescued these phenotypes in all model systems tested and even increased sperm motility in wild-type sperm. These positive effects seem to be mediated through an increase in NAD(P)H production and the regulation of intracellular calcium. These findings not only strongly suggest GA as a new therapeutic candidate to improve male and female fertility but also show its potential to treat diseases associated with a decline in mitochondrial function or to improve mitochondrial function in aging.
Conditional deletion of HIF-1α provides new insight regarding the murine response to gastrointestinal infection withSalmonellaTyphimurium
Authors: Robrahn Laura , Dupont Aline , Jumpertz Sandra , Zhang Kaiyi , Holland Christian H. , Guillaume Joël , Rappold Sabrina , Cerovic Vuk , Saez-Rodriguez Julio , Hornef Mathias W. , Cramer Thorsten 
Published: January 2021

AbstractThe hypoxia-inducible transcription factor 1 (HIF-1) has been shown to ameliorate different bacterial infections through enhancement of microbial killing. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the intestine remains largely elusive. With the help of a publicly available gene expression data set, we could infer significant activation of the HIF-1 transcription factor after oral infection of mice withSalmonellaTyphimurium. This prompted us to apply lineage-restricted deletion of theHif1alocus in mice to examine cell type-specific functions of HIF-1 in this model. We show hypoxia-independent induction of HIF-1 activity uponSalmonellainfection in the intestinal epithelium as well as in macrophages. Surprisingly,Hif1adeletion in intestinal epithelial cells impacted neither disease outcome nor inflammatory activity. The conditional knockout ofHif1ain myeloid cells enhanced the mRNA expression of the largely pro-inflammatory chemokineCxcl2, revealing a potentially inflammatory effect of HIF-1 deficiency in myeloid cells in the gutin vivo. Again, the disease outcome was not affected.In vitroHIF-1-deficient macrophages showed an overall impaired transcription of pro-inflammatory factors, however,Salmonellabypassed direct intracellular, bactericidal HIF-1-dependent mechanisms in aSalmonellapathogenicity island (SPI)-2 independent manner. Taken together, our data suggest that HIF-1 in intestinal epithelial and myeloid cells is either dispensable or compensable in the immune defense againstSalmonellaTyphimurium.
Conditions under which distributions of edge length ratios on phylogenetic trees can be used to order evolutionary events
Authors: Susko Edward , Steel Mike , Roger Andrew J. 
Published: January 2021

AbstractTwo recent high profile studies have attempted to use edge (branch) length ratios from large sets of phylogenetic trees to determine the relative ages of genes of different origins in the evolution of eukaryotic cells. This approach can be straightforwardly justified if substitution rates are constant over the tree for a given protein. However, such strict molecular clock assumptions are not expected to hold on the billion-year timescale. Here we propose an alternative set of conditions under which comparisons of edge length distributions from multiple sets of phylogenies of proteins with different origins can be validly used to discern the order of their origins. We also point out scenarios where these conditions are not expected to hold and caution is warranted.
Nucleus-accumbens dopamine tracks aversive-stimulus duration and prediction but not value or prediction error
Authors: Goedhoop J.N. , van den Boom B.J.G. , Fellinger L. , Arbab T. , Willuhn I. 
Published: January 2021

ABSTRACTThere is active debate on the role of dopamine in processing aversive stimuli, where inferred roles range from no involvement at all, to signaling an aversive-prediction error (APE). Here, we systematically investigate dopamine release in the nucleus-accumbens core (NAC), which is closely linked to reward-prediction errors, in rats exposed to white noise (WN, a versatile, underutilized, aversive stimulus) and its predictive cues. Both induced a negative dopamine ramp, followed by slow signal recovery upon stimulus cessation. In contrast to reward conditioning, this dopamine signal was unaffected by WN value, context valence, or probabilistic contingencies, and the WN dopamine-response shifted only partially towards its predictive cue. However, unpredicted WN provoked slower post-stimulus signal recovery than predicted WN. Despite differing signal qualities, dopamine responses to simultaneous presentation of rewarding and aversive stimuli were additive. Together, our findings demonstrate that instead of an APE, NAC dopamine primarily tracks prediction and duration of aversive events.
Random sub-diffusion and capture of genes by the nuclear pore reduces dynamics and coordinates interchromosomal movement
Authors: Sumner Michael Chas , Torrisi Steven B. , Brickner Donna Garvey , Brickner Jason H. 
Published: January 2021

ABSTRACTHundreds of genes interact with the yeast nuclear pore complex (NPC), localizing at the nuclear periphery and clustering with co-regulated genes. Dynamic tracking of peripheral genes shows that they cycle on and off the NPC and that interaction with the NPC slows their sub-diffusive movement. Furthermore, NPC-dependent inter-chromosomal clustering leads to coordinated movement of pairs of loci separated by hundreds of nanometers. We developed Fractional Brownian Motion simulations for chromosomal loci in the nucleoplasm and interacting with NPCs. These simulations predict the rate and nature of random sub-diffusion during repositioning from nucleoplasm to periphery and match measurements from two different experimental models, arguing that recruitment to the nuclear periphery is due to random subdiffusion, collision, and capture by NPCs. Finally, the simulations do not lead to inter-chromosomal clustering or coordinated movement, suggesting that interaction with the NPC is necessary, but not sufficient, to cause clustering.
A sexual dimorphic role of themiR-465cluster in placental development
Authors: Wang Zhuqing , Meng Nan , Wang Yue , Zhou Tong , Li Musheng , Wang Shawn , Chen Sheng , Zheng Huili , Kong Shuangbo , Wang Haibin , Yan Wei 
Published: January 2021

AbstractA sexually dimorphic role of miRNAs in placental development has never been reported. Here, we show that ablation of themiR-465cluster caused selective degeneration of female conceptuses as early as embryonic day (E)8.5, leading to a male-biased sex ratio (60% males) amongmiR-465KO mice. Given that themiR-465cluster miRNAs were predominantly expressed in the extraembryonic tissue and ablation of these miRNAs led to dysregulation of numerous critical placental genes, our data strongly suggest themiR-465cluster is required for full developmental potential of the female, but not the male, extraembryonic tissue/placenta.
T cell self-reactivity during thymic development dictates the timing of positive selection
Authors: Lutes Lydia K. , Steier Zoë , McIntyre Laura L. , Pandey Shraddha , Kaminski James , Hoover Ashley R. , Ariotti Silvia , Streets Aaron , Yosef Nir , Robey Ellen A. 
Published: January 2021

AbstractFunctional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced TCR sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity down-regulate TCR sensitivity more slowly during positive selection, and suggest that modulation of membrane ion channel function may play a role in regulating TCR tuning throughout development.Impact StatementDeveloping T cells whose TCRs have relatively low reactivity experience very brief TCR signaling events, delayed positive selection, and do not fully down regulate their TCR sensitivity as they mature.
Impact of Immediate and Preferential Relaxation of Social and Travel Restrictions for Vaccinated People on the Spreading Dynamics of COVID-19 : a Model-Based Analysis
Authors: Shayak B , Sharma Mohit M , Mishra Anand K 
Published: January 2021

AbstractBackgroundFour COVID-19 vaccine candidates developed by Pfizer, Moderna, University of Oxford/ Astra Zeneca (also Oxford/ Serum Institute of India) and ICMR/ Bharat Biotech have been granted emergency use authorization in the democratic world following established clinical trial procedures in their respective countries. Vaccination of the general public is expected to begin in several weeks. We consider the question of whether people who have received the vaccine can be selectively and immediately cleared to return to normal activities, including hassle-free travel.MethodsWe use a delay differential equation model developed previously by our group to calculate the effects of vaccinee “immunity passports” on the spreading trajectories of the disease. We consider default virus strains as well as high-transmissibility variants such as B1.1.7 in our analysis.ResultsWe find that with high vaccine efficacy of 80 percent or greater, vaccinees may be immediately cleared for normal life with no significant increase in case counts. Free travel of such vaccinees between two regions should not jeopardize the infection control performance of either. At current vaccine administration rates, it may be eight months or more before COVID-19 transmission is significantly reduced or eliminated. With lower vaccine efficacy of approximately 60 percent however, social as well as travel restrictions for vaccinees may need to remain in place until transmission of the disease is eliminated.ConclusionsDesigning high-efficacy vaccines with easily scalable manufacturing and distribution capacity should remain on the priority list in academic as well as industrial circles. Performance of all vaccines should continue to be monitored in real time during vaccination drive with a view to analysing socio-demographic determinants if any of efficacy, and optimizing distribution accordingly. A speedy and efficacious vaccination drive will provide the smoothest path out of the pandemic with the least additional caseloads, death toll and socioeconomic cost.
Changes in healthcare workers’ knowledge, attitudes, practices, and stress during the COVID-19 pandemic
Authors: Temsah Mohamad-Hani , Al Huzaimi Abdullah , Alrabiaah Abdulkarim , Alamro Nurah , Al-Sohime Fahad , Al-Eyadhy Ayman , Alhasan Khalid , Kari Jameela A , Alhaboob Ali , Salmi Amro Al , AlMuhanna Wejdan , Almaghlouth Ibrahim , Aljamaan Fadi , Halwani Rabih , Barry Mazin , Al-Zamil Fahad , Al-Hadi Ahmad , Al-Subaie Sarah , Jamal Amr , Somily Ali Mohammed 
Published: January 2021

AbstractIntroductionCoronavirus disease 2019 (COVID-19) has caused an unprecedented health crisis around the world, not least because of its heterogeneous clinical presentation and course. The new information on the pandemic emerging daily has made it challenging for healthcare workers (HCWs) to stay current with the latest knowledge, which could influence their attitudes and practices during patient care.MethodsThis study is a follow-up evaluation of changes in HCWs’ knowledge, attitudes, and practices as well as anxiety levels regarding COVID-19 since the beginning of the pandemic. Data were collected through an anonymous, predesigned, self-administered questionnaire that was sent online to HCWs in Saudi Arabia.ResultsThe questionnaire was sent to 1500 HCWs, with a 63.8% response rate (N=957). The majority of respondents were female (83%), and the most common age group was 31–40 years (52.2%). Nurses constituted 86.3% of the respondents. HCWs reported higher anxiety during the COVID-19 pandemic which increased from 4.91±2.84 to 8.6±2.27 on an 11-point Likert scale compared to other viral outbreaks. HCWs believed that their own preparedness as well as that of their hospital’s intensive care unit (ICU) or emergency room (ER) was higher during the COVID-19 pandemic than during the Middle East respiratory syndrome coronavirus pandemic (2012–2015). About 58% of HCWs attended one or more simulations concerning the management of COVID-19 patients in their ICU/ER, and nearly all had undergone N95 mask fit testing. The mean score of HCWs’ knowledge of COVID-19 was 9.89/12. For most respondents (94.6%), the perception of being at increased risk of infection was the main cause of anxiety related to COVID-19; the mean score of anxiety over COVID-19 increased from 4.91±2.84 before to 8.6±2.27 during the pandemic in Saudi Arabia.ConclusionsHCWs’ anxiety levels regarding COVID-19 have increased since a pandemic was declared. It is vital that healthcare facilities provide more emotional and psychological support for all HCWs.