bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections
Authors: Heemskerk M. T. , Korbee C. J. , Esselink J. J. , dos Santos C. Carvalho , van Veen S. , Gordijn I. F. , Vrieling F. , Walburg K. V. , Engele C. G. , Dijkman K. , Wilson L. , Verreck F. A. W. , Ottenhoff T. H. M. , Haks M. C. 
Published: October 2021

AbstractThe persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.
Specialization of a mobile, apex predator affects trophic coupling among adjacent habitats
Authors: Cloyed Carl S. , Wilson Rachel M. , Balmer Brian C. , Hohn Aleta A. , Schwacke Lori H. , Zolman Eric S. , Tumlin Mandy C. , Wells Randall S. , Barleycorn Aaron A. , Allen Jason B. , Carmichael Ruth H. 
Published: October 2021

AbstractMobile, apex predators are commonly assumed to stabilize food webs through trophic coupling across spatially distinct habitats. The assumption that trophic coupling is common remains largely untested, despite evidence that individual behaviors might limit trophic coupling. We used stable isotope data from common bottlenose dolphins across the Gulf of Mexico to determine if these apex predators coupled estuarine and adjacent, nearshore marine habitats. δ13C values differed among the sites, likely driven by environmental factors that varied at each site, such as freshwater input and seagrass cover. Within most sites, δ13C values differed such that dolphins sampled in the upper reaches of embayments had values indicative of estuarine habitats while those sampled outside or in lower reaches of embayments had values indicative of marine habitats. δ15N values were more similar among and within sites than δ13C values. Data from multiple tissues within individuals corroborated that most dolphins consistently used a narrow range of habitats but fed at similar trophic levels in estuarine and marine habitats. Because these dolphins exhibited individual habitat specialization, they likely do not contribute to trophic coupling between estuarine and adjacent marine habitats at a regional scale, suggesting that not all mobile, apex predators trophically couple adjacent habitats.
Prediction of habitat suitability for Patrinia sibirica Juss. in the Southern Urals
Authors: Fedorov Nikolai , Kutueva Aliya , Muldashev Albert , Mikhaylenko Oksana , Martynenko Vasiliy , Fedorova Yulia 
Published: October 2021

AbstractThe paper presents the results of predictions of the habitat persistence for rare relict of the Pleistocene floristic complexPatrinia sibirica(L.) Juss. in the Southern Urals under various forecasted climate change scenarios. Climate variables from CHELSA BIOCLIM, elevation data (GMTED2010) and coarse fragment content in the top level of soil were used as predictors for modeling in the MaxEnt software. The impact of climate change onP. sibiricahabitats under the RCP4.5 and RCP8.5 scenarios calculated from an ensemble of four general circulation models has been analyzed. The modeling has shown that the changes in the habitat suitability depend on the altitude. Deterioration of the habitats could be attributed to a temperature increase in mountain forest locations, and to a precipitation of driest quarter increase in mountain forest-steppe locations. In both cases, this leads to the expansion of forest and shrub vegetation. Monitoring of the habitat persistence ofP. sibiricaand other relict species of the Pleistocene floristic complex can play a major role in predictions, as their massive decline would constitute that climatic changes exceed the ranges of their fluctuations in the Holocene.
Potential roles of 1,5-anhydro-d-fructose in modulating gut microbiome in mice
Authors: Ito Takashi , Totoki Takaaki , Takada Seiya , Otsuka Shotaro , Maruyama Ikuro 
Published: October 2021

AbstractThe gut microbiota has tremendous potential to affect the host’s health, in part by synthesizing vitamins and generating nutrients from food that is otherwise indigestible by the host. 1,5-Anhydro-d-fructose (1,5-AF) is a monosaccharide with a wide range of bioactive potentials, including anti-oxidant, anti-inflammatory, and anti-microbial effects. Based on its potential benefits and minimal toxicity, it is anticipated that 1,5-AF will be used as a dietary supplement to support general health. However, the effects of 1,5-AF on the gut microbiota are yet to be clarified. Here, using an unbiased metagenomic approach, we profiled the bacterial taxa and functional genes in the caecal microbiota of mice fed a diet containing either 2% 1,5-AF or a reference sweetener. Supplementation with 1,5-AF altered the composition of the gut microbiota, enriching the proportion of Faecalibacterium prausnitzii. 1,5-AF also altered the metabolomic profile of the gut microbiota, enriching genes associated with nicotinamide adenine dinucleotide biosynthesis. These findings support the potential benefits of 1,5-AF, but further studies are required to clarify the impact of 1,5-AF on health and disease.
Exceptional fossil assemblages confirm the existence of complex Early Triassic ecosystems during the early Spathian
Authors: Smith Christopher P. A. , Laville Thomas , Fara Emmanuel , Escarguel Gilles , Olivier Nicolas , Vennin Emmanuelle , Goudemand Nicolas , Bylund Kevin G. , Jenks James F. , Stephen Daniel A. , Hautmann Michael , Charbonnier Sylvain , Krumenacker L. J. , Brayard Arnaud 
Published: October 2021

AbstractThe mass extinction characterizing the Permian/Triassic boundary (PTB; ~ 252 Ma) corresponds to a major faunal shift between the Palaeozoic and the Modern evolutionary fauna. The temporal, spatial, environmental, and ecological dynamics of the associated biotic recovery remain highly debated, partly due to the scarce, or poorly-known, Early Triassic fossil record. Recently, an exceptionally complex ecosystem dated from immediately after the Smithian/Spathian boundary (~ 3 myr after the PTB) was reported: the Paris Biota (Idaho, USA). However, the spatiotemporal representativeness of this unique assemblage remained questionable as it was hitherto only reported from a single site. Here we describe three new exceptionally diverse assemblages of the same age as the Paris Biota, and a fourth younger one. They are located in Idaho and Nevada, and are taxonomic subsets of the Paris Biota. We show that the latter covered a region-wide area and persisted at least partially throughout the Spathian. The presence of a well-established marine fauna such as the Paris Biota, as soon as the early Spathian, indicates that the post-PTB biotic recovery and the installation of complex ecosystems probably took place earlier than often assumed, at least at a regional scale.
The variability of antennal sensilla in Naucoridae (Heteroptera: Nepomorpha)
Authors: Nowińska Agnieszka , Brożek Jolanta 
Published: October 2021

AbstractThe morphology and distribution of sensilla on the surface of the antennae of the naucorids’ species were studied via scanning electron microscopy. Eleven types of sensilla were identified regarding specific sensory modalities, based on their cuticular morphology. Cuticle morphology identifies five types of sensilla trichodea, four types of sensilla basiconica, one type of sensillum coeloconicum and sensillum ampullaceum. Three new types of mechanosensitive sensilla were found. Moreover, the morphological diversity between the antennae allowed the distinction of ten different antennal types that correspond to different sensillar sets. The sensilla found in Naucoridae share similarities with the sensilla of other nepomorphan taxa, as well as of terrestrial insects. However, no sensillar synapomorphy was found between Naucoridae and Aphelocheiridae.
An efficient and accurate distributed learning algorithm for modeling multi-site zero-inflated count outcomes
Authors: Edmondson Mackenzie J. , Luo Chongliang , Duan Rui , Maltenfort Mitchell , Chen Zhaoyi , Locke Kenneth , Shults Justine , Bian Jiang , Ryan Patrick B. , Forrest Christopher B. , Chen Yong 
Published: October 2021

AbstractClinical research networks (CRNs), made up of multiple healthcare systems each with patient data from several care sites, are beneficial for studying rare outcomes and increasing generalizability of results. While CRNs encourage sharing aggregate data across healthcare systems, individual systems within CRNs often cannot share patient-level data due to privacy regulations, prohibiting multi-site regression which requires an analyst to access all individual patient data pooled together. Meta-analysis is commonly used to model data stored at multiple institutions within a CRN but can result in biased estimation, most notably in rare-event contexts. We present a communication-efficient, privacy-preserving algorithm for modeling multi-site zero-inflated count outcomes within a CRN. Our method, a one-shot distributed algorithm for performing hurdle regression (ODAH), models zero-inflated count data stored in multiple sites without sharing patient-level data across sites, resulting in estimates closely approximating those that would be obtained in a pooled patient-level data analysis. We evaluate our method through extensive simulations and two real-world data applications using electronic health records: examining risk factors associated with pediatric avoidable hospitalization and modeling serious adverse event frequency associated with a colorectal cancer therapy. In simulations, ODAH produced bias less than 0.1% across all settings explored while meta-analysis estimates exhibited bias up to 12.7%, with meta-analysis performing worst in settings with high zero-inflation or low event rates. Across both applied analyses, ODAH estimates had less than 10% bias for 18 of 20 coefficients estimated, while meta-analysis estimates exhibited substantially higher bias. Relative to existing methods for distributed data analysis, ODAH offers a highly accurate, computationally efficient method for modeling multi-site zero-inflated count data.
Leu-to-Phe substitution at prM146 decreases the growth ability of Zika virus and partially reduces its pathogenicity in mice
Authors: Inagaki Takuya , Taniguchi Satoshi , Kawai Yasuhiro , Maeki Takahiro , Nakayama Eri , Tajima Shigeru , Takeyama Haruko , Lim Chang Kweng , Saijo Masayuki 
Published: October 2021

AbstractZika virus (ZIKV) is a mosquito-borne flavivirus that causes febrile illness. The recent spread of ZIKV from Asia to the Americas via the Pacific region has revealed unprecedented features of ZIKV, including transplacental congenital infection causing microcephaly. Amino acid changes have been hypothesized to underlie the spread and novel features of American ZIKV strains; however, the relationship between genetic changes and the epidemic remains controversial. A comparison of the characteristics of a Southeast Asian strain (NIID123) and an American strain (PRVABC59) revealed that the latter had a higher replication ability in cultured cells and higher virulence in mice. In this study, we aimed to identify the genetic region of ZIKV responsible for these different characteristics using reverse genetics. A chimeric NIID123 strain in which the E protein was replaced with that of PRVABC59 showed a lower growth ability than the recombinant wild-type strain. Adaptation of the chimeric NIID123 to Vero cells induced a Phe-to-Leu amino acid substitution at position 146 of the prM protein; PRVABC59 also has Leu at this position. Leu at this position was found to be responsible for the viral replication ability and partially, for the pathogenicity in mouse testes.
Probabilistic threshold analysis by pairwise stochastic approximation for decision-making under uncertainty
Authors: Goda Takashi , Yamada Yuki 
Published: October 2021

AbstractThe concept of probabilistic parameter threshold analysis has recently been introduced as a way of probabilistic sensitivity analysis for decision-making under uncertainty, in particular, for health economic evaluations which compare two or more alternative treatments with consideration of uncertainty on outcomes and costs. In this paper we formulate the probabilistic threshold analysis as a root-finding problem involving the conditional expectations, and propose a pairwise stochastic approximation algorithm to search for the threshold value below and above which the choice of conditionally optimal decision options changes. Numerical experiments for both a simple synthetic testcase and a chemotherapy Markov model illustrate the effectiveness of our proposed algorithm, without any need for accurate estimation or approximation of conditional expectations which the existing approaches rely upon. Moreover we introduce a new measure called decision switching probability for probabilistic sensitivity analysis in this paper.
Anti-inflammatory role of Gpnmb in adipose tissue of mice
Authors: Nickl Bernadette , Qadri Fatimunnisa , Bader Michael 
Published: October 2021

AbstractObesity can cause a chronic, low-grade inflammation, which is a critical step in the development of type II diabetes and cardiovascular diseases. Inflammation is associated with the expression of glycoprotein nonmetastatic melanoma protein b (Gpnmb), which is mainly expressed by macrophages and dendritic cells. We generated a Gpnmb-knockout mouse line using Crispr-Cas9 to assess the role of Gpnmb in a diet-induced obesity. The absence of Gpnmb did not affect body weight gain and blood lipid parameters. While wildtype animals became obese but remained otherwise metabolically healthy, Gpnmb-knockout animals developed, in addition to obesity, symptoms of metabolic syndrome such as adipose tissue inflammation, insulin resistance and liver fibrosis. We observed a strong Gpnmb expression in adipose tissue macrophages in wildtype animals and a decreased expression of most macrophage-related genes independent of their inflammatory function. This was corroborated by in vitro data showing that Gpnmb was mostly expressed by reparative macrophages while only pro-inflammatory stimuli induced shedding of Gpnmb. The data suggest that Gpnmb is ameliorating adipose tissue inflammation independent of the polarization of macrophages. Taken together, the data suggest an immune-balancing function of Gpnmb that could delay the metabolic damage caused by the induction of obesity.
Longitudinal urinary biomarkers of immunological activation in covid-19 patients without clinically apparent kidney disease versus acute and chronic failure
Authors: Laudanski Krzysztof , Okeke Tony , Hajj Jihane , Siddiq Kumal , Rader Daniel J. , Wu Junnan , Susztak Katalin 
Published: October 2021

AbstractKidney function is affected in COVID-19, while kidney itself modulates the immune response. Here, hypothesize if COVID-19 urine biomarkers level can assess immune activation vs. clinical trajectory. Considering the kidney’s critical role in modulating the immune response, we sought to analyze activation markers in patients with pre-existing dysfunction. This was a cross-sectional study of 68 patients. Blood and urine were collected within 48 h of hospital admission (H1), followed by 96 h (H2), seven days (H3), and up to 25 days (H4) from admission. Serum level ferritin, procalcitonin, IL-6 assessed immune activation overall, while the response to viral burden was gauged with serum level of spike protein and αspike IgM and IgG. 39 markers correlated highly between urine and blood. Age and race, and to a lesser extend gender, differentiated several urine markers. The burden of pre-existing conditions correlated with urine DCN, CAIX and PTN, but inversely with IL-5 or MCP-4. Higher urinary IL-12 and lower CAIX, CCL23, IL-15, IL-18, MCP-1, MCP-3, MUC-16, PD-L1, TNFRS12A, and TNFRS21 signified non-survivors. APACHE correlated with urine TNFRS12, PGF, CAIX, DCN, CXCL6, and EGF. Admission urine LAG-3 and IL-2 predicted death. Pre-existing kidney disease had a unique pattern of urinary inflammatory markers. Acute kidney injury was associated, and to a certain degree, predicted by IFNg, TWEAK, MMP7, and MUC-16. Remdesavir had a more profound effect on the urine biomarkers than steroids. Urinary biomarkers correlated with clinical status, kidney function, markers of the immune system activation, and probability of demise in COVID-19.
A T cell-intrinsic function for NF-κB RelB in experimental autoimmune encephalomyelitis
Authors: Lalle Guilhem , Lautraite Raphaëlle , Voisin Allison , Twardowski Julie , Stéphan Pierre , Perrin-Niquet Marlène , Igalouzene Ramdane , Soudja Saidi M. , Marie Julien C. , Vocanson Marc , De Silva Nilushi , Klein Ulf , Ghosh Sankar , Grinberg-Bleyer Yenkel 
Published: October 2021

AbstractNF-kappaB (NF-κB) is a family of transcription factors with pleiotropic functions in immune responses. The alternative NF-κB pathway that leads to the activation of RelB and NF-κB2, was previously associated with the activation and function of T cells, though the exact contribution of these NF-κB subunits remains unclear. Here, using mice carrying conditional ablation of RelB in T cells, we evaluated its role in the development of conventional CD4+ T (Tconv) cells and their function in autoimmune diseases. RelB was largely dispensable for Tconv cell homeostasis, activation and proliferation, and for their polarization toward different flavors of Thelper cells in vitro. Moreover, ablation of RelB had no impact on the capacity of Tconv cells to induce autoimmune colitis. Conversely, clinical severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS) was significantly reduced in mice with RelB-deficient T cells. This was associated with impaired expression of granulocyte–macrophage colony-stimulating factor (GM-CSF) specifically in the central nervous system. Our data reveal a discrete role for RelB in the pathogenic function of Tconv cells during EAE, and highlight this transcription factor as a putative therapeutic target in MS.
Distinct timescales for the neuronal encoding of vocal signals in a high-order auditory area
Authors: Cazala Aurore , Del Negro Catherine , Giret Nicolas 
Published: October 2021

AbstractThe ability of the auditory system to selectively recognize natural sound categories while maintaining a certain degree of tolerance towards variations within these categories, which may have functional roles, is thought to be crucial for vocal communication. To date, it is still largely unknown how the balance between tolerance and sensitivity to variations in acoustic signals is coded at a neuronal level. Here, we investigate whether neurons in a high-order auditory area in zebra finches, a songbird species, are sensitive to natural variations in vocal signals by recording their responses to repeated exposures to identical and variant sound sequences. We used the songs of male birds which tend to be highly repetitive with only subtle variations between renditions. When playing these songs to both anesthetized and awake birds, we found that variations between songs did not affect the neuron firing rate but the temporal reliability of responses. This suggests that auditory processing operates on a range of distinct timescales, namely a short one to detect variations in vocal signals, and longer ones that allow the birds to tolerate variations in vocal signal structure and to encode the global context.
Increased serum catalytic iron may mediate tissue injury and death in patients with COVID-19
Authors: Chakurkar Vipul , Rajapurkar Mohan , Lele Suhas , Mukhopadhyay Banibrata , Lobo Valentine , Injarapu Ramakrishna , Sheikh Muddassir , Dholu Bharatkumar , Ghosh Arpita , Jha Vivekanand 
Published: October 2021

AbstractThe pathophysiology and the factors determining disease severity in COVID-19 are not yet clear, with current data indicating a possible role of altered iron metabolism. Previous studies of iron parameters in COVID-19 are cross-sectional and have not studied catalytic iron, the biologically most active form of iron. The study was done to determine the role of catalytic iron in the adverse outcomes in COVID-19. We enrolled adult patients hospitalized with a clinical diagnosis of COVID-19 and measured serum iron, transferrin saturation, ferritin, hepcidin and serum catalytic iron daily. Primary outcome was a composite of in-hospital mortality, need for mechanical ventilation, and kidney replacement therapy. Associations between longitudinal iron parameter measurements and time-to-event outcomes were examined using a joint model. We enrolled 120 patients (70 males) with median age 50 years. The primary composite outcome was observed in 25 (20.8%) patients—mechanical ventilation was needed in 21 (17.5%) patients and in-hospital mortality occurred in 21 (17.5%) patients. Baseline levels of ferritin and hepcidin were significantly associated with the primary composite outcome. The joint model analysis showed that ferritin levels were significantly associated with primary composite outcome [HR (95% CI) = 2.63 (1.62, 4.24) after adjusting for age and gender]. Both ferritin and serum catalytic iron levels were positively associated with in-hospital mortality [HR (95% CI) = 3.22 (2.05, 5.07) and 1.73 (1.21, 2.47), respectively], after adjusting for age and gender. The study shows an association of ferritin and catalytic iron with adverse outcomes in COVID-19. This suggests new pathophysiologic pathways in this disease, also raising the possibility of considering iron chelation therapy.