bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-1 Protease Evolvability is Affected by Synonymous Nucleotide Recoding
Authors: Nevot Maria , Jordan-Paiz Ana , Martrus Glòria , Andrés Cristina , García-Cehic Damir , Gregori Josep , Franco Sandra , Quer Josep , Martinez Miguel Angel 
Published: May 2018

ABSTRACTOne unexplored aspect of HIV-1 genetic architecture is how codon choice influences population diversity and evolvability. Here we compared the development of HIV-1 resistance to protease inhibitors (PIs) between wild-type (WT) virus and a synthetic virus (MAX) carrying a codon-pair re-engineered protease sequence including 38 (13%) synonymous mutations. WT and MAX viruses showed indistinguishable replication in MT-4 cells or PBMCs. Both viruses were subjected to serial passages in MT-4 cells with selective pressure from the PIs atazanavir (ATV) and darunavir (DRV). After 32 successive passages, both the WT and MAX viruses developed phenotypic resistance to PIs (IC5014.6 ± 5.3 and 21.2 ± 9 nM for ATV, and 5. 9 ± 1.0 and 9.3 ± 1.9 for DRV, respectively). Ultra-deep sequence clonal analysis revealed that both viruses harbored previously described resistance mutations to ATV and DRV. However, the WT and MAX virus proteases showed different resistance variant repertoires, with the G16E and V77I substitutions observed only in WT, and the L33F, S37P, G48L, Q58E/K, and L89I substitutions detected only in MAX. Remarkably, G48L and L89I are rarely foundin vivoin PI-treated patients. The MAX virus showed significantly higher nucleotide and amino acid diversity of the propagated viruses with and without PIs (P< 0.0001), suggesting higher selective pressure for change in this recoded virus. Our results indicate that HIV-1 protease position in sequence space delineates the evolution of its mutant spectra. Nevertheless, the investigated synonymously recoded variant showed mutational robustness and evolvability similar to the WT virus.IMPORTANCELarge-scale synonymous recoding of virus genomes is a new tool for exploring various aspects of virus biology. Synonymous virus genome recoding can be used to investigate how a virus’s position in sequence space defines its mutant spectrum, evolutionary trajectory, and pathogenesis. In this study, we evaluated how synonymous recoding of the human immunodeficiency virus type 1 (HIV-1) protease impacts the development of protease inhibitor (PI) resistance. HIV-1 protease is a main target of current antiretroviral therapies. Our present results demonstrate that the wild-type (WT) virus and the virus with the recoded protease exhibited different patterns of resistance mutations after PI treatment. Nevertheless, the developed PI resistance phenotype was indistinguishable between the recoded virus and the WT virus, suggesting that the synonymously recoded protease HIV-1 and the WT protease virus were equally robust and evolvable.
The developing premature infant gut microbiome is a major factor shaping the microbiome of neonatal intensive care unit rooms
Authors: Brooks Brandon , Olm Matthew R. , Firek Brian A. , Baker Robyn , Geller-McGrath David , Reimer Sophia R. , Soenjoyo Karina R. , Yip Jennifer S. , Dahan Dylan , Thomas Brian C. , Morowitz Michael J. , Banfield Jillian F. 
Published: May 2018

1.1AbstractBackgroundThe neonatal intensive care unit (NICU) contains a unique cohort of patients with underdeveloped immune systems and nascent microbiome communities. Patients often spend several months in the same room and it has been previously shown that the gut microbiomes of these infants often resemble the microbes found in the NICU. Little is known, however, about the identity, persistence and absolute abundance of NICU room-associated bacteria over long stretches of time. Here we couple droplet digital PCR (ddPCR), 16S rRNA gene surveys, and recently published metagenomics data from infant gut samples to infer the extent to which the NICU microbiome is shaped by its room occupants.ResultsOver 2,832 swabs, wipes, and air samples were collected from sixteen private-style NICU rooms housing very low birthweight (<1,500 g), premature (<31 weeks’ gestation) infants. For each infant, room samples were collected daily, Monday through Friday, for one month. The first samples from the first infant and last samples from the last infant were collected 383 days apart. Twenty-two NICU locations spanning room surfaces, hands, electronics, sink basins, and air were collected. Results point to an incredibly simple room community where 5-10 taxa, mostly skin associated, account for over 50% of 16S reads. Biomass estimates reveal 4-5 orders of magnitude difference between the least to the most dense microbial communities, air and sink basins, respectively. Biomass trends from bioaerosol samples and petri dish dust collectors suggest occupancy to be a main driver of suspended biological particles within the NICU. Using a machine learning algorithm to classify the origin of room samples, we show that each room has a unique microbial fingerprint. Several important taxa driving this model were dominant gut colonizers of infants housed within each room.ConclusionsDespite regular cleaning of hospital surfaces, bacterial biomass was detectable at varying densities. A room specific microbiome signature was detected, suggesting microbes seeding NICU surfaces are sourced from reservoirs within the room and that these reservoirs contain actively dividing cells. Collectively, the data suggests that hospitalized infants, in combination with their caregivers, shape the microbiome of NICU rooms.
Exendin-4 disrupts responding to reward predictive incentive cues in rats
Authors: Wakabayashi Ken T. , Baindur Ajay N. , Feja Malte , Chen Karie , Bernosky-Smith Kimberly , Bass Caroline E. 
Published: May 2018

AbstractExendin-4 (EX4) is a GLP-1 receptor agonist used clinically to control glycemia in Type-2 Diabetes Mellitus (T2DM), with the additional effect of promoting weight loss. The weight loss seen with EX4 is attributable to the varied peripheral and central effects of GLP-1, with contributions from the mesolimbic dopamine pathway that are implicated in cue-induced reward seeking. GLP-1 receptor agonists reduce preference for palatable foods (i.e. sweet and fat) as well as the motivation to obtain and consume these foods. Accumulating evidence suggest that GLP-1 receptor activity can attenuate cue-induced reward seeking behaviors. In the present study, we tested the effects of EX4 (0.6, 1.2, and 2.4 µg/kg i.p.) on incentive cue (IC) responding. This rat model required rats to emit a nosepoke response during an intermittent audiovisual cue to obtain a sucrose reward (10% solution). EX4 dose-dependently attenuated responding to reward predictive cues, and increased latencies of the cue response and reward cup entry to consume the sucrose reward. Moreover, EX4 dose-dependently decreased the number of nosepokes relative to the number of cue presentations during the session. There was no drug effect on the number of reward cup entries per reward earned during the session, a related reward-seeking behavior with similar locomotor demand. Interestingly, there was a dose-dependent effect of time on the responding to reward predictive cues and nosepoke response latency, such that 2.4 µg/kg of EX4 delayed responding to the initial IC of the behavioral session. Together, these findings suggest that agonism of the GLP-1 receptor with EX4 modulates the incentive properties of cues attributed with motivational significance.
A First-principles Approach to Large-scale Nuclear Architecture
Authors: Agrawal Ankit , Ganai Nirmalendu , Sengupta Surajit , Menon Gautam I. 
Published: May 2018

AbstractModel approaches to nuclear architecture have traditionally ignored the biophysical consequences of ATP-fueled active processes acting on chromatin. However, transcription-coupled activity is a source of stochastic forces that are substantially larger than the Brownian forces present at physiological temperatures. Here, we describe a first-principles approach to large-scale nuclear architecture in metazoans that incorporates cell-type-specific active processes. The model predicts the statistics of positional distributions, shapes and overlaps of each chromosome. Our simulations reproduce common organising principles underlying large-scale nuclear architecture across human cell nuclei in interphase. These include the differential positioning of euchromatin and heterochromatin, the territorial organisation of chromosomes including both gene-density-based and size-based chromosome radial positioning schemes, the non-random locations of chromosome territories and the shape statistics of individual chromosomes. We propose that the biophysical consequences of the distribution of transcriptional activity across chromosomes should be central to any chromosome positioning code.
Differences in the temporal processing between identification and categorization of durations: a behavioral and ERP study
Authors: Bannier Dorian , Wearden J. , Le Dantec Christophe C. , Rebaï Mohamed 
Published: May 2018

AbstractThis study examined how different forms of decision-making modulate time perception. Participants performed temporal bisection and generalization tasks, requiring them to either categorize a stimulus duration as more similar to short or long standards (bisection), or identify whether or not a duration was the same as a previously-presented standard (generalization). They responded faster in the bisection task than in the generalization one for long durations. This behavioral effect was accompanied by modulation of event-related potentials (ERPs). More specifically, between 500 ms and 600 ms after stimulus offset, a late positive component (LPC), appearing in the centro-parietal region, showed lower amplitude in the bisection task than in the generalization one, for long durations, mirroring the behavioral result. Before (200-500 ms) and after (600-800 ms) this window, the amplitude of the LPC was globally larger in the generalization paradigm, independently of the presented duration. Finally, the latency of the LPC’s peak was earlier for long durations than for the short ones, indicating that the decision about the former stimuli was made earlier than for the latter ones. Taken together, these results indicate that the categorization of durations engages fewer cognitive resources than their identification.
TRAF6 directs Foxp3 localization and facilitates Treg function through K63-type ubiquitination
Authors: Ni Xuhao , Tao Jinhui , Gu Jian , Park Benjamin V. , Chen Zuojia , Newman Stephanie , Shen Hongbin , Wang Xuehao , Li Bin , Blazar Bruce R. , Barbi Joseph , Pan Fan , Lu Ling 
Published: May 2018

AbstractRegulatory T cells (Treg) are crucial mediators of immune control. The characteristic gene expression and suppressive function of Treg depend considerably on the stable expression and activity of the transcription factor Foxp3. While transcriptional regulation of the Foxp3 gene has been studied in depth, both the expression and function of Foxp3 are also modulated at the protein level. However, the molecular players involved in posttranslational Foxp3 regulation are just beginning to be elucidated. Here we found TRAF6-deficient Tregs were dysfunctional in vivo; mice with Treg-restricted deletion of TRAF6 were resistant to B16 melanomas and displayed enhanced anti-tumor immunity. We further determined that Foxp3 undergoes lysine-63 chain (K63) ubiquitination at lysine 262 mediated by the E3 ligase TRAF6. When deprived of TRAF6 activity or rendered insensitive to K63 ubiquitination, Foxp3 displayed aberrant, perinuclear accumulation, disrupted function. Thus, Foxp3 ubiquitination by TRAF6 ensures proper localization of Foxp3 and facilitates Foxp3’s gene-regulating activity in Tregs. These results implicate TRAF6 as a key posttranslational, Treg-stabilizing force that may be targeted in novel tolerance-breaking therapies.
Paracoccidioides restrepiensis B339 (PS3) and P. lutzii LDR2 yeast cells and soluble components display in vitro hemolytic and hemagglutinating activities on human erythrocytes
Authors: Cezar‐dos‐Santos Fernando , Lenhard‐Vidal Adriane , Assolini João Paulo , Marquez A. S. , Ono Mário Augusto , Itano Eiko Nakagawa 
Published: May 2018

ABSTRACTParacoccidioidomycosis (PCM) is a systemic mycosis caused by thermally dimorphic fungi of the Paracoccidioides species complex. Several pathogenic fungi produce hemagglutinins and hemolysins, which are virulence factors involved in adhesion of pathogens to host tissues or cells and in destruction of erythrocytes. The present research investigated hemolytic and hemagglutinating activities of yeast cells and soluble components from P. restrepiensis (PS3; formerly P. brasiliensis B339) and P. lutzii (LDR2). Different concentrations of live and heat‐killed yeast cells and soluble components from a cell free antigen preparation (native or heated, 56°C or 100°C, 30 min) were mixed with 1% human erythrocyte suspensions. Yeast cells from both species caused hemolysis, P. lutzii LDR2 being more strongly hemolytic than P. restrepiensis B339, whereas the opposite phenomena occurred with soluble components in most conditions. Live or heat‐killed yeast cells of both fungi agglutinated erythrocytes, but only heated soluble components from P. restrepiensis B339 showed hemagglutinating activity. In conclusion, yeast cells of P. restrepiensis B339 and P. lutzii LDR2 produce hemolysins and hemagglutinins, which are most likely predominantly restricted to yeast cells in P. lutzii LDR2 and predominantly released in soluble form by P. restrepiensis B339, requiring further study.
Rosuvastatin‐Induced Rhabdomyolysis – Possible Role of Ticagrelor and Patients’ Pharmacogenetic Profile
Authors: Vrkić Kirhmajer Majda , Macolić Šarinić Viola , Šimičević Livija , Ladić Iva , Putarek Krešimir , Banfić Ljiljana , Božina Nada 
Published: May 2018

AbstractUp to the beginning of 2018, a total of eight cases describing rare but clinically important drug interactions between rosuvastatin and ticagrelor which resulted in rhabdomyolysis have been noted in the Global World Health Organization (WHO) adverse drug reaction (ADR) database (VigiBase) as well as in available literature. There are several possible factors which could contribute to the onset of rhabdomyolysis: old age, initially excessive rosuvastatin dose, drug–drug interactions (DDI) on metabolic enzymes (CYPs and UGTs) and drug transporter levels (ABCB1, ABCG2, OATP1B1) and pharmacogenetic predisposition. We reviewed all available cases plus the case of an 87‐year‐old female Croatian/Caucasian patient who developed rhabdomyolysis following concomitant treatment with rosuvastatin and ticagrelor. The results of the pharmacogenetic analysis indicated that the patient was a carrier of inactivating alleles CYP2C9*1/*3, CYP3A4*1/*22, CYP3A5*3/*3, CYP2D6*1/*4, UGT1A1*28/*28, UGT2B7 ‐161C/T, ABCB1 3435C/T and ABCB1 1237C/T which could have added to the interactions not only between ticagrelor and rosuvastatin but also other concomitantly prescribed medicines, such as amiodarone and proton pump inhibitors. In this case report, the possible multifactorial causes for rhabdomyolysis following concomitant use of rosuvastatin and ticagrelor such as old age, polypharmacy, renal impairment, along with pharmacogenetics will be discussed.
The Out‐Group Homogeneity Effect Across Development: A Cross‐Cultural Investigation
Authors: Shilo Reut , Weinsdörfer Anika , Rakoczy Hannes , Diesendruck Gil 
Published: May 2018

The present studies investigated the out‐group homogeneity effect in 5‐ and 8‐year‐old Israeli and German children (n = 150) and adults (n = 96). Participants were asked to infer whether a given property (either biological or psychological) was true of an entire group—either the participants' in‐group (“Jews” or “Germans”) or their out‐group (“Arabs” or “Turks”). To that end, participants had to select either a homogenous or a heterogeneous sample of group members. It was found that across ages and countries, participants selected heterogeneous samples less often when inferring the biological properties of out‐compared to in‐group members. No effect was found regarding psychological properties. These findings have important implications for our understanding of the origins of intergroup bias.
Monocyte‐derived extracellular vesicles stimulate cytokine secretion and gene expression of matrix metalloproteinases by mesenchymal stem/stromal cells
Authors: Gebraad Arjen , Kornilov Roman , Kaur Sippy , Miettinen Susanna , Haimi Suvi , Peltoniemi Hilkka , Mannerström Bettina , Seppänen‐Kaijansinkko Riitta 
Published: May 2018

Intercellular communication is essential in bone remodelling to ensure that new bone is formed with only temporary bone loss. Monocytes (MCs) and osteoclasts actively take part in controlling bone remodelling by providing signals that promote osteogenic differentiation of mesenchymal stem/stromal cells (MSCs). Extracellular vesicles (EVs) have attracted attention as regulators of bone remodelling. EVs facilitate intercellular communication by transferring a complex cargo of biologically active molecules to target cells. In the present study, we evaluated the potency of EVs from MCs and osteoclasts to induce a lineage‐specific response in MSCs. We analysed gene expression and protein secretion by both adipose tissue‐derived MSCs and bone marrow‐derived MSCs after stimulation with EVs from lipopolysaccharide‐activated primary human MCs and (mineral‐resorbing) osteoclasts. Isolated EVs were enriched in exosomes (EVs of endosomal origin) and were free of cell debris. MC‐ and osteoclast‐derived EVs were taken up by adipose tissue‐derived MSCs. EVs from activated MCs promoted the secretion of cytokines by MSCs, which may represent an immunomodulatory mechanism. MC‐derived EVs also upregulated the expression of genes encoding for matrix metalloproteinases. Therefore, we hypothesize that MCs facilitate tissue remodelling through EV‐mediated signalling. We did not observe a significant effect of osteoclast‐derived EVs on gene expression or protein secretion in MSCs. EV‐mediated signalling might represent an additional mode of cell‐cell signalling during the transition from injury and inflammation to bone regeneration and play an important role in the coupling between bone resorption and bone formation.DatabaseGene expression data are available in the GEO database under the accession number GSE102401.
An Analytical Method for Assessing Recharge Using Groundwater Travel Time in Dupuit‐Forchheimer Aquifers
Authors: Chesnaux R. , Santoni S. , Garel E. , Huneau F. 
Published: May 2018

AbstractAn analytical solution to calculate the recharge of unconfined aquifers with Dupuit‐Forchheimer type flow conditions is proposed. This solution is derived from an existing closed‐form analytical solution initially developed to determine groundwater travel time when the recharge of the aquifer is known. This existing solution has been modified to determine recharge when groundwater travel time is known. An illustration is given with a field case example for the Bonifacio aquifer of the island of Corsica (France), in the Mediterranean. In this aquifer, previously established differences in groundwater residence time between two water samples were determined from anthropogenic atmospheric gas (chlorofluorocarbons and sulfur hexafluoride) measurements. The time difference is entered into the new analytical solution to determine recharge. The calculations yield a value of average recharge that agrees with the results obtained by several other methods that were presented in previous studies to assess the recharge of the Bonifacio aquifer. Also presented in this study is a sensitivity analysis of the new analytical solution, to quantify the influence of different parameters that control recharge: hydraulic conductivity, effective porosity and the groundwater travel time. This study illustrates how geochemical data can be combined with physical models to measure recharge. Such an approach could be adopted in other homogeneous aquifers worldwide that satisfy Dupuit‐Forchheimer type flow conditions.
Association between sarcopenia and osteoporosis in chronic liver disease
Authors: Hayashi Manabu , Abe Kazumichi , Fujita Masashi , Okai Ken , Takahashi Atsushi , Ohira Hiromasa 
Published: May 2018

AimSarcopenia and osteoporosis are important complications in chronic liver disease (CLD). The aim of this study was to investigate the relationship between sarcopenia and osteoporosis in patients with CLD.MethodsWe retrospectively investigated the relationship between sarcopenia and osteoporosis in 112 CLD patients (57 men and 55 women), including 40 cirrhotic patients (36%), by measuring the appendicular skeletal muscle mass index (ASMI) using bio‐impedance analysis. Bone mineral density (BMD) was measured by dual‐energy X‐ray absorptiometry.ResultsThe sarcopenia rate was 13% (14/112), and the osteoporosis and osteopenia rates were 17% (19/112) and 65% (73/112), respectively. The rate of osteoporosis was significant and high in patients with sarcopenia or cirrhosis. In linear regression analysis, sarcopenia was significantly associated with the BMD of the lumbar spine (coefficient = −0.149, P = 0.014) and the femur neck (coefficient = −0.110, P = 0.003). Cirrhosis was also significantly associated with low BMD of the lumbar spine (coefficient = −0.160, P < 0.001) and the femur neck (coefficient = −0.066, P = 0.015). In the logistic analysis, sarcopenia (odds ratio = 6.16, P = 0.039) and cirrhosis (odds ratio = 15.8, P = 0.002) were independent risk factors for osteoporosis. The ASMI cut‐off values for osteoporosis were 7.33 kg/m2 in men and 5.71 kg/m2 in women.ConclusionsSarcopenia was closely associated with osteoporosis, and a low ASMI was a potential predictor of osteoporosis in CLD patients. Screening for BMD might be required to detect osteoporosis in cirrhotic patients.
Genetic parameter estimation for long endurance trials in the Uruguayan Criollo horse
Authors: López‐Correa R.D. , Peñagaricano F. , Rovere G. , Urioste J.I. 
Published: May 2018

SummaryThe aim of this study was to estimate the genetic parameters of performance in a 750‐km, 15‐day ride in Criollo horses. Heritability (h2) and maternal lineage effects (mt2) were obtained for rank, a relative placing measure of performance. Additive genetic and maternal lineage (rmt) correlations among five medium‐to‐high intensity phase ranks (pRK) and final rank (RK) were also estimated. Individual records from 1,236 Criollo horses from 1979 to 2012 were used. A multivariate threshold animal model was applied to the pRK and RK. Heritability was moderate to low (0.156–0.275). Estimates of mt2 were consistently low (0.04–0.06). Additive genetic correlations between individual pRK and RK were high (0.801–0.924), and the genetic correlations between individual pRKs ranged from 0.763 to 0.847. The pRK heritabilities revealed that some phases were explained by a greater additive component, whereas others showed stronger genetic relationships with RK. Thus, not all pRK may be considered as similar measures of performance in competition.