bluuebunny/crossref_metadata_2025_split huggingface dataset:
Focal seizures are organized by feedback between neural activity and ion concentration changes
Authors: Gentiletti Damiano , de Curtis Marco , Gnatkovsky Vadym , Suffczynski Piotr 
Published: March 2021

AbstractHuman and animal EEG data demonstrate that focal seizures start with low-voltage fast activity, evolve into rhythmic burst discharges and are followed by a period of suppressed background activity. This suggests that processes with dynamics in the range of tens of seconds govern focal seizure evolution. We investigate the processes associated with seizure dynamics by complementing the Hodgkin-Huxley mathematical model with the physical laws that dictate ion movement and maintain ionic gradients. Our biophysically realistic computational model closely replicates the electrographic pattern of a typical human focal seizure characterized by low voltage fast activity onset, tonic phase, clonic phase and postictal suppression. Our study demonstrates, for the first timein silico, the potential mechanism of seizure initiation by inhibitory interneurons via the initial build-up of extracellular K+due to intense interneuronal spiking. The model also identifies ionic mechanisms that may underlie a key feature in seizure dynamics, i.e., progressive slowing down of ictal discharges towards the end of seizure. Our model prediction of specific scaling of inter-burst intervals is confirmed by seizure data recorded in the whole guinea pig brain in vitro and in humans, suggesting that the observed termination pattern may hold across different species. Our results emphasize ionic dynamics as elementary processes behind seizure generation and indicate targets for new therapeutic strategies.
Insights into single hiPSC-derived cardiomyocyte phenotypes and maturation using ConTraX, an efficient pipeline for tracking contractile dynamics
Authors: Pardon Gaspard , Lewis Henry , Vander Roest Alison S. , Castillo Erica A. , Wilson Robin , Denisin Aleksandra K. , Blair Cheavar A. , Birnbaum Foster , Holbrook Colin , Koleckar Kassie , Chang Alex C-Y , Blau Helen M. , Pruitt Beth L. 
Published: March 2021

AbstractCardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerfulin-vitromodels to study the mechanisms underlying cardiomyopathies and cardiotoxicity. To understand how cellular mechanisms affect the heart, it is crucial to quantify the contractile function in single hiPSC-CMs over time, however, such measurements remain demanding and low-throughput, and are too seldom considered.We developed an open-access, versatile, streamlined, and highly automated pipeline to address these challenges and enable quantitativetrackingof thecontractiledynamics of single hiPSC- CMs over time:ConTraX. Three interlocking software modules enable: (i) parameter-based localization and selection of single hiPSC-CMs; (ii) automated video acquisition of >200 cells/hour; and (iii) streamlined measurements of the contractile parameters via traction force microscopy. UsingConTraX, we analyzed >2,753 hiPSC-CMs over time under orthogonal experimental conditions in terms of culture media and substrate stiffnesses. Using undirected high-dimensional clustering, we dissected the complex diversity of contractile phenotypes in hiPSC-CM populations and revealed converging maturation patterns.Our modularConTraXpipeline empowers biologists with a potent quantitative analytic tool applicable to the development of cardiac therapies.
ODOR IDENTITY CAN BE EXTRACTED FROM THE RECIPROCAL CONNECTIVITY BETWEEN OLFACTORY BULB AND PIRIFORM CORTEX IN HUMANS
Authors: Iravani Behzad , Arshamian Artin , Lundqvist Mikael , Kay Leslie , Wilson Donald A. , Lundström Johan N. 
Published: March 2021

ABSTRACTNeuronal oscillations route external and internal information across brain regions. In the olfactory system, the two central nodes—the olfactory bulb (OB) and the piriform cortex (PC)—communicate with each other via neural oscillations to shape the olfactory percept. Communication between these nodes have been well characterized in non-human animals but less is known about their role in the human olfactory system. Using a recently developed and validated EEG-based method to extract signals from the OB and PC sources, we show in healthy human participants that there is a bottom-up information flow from the OB to the PC in the beta and gamma frequency bands, while top-down information from the PC to the OB is facilitated by delta and theta oscillations. Importantly, we demonstrate that there was enough information to decipher odor identity above chance from the low gamma in the OB-PC oscillatory circuit as early as 100ms after odor onset. These data further our understanding of the critical role of bidirectional information flow in human sensory systems to produce perception. However, future studies are needed to determine what specific odor information is extracted and communicated in the information exchange.
Diet-induced changes in titer support a threshold effect ofWolbachia-associated plastic recombination inDrosophila melanogaster
Authors: Mostoufi Sabrina L. , Singh Nadia D. 
Published: March 2021

ABSTRACTPlastic recombination inDrosophila melanogasterhas been associated with a variety of extrinsic and intrinsic factors such as temperature, starvation, and parasite infection. The bacterial endosymbiontWolbachia pipientishas also been associated with plastic recombination inD. melanogaster. Wolbachiainfection is pervasive in arthropods and this infection induces a variety of phenotypes in its hosts, the strength of which can depend on bacterial concentration, or titer. Here we test the hypothesis that the magnitude ofWolbachia-associated plastic recombination inD. melanogasterdepends on titer. To manipulate titer, we raisedWolbachia-infected and uninfected flies on diets that have previously been shown to increase or decreaseWolbachiatiter relative to controls. We measured recombination in treated and control individuals using a standard backcrossing scheme with two X-linked visible markers. Our results recapitulate previous findings thatWolbachiainfection is associated with increased recombination rate across theyellow-vermillioninterval of the X chromosome. Our data show no significant effect of diet or diet byWolbachiainteractions on recombination, suggesting that diet-induced changes inWolbachiatiter have no effect on the magnitude of plastic recombination. These findings represent the first step toward investigating the mechanisms behindWolbachia-associated plastic recombination and demonstrate that the effect may be threshold-based as opposed to dose-dependent.
Joint effects of genes underlying a temperature specialization tradeoff in yeast
Authors: AlZaben Faisal , Chuong Julie N. , Abrams Melanie B. , Brem Rachel B. 
Published: March 2021

AbstractA central goal of evolutionary genetics is to understand, at the molecular level, how organisms adapt to their environments. For a given trait, the answer often involves the acquisition of variants at unlinked sites across the genome. Genomic methods have achieved landmark successes in pinpointing adaptive loci. To figure out how a suite of adaptive alleles work together, and to what extent they can reconstitute the phenotype of interest, requires their transfer into an exogenous background. We studied the joint effect of adaptive, gain-of-function thermotolerance alleles at eight unlinked genes fromSaccharomyces cerevisiae, when introduced into a thermosensitive sister species,S. paradoxus. Although the loci damped each other’s beneficial impact (that is, they were subject to negative epistasis), most boosted high-temperature growth alone and in combination, and none was deleterious. The complete set of eight genes was sufficient to confer ∼15% of theS. cerevisiaephenotype in theS. paradoxusbackground. The same loci also contributed to a heretofore unknown advantage in cold growth byS. paradoxus. Together, our data establish temperature resistance in yeasts as a model case of a genetically complex evolutionary tradeoff, which can be partly reconstituted from the sequential assembly of unlinked underlying loci.Author summaryOrganisms adapt to threats in the environment by acquiring DNA sequence variants that tweak traits to improve fitness. Experimental studies of this process have proven to be a particular challenge when they involve manipulation of a suite of genes, all on different chromosomes. We set out to understand how so many loci could work together to confer a trait. We used as a model system eight genes that govern the ability of the unicellular yeastSaccharomyces cerevisiaeto grow at high temperature. We introduced these variant loci stepwise into a non-thermotolerant sister species, and found that the moreS. cerevisiaealleles we added, the better the phenotype. We saw no evidence for toxic interactions between the genes as they were combined. We also used the eight-fold transgenic to dissect the biological mechanism of thermotolerance. And we discovered a tradeoff: the same alleles that boosted growth at high temperature eroded the organism’s ability to deal with cold conditions. These results serve as a case study of modular construction of a trait from nature, by assembling the genes together in one genome.
Inhibition of select actinobacteria by the organophosphate pesticide chlorpyrifos
Authors: McDonald Nathan D. , Love Courtney E. , Killens-Cade Rushyannah , Werth Jason , Gebert Matthew , Weber Carolyn F. , Nealon Christopher , Sweet Charles , Fierer Noah , Gibbons Henry S. 
Published: March 2021

ABSTRACTOrganophosphorus compounds have an extensive history as both agricultural pesticides as well as chemical nerve agents. Decades of research have demonstrated numerous links between these chemicals and their direct and indirect effects on humans and other organisms. The inhibitory effects of organophosphate pesticides (OPPs) on metazoan physiology, are well-characterized; however, the effects of organophosphorus compounds on soil microbes - essential contributors to key agricultural processes - are poorly understood. Chlorpyrifos (CPF) is an OPP that is used globally for crop protection. Studies of CPF application to soils have shown transient effects on soil microbial communities with conflicting data. Here, we directly test the effect of CPF on a panel of 196 actinobacteria strains, examining the effects of CPF on their growth andin vitrophenotypes on solid media. Strains were grown and replica-plated onto media containing CPF or a vehicle control and grown at 28°C. CPF dramatically inhibited the growth of most strains and/or altered colony morphologies, with 13 strains completely inhibited by CPF. In disk diffusion assays with CPF, its degradation product 3,5,6-trichloropyridinol (TCP), malathion, parathion, monocrotophos and mevinphos, only CPF exhibited direct antimicrobial activity suggesting that the observed effects were due to CPF itself.IMPORTANCEChlorpyrifos is a globally used pesticide with documented neurological effects on non-target organisms in the environment. Finding that chlorpyrifos can inhibit the growth of some soil microbesin vitromay have implications for the composition, stability, and health of the soil microbiome. Due to the importance of soil microbes to numerous biogeochemical processes in agricultural systems, additional investigations into the non-target effects of CPF on soil microbes are clearly needed.
Treatment and Cost -outcomes of a simplified antiretroviral treatment strategy for hepatitis C among HCV and HIV co-infected patients in Ukraine
Authors: Antoniak Sergie , Charles Chasela C , Freiman Morgan J , Stopolianska Yulia , Barnard Tetiana , Gandhi MM , Liulchuk Maria , Tsenilova Zhanna , Tretiakov V , Dible Jeri , Kinge Constance Wose , Minior T , Mohamed Sofiane , Marange Fadzai , Cavenaugh Clint , van der Horst Charles , Antonyak Svitlana , Xulu Thembisile , Chew Kara W , Sanne Ian , Rosen Sydney ,   for EQUIP Health
Published: March 2021

AbstractBackgroundWe conducted a demonstration project of an integrated HIV and viral hepatitis testing and treatment strategy using generic ledipasvir/sofosbuvir (LDV/SOF).MethodsEligible HCV viraemic adults from two clinics in Kyiv were treated with LDV/SOF +/-weight-based ribavirin for 12 weeks. Clinical assessments were performed at screening and week 24 and as needed; treatment was dispensed every 4 weeks. The primary outcome was sustained virologic response (SVR)12 weeks after treatment. Program costs in 2018 USD were estimated per patient treated using observed resource utilization, local unit, and antiretroviral therapy (ART) costs over the 24-week period.Results868 participants initiated on treatment, 87% (755) were PWID and 55.5% (482) were HIV co-infected. The common genotypes were 1 (74.1%) and 3 (22%) and SVR was achieved in 831/868 (95.7%) by intention-to-treat analysis. The average cost per patient treated was $680, assuming generic LDV/SOF and ribavirin pricing and standard quantitative HCV viral load testing. Medications comprised 38% of the average cost/patient, laboratory tests 26%, events (clinic visits, counselling) 10%, and indirect costs 26%. ART accounted for 60% of all drug costs, with HCV medications just 40%.ConclusionGeneric LDV/SOF +/- ribavirin provided produced exceptionally good outcomes including amongst patients with genotype 3 HCV and PWID at an average cost of <$700/patient year, including ART for those with HIV. Under the assumptions of generic drug pricing but higher laboratory costs, an average cost of $750/patient is likely a reasonable estimate for this intervention in Ukraine, excluding costs for scaling or maintaining the treatment program.
The effect of COVID-19 vaccination in Italy and perspectives for “living with the virus”
Authors: Marziano Valentina , Guzzetta Giorgio , Mammone Alessia , Riccardo Flavia , Poletti Piero , Trentini Filippo , Manica Mattia , Siddu Andrea , Bella Antonino , Stefanelli Paola , Pezzotti Patrizio , Ajelli Marco , Brusaferro Silvio , Rezza Giovanni , Merler Stefano 
Published: March 2021

AbstractVaccination campaigns against COVID-19 are allowing the progressive release of physical distancing restrictions in many countries. However, the global spread of the highly transmissible Delta variant has likely suppressed the residual chances of SARS-CoV-2 elimination through herd immunity alone. Here we assess the impact of the vaccination program in Italy since its start on December 27, 2020 and evaluate possible prospects for reopening the society while at the same time keeping COVID-19 under control. To this aim, we propose a mathematical modeling framework where levels of social activity are adjusted to match the time-series of the net reproduction number as estimated from surveillance data. We compared the estimated level of social contacts, number of deaths, and transmission potential with those of a counterfactual scenario where the same epidemic trajectory is obtained in absence of vaccination. We then evaluate the prospective impact of different scenarios of vaccination coverage and different social activity levels on SARS-CoV-2 reproduction number. We estimate that by June 30, 2021, the COVID-19 vaccination program allowed the resumption of about half the social contacts that were recorded in pre-pandemic times; in absence of vaccination, only about one third could have been resumed to obtain the same number of cases, with the added cost of about 12,100 (95%CI: 6,600-21,000) extra deaths (+27%; 95%CI: 15-47%) between December 27, 2020 and June 30, 2021. We show that the negative effect of the Delta variant diffusion in July was entirely offset by vaccination in the month of July and August 2021. Finally, we estimate that a complete return to the pre-pandemic life could be safely attained only if >90%, including children from 5 years on, will be vaccinated using mRNA vaccines developed in 2020. In any case, increasing the vaccination coverage will allow further margins for societal reopening even in absence of a pediatric vaccine. These results may support the definition of vaccination targets for countries that have already achieved a broad population coverage.
Statistical challenges of investigating a disease with a complex diagnosis
Authors: Malato João , Graça Luís , Nacul Luís , Lacerda Eliana , Sepúlveda Nuno 
Published: March 2021

AbstractGiven the absence of a disease-specific biomarker, there are more than 20 symptoms-based case definitions of myalgic encephalomyelitis/chronic fatigue syndrome. As a consequence, the diagnosis for a given patient could vary from one case definition to another. In this context, we analyse data from a biobank dedicated to this disease in order to study the agreement between different case definitions, the similarity between symptom’s profile among all participants including healthy controls and patients with multiple sclerosis. We also investigate the impact of patients’ misclassification on a hypothetical association analysis using data simulation.
Arresting Vertical Transmission of Hepatitis B Virus (AVERT-HBV) in the Democratic Republic of the Congo
Authors: Thompson Peyton , Morgan Camille E. , Ngimbi Patrick , Mwandagalirwa Kashamuka , Ravelomanana Noro , Tabala Martine , Fathy Malongo , Kawende Bienvenu , Muwonga Jérémie , Misingi Pacifique , Mbendi Charles , Luhata Christophe , Jhaveri Ravi , Cloherty Gavin , Kaba Didine , Yotebieng Marcel , Parr Jonathan B. 
Published: March 2021

ABSTRACTBackgroundHepatitis B virus (HBV) remains endemic throughout sub-Saharan Africa despite the widespread availability of effective vaccines. We evaluated the feasibility of adding HBV testing and treatment of pregnant women and birth-dose vaccination of HBV-exposed infants to the HIV prevention of MTCT (PMTCT) program infrastructure in the Democratic Republic of the Congo (DRC), where HBV treatment and birth-dose vaccination programs are not established.MethodsAs part of the HIV PMTCT program at two maternity centers in Kinshasa, DRC, pregnant women were screened for HBV at routine prenatal care registration. Pregnant women with high viral load and/or HBeAg positivity were offered tenofovir disoproxil fumarate (TDF). HBV-exposed infants received a birth-dose of HBV vaccine within 24 hours of life. The primary endpoint was the feasibility and acceptability of the study.FindingsOf 4,016 women screened, 109 (2.7%) were HBsAg-positive. Ten of 91 (11.1%) women evaluated had high-risk disease. Of 88 infants, 60 (68.2%) received a birth-dose vaccine; of these, 46 (76.7%) received a timely birth-dose. No cases of HBV MTCT were observed in our cohort. There were no serious adverse events associated with TDF nor with birth-dose vaccine. The study procedures were highly acceptable (>80%) among mothers.InterpretationAdding HBV screening and treatment of pregnant women and infant birth-dose vaccination to existing HIV PMTCT platforms is feasible in countries like the DRC. Birth-dose vaccination against HBV integrated within the current Expanded Programme on Immunization (EPI) and HIV PMTCT program could accelerate progress toward HBV elimination in Africa.
Barriers to early initiation of breastfeeding in healthy neonates in an urban hospital setting
Authors: Rubagumya Davis , Abeid Muzdalfat , Aghan Eric , Noorani Mariam 
Published: March 2021

ABSTRACTBackgroundBreastfeeding is a key intervention to improve global targets on nutrition, health and survival. The World Health Organization (WHO) recommends early initiation of breastfeeding to prevent infections in the newborn and achieve targets of exclusive breastfeeding for the first six months of life. Early initiation of breastfeeding improves neonatal-maternal bonding, reduces jaundice and prevents gastrointestinal and respiratory tract infections. Global prevalence of early initiation of breastfeeding is 45% and 51% for Tanzania. The recommended prevalence is at least 80% by WHO guidelines.ObjectiveTo explore barriers to early initiation of breastfeeding in a hospital setting.MethodsA descriptive exploratory qualitative study with semi-structured individual interviews was employed to explore the barriers to early initiation of breastfeeding in a hospital setting. Three midwives and six mothers were interviewed. The interview topic guide covered experiences and challenges of early initiation of breastfeeding. Data was analyzed using Systematic Text Condensation as described by Malterud.ResultsParticipants perceived that inadequate breastfeeding information especially on ideal time to start breastfeeding contributed to delayed initiation. The practices and environment post-delivery such as perineal tear repair and dirty labor room prevented women from initiating breastfeeding immediately.ConclusionsThe barriers identified were related to gaps in knowledge, immediate postpartum practices and individual perceptions of a non-conducive environment.
Human lipoproteins comprise at least 12 different classes that are lognormally distributed
Authors: Konishi Tomokazu , Fujiwara Risako , Saito Tadaaki , Satou Nozomi , Crofts Naoko , Iwasaki Ikuko , Abe Yoshihisa , Kawata Shinpei , Ishikawa Tatsuya 
Published: March 2021

SummaryLipoproteins in medical samples have been measured by enzymatic methods that coincide with conventional ultracentrifugation. However, the high gravity and time required for ultracentrifugation can cause sample degradation. This study presents the results of HPLC, a gentler and rapid separation method, for 55 human serum samples. The elution patterns were analysed parametrically, and the attribute of each class was confirmed biochemically. Human samples contained 12 classes of lipoproteins, each of which may consist primarily of proteins. There are three classes of VLDLs. The level of each class was distributed lognormally, and the standard amount and the 95% range were estimated. Enzymatic methods measure the levels of several mixed classes. This lognormal character suggests that the levels are controlled by the synergy of multiple factors.