bluuebunny/crossref_metadata_2025_split huggingface dataset:
Challenges and Strategies for Recruiting Type 1 Diabetes Families in Kuwait with Strong Beliefs in Familism
Authors: Rahme Zahra , Taha Nehad , Abdalla Hidaia , Abraham Smitha , Alhubail Asma , AlSanae Hala , AlMahdi Maria , Aljaser Fahed , Abdelrasoul Majda , Khawari Mona Al , Jahromi Mohamed 
Published: March 2019

AbstractType 1 diabetes (T1D) is one of the most common endocrine and metabolic conditions in children. In fact, this disease in children and adolescents has been increasing exponentially, with Kuwait being ranked second highest in the world regarding the number of T1D incidences. Kuwait is an oil-rich country known for its strong sense of familism, affiliative obedience, and filial obligation. Therefore, a familial study of this disease may disclose certain causative agents responsible for passing the disease on to subsequent generations.To recruit T1D patients and their family members, three different scenarios were developed. First, since Kuwaiti families are generally obedient to their doctors, the authors decided to recruit the patients through their endocrine physicians. Second, home visits were performed for meeting the families’ requirements. In this case, a team consisting of one nurse, two phlebotomists (a male and a female, since some refused to be seen by the opposite gender), and a driver of the institute’s car was arranged. Finally, two diabetes educators were employed to resolve any issues raised during the recruitment process. Utilizing these approaches helped convince the culturally and religiously oriented Kuwaiti families to participate in this study. In this case, the doctors and educators were not only aware of the obstacles in this population but also sensitive to the families’ beliefs. This paper reports on our experience in recruitment and presents a roadmap for any future familial studies on culturally tailored societies i.e. Arab populations.
Short translational ramp determines efficiency of protein synthesis
Authors: Verma Manasvi , Choi Junhong , Cottrell Kyle A. , Lavagnino Zeno , Thomas Erica N. , Pavlovic-Djuranovic Slavica , Szczesny Pawel , Piston David W. , Zaher Hani , Puglisi Joseph D. , Djuranovic Sergej 
Published: March 2019

AbstractIt is generally assumed that translation efficiency is governed by translation initiation. However, the efficiency of protein synthesis is regulated by multiple factors including tRNA abundance, codon composition, mRNA motifs and amino-acid sequence1–4. These factors influence the rate of protein synthesis beyond the initiation phase of translation, typically by modulating the rate of peptide-bond formation and to a lesser extent that of translocation. The slowdown in translation during the early elongation phase, known as the 5’ translational ramp, likely contributes to the efficiency of protein synthesis 5–9. Multiple mechanisms, which could explain the molecular basis for this translational ramp, have been proposed that include tRNA abundance bias6,9, the rate of translation initiation10–15, mRNA and ribosome structure 11,12,14,16–18, or retention of initiation factors during early elongation events 19. Here, we show that the amount of synthesized protein (translation efficiency) depends on a short translational ramp that comprises the first 5 codons in mRNA. Using a library of more than 250,000 reporter sequences combined with in vitro and in vivo protein expression assays, we show that differences in the short ramp can lead to 3 to 4 orders of magnitude changes in protein abundance. The observed difference is not dependent on tRNA abundance, efficiency of translation initiation, or overall mRNA structure. Instead, we show that translation is regulated by amino-acid-sequence composition and local mRNA sequence. Single-molecule measurements of translation kinetics indicate substantial pausing of ribosome and abortion of protein synthesis on the 4th or 5th codon for distinct amino acid or nucleotide compositions. Introduction of preferred sequence motifs, only at the exact positions within the mRNA, improves protein synthesis for recombinant proteins, indicating an evolutionarily conserved mechanism for controlling translational efficiency.
Targeted DNA transposition using a dCas9-transposase fusion protein
Authors: Bhatt Shivam , Chalmers Ronald 
Published: March 2019

SUMMARYHomology directed genome engineering is limited by transgene size. Although DNA transposons are more efficient with large transgenes, random integrations are potentially mutagenic. Catalytically inactive Cas9 is attractive candidate for targeting a transposase fusion-protein because of its high specificity and affinity for its binding site. Here we demonstrate efficient Cas9 targeting of a mariner transposon. Targeted integrations were tightly constrained at two adjacent TA dinucleotides about 20 bp to one side of the gRNA binding site. Biochemical analysis of the nucleoprotein complexes demonstrated that the transposase and Cas9 moieties of the fusion protein can bind their respective substrates independently. In the presence of the Cas9 target DNA, kinetic analysis revealed a delay between first and second strand cleavage at the transposon end. This step involves a significant conformational change that may be hindered by the properties of the interdomainal linker. Otherwise, the transposase behaved normally and was proficient for integration in vitro and in vivo.
Connectional heterogeneity in the mouse auditory corticocollicular system
Authors: Yudintsev Georgiy , Asilador Alexander , Coppinger Macey , Nair Kavyakrishna , Prasad Masumi , Llano Daniel A. 
Published: March 2019

AbstractThe auditory cortex (AC) sends long-range projections to virtually all subcortical structures important for hearing. One of the largest and most complex of these - the projection between AC and inferior colliculus (IC, the corticocollicular pathway) - has attracted attention due to its potential to alter IC response properties. The corticocollicular pathway comprises a component originating from layer 5, but recent evidence suggests a significant contribution from deep layer 6, constituting 25% of corticocollicular neurons in mouse. The functions of layer-specific corticocollicular projections are poorly understood. Here, using a combination of tracers and in vivo imaging, we observed that layer 5 and layer 6 corticocollicular neurons differ in their cortical areas of origin, as well as IC termination patterns. Layer 5 corticocollicular neurons are concentrated in primary AC areas while layer 6 corticocollicular neurons emanate from broad auditory and non-auditory areas of temporal cortex. In addition, layer 5 projects to three IC subdivisions with axo-somatic terminals in the central nucleus, while layer 6 projects to non-central nuclei and targets the most superficial layers. These findings suggest that layer 5 corticocollicular neurons form a direct connection between primary AC and IC while the layer 6 projection is more diffusely organized and carries non-auditory information to modulate IC.
A novel Ca2+-binding protein influences photosynthetic electron transport inAnabaenasp. PCC 7120
Authors: Walter Julia , Selim Khaled A. , Leganés Francisco , Fernández-Piñas Francisca , Vothknecht Ute C. , Forchhammer Karl , Aro Eva-Mari , Gollan Peter J. 
Published: March 2019

SummaryCa2+is a potent signalling molecule that regulates many cellular processes. In cyanobacteria, Ca2+has been linked to cell growth, stress response and photosynthesis, and to the development of specialist heterocyst cells in certain nitrogen-fixing species. Despite this, the pathways of calcium signal transduction in cyanobacteria are poorly understood, and only a few protein components are known. The current study describes a previously unreported calcium-binding protein which was called the Calcium Sensor EF-hand (CSE), which is conserved in filamentous, nitrogen-fixing cyanobacteria. CSE is shown to bind calcium, which induces a conformational change in the protein structure. Poor growth of a strain ofAnabaenasp. PCC 7120 overexpressing CSE was attributed to diminished photosynthetic performance. Transcriptomics, biophysics and proteomics analyses revealed modifications in the light-harvesting phycobilisome and photosynthetic reaction center-protein complexes, and downregulated respiration.
Fertility intentions and influential factors in Dalian urban city ---A cross-sectional study based on Universal Two-child policy in China
Authors: Qiu Hongyan , Zhang Qun , Zhang Jin , Ren Yangjie , Zhou Xujuan , Li Shuangyue , Liang Hong , Luo Jiajia , Wang Qingshan , Hou Liyan 
Published: March 2019

AbstractBackgroundIn October, 2015, Chinese government announced that one-child policy had finally been replaced by a universal two-child policy. However, the effects of new policy may be far less than expected. So we conducted this research to explore potential influential factors of fertility intention.MethodsThis cross-sectional study was conducted and a self-administered questionnaire was designed for collecting socio-demographic information, future fertility intention and influential factors of individual reproductive behavior. The analyses were performed using the SPSS 19.0 statistical software package.ResultsA total of 1370 respondents were interviewed. Our research indicated that the mean ideal number of children was only 1.73 and urban respondents’ sex preference was symmetrical preference. 79.1% (884) married people had the first child already, only 7.6% (71) respondents had two children. Among 1370 participants, 30.4% respondents stated that they would have a second child; while 69.6% respondents refused to have two children in future (just wanted only a child). Binary logistic regression analysis (model 1) showed that female, older age, lower education lever, birth place was Dalian, lower family income, the ideal number of children were associated with having 1 child in the future. Model 2 (only respondents with childbearing experience) showed that female, lower family income, couldn’t get additional financial support from parents were more likely refused to have two children; in additional, the ideal number of children and childbearing experience were significantly influences on future fertility intention.ConclusionFertility intention and reproductive behavior still below replacement in Dalian city. Our results suggest that several factors (including socioeconomic characteristics, economic factors, desired number of child, childbearing experience) have distinctive effects on fertility intention.
Microsecond Molecular Dynamics Simulations of Diphtheria Toxin Translocation T-Domain pH-Dependent Unfolding in Solution
Authors: Flores-Canales Jose C. , Simakov Nikolay A. , Kurnikova Maria 
Published: March 2019

ABSTRACTDiphtheria toxin is a multi-domain protein that invades cells by using their own endocytosis mechanism. In endocytosis, an endosome, a lipid bilayer vesicle, is formed to encapsulate an extracellular molecule. Subsequent acidification of endosome internal solution induces conformational rearrangements and membrane insertion of such encapsulated diphtheria toxin translocation domain (T-domain). In solution at neutral pH, a stand-alone T-domain adopts an all alpha-helical globular structure; however, atomistic details of the pH-dependent conformational changes of the protein are not completely understood. We model structural rearrangements in T-domain in 18 µs long molecular dynamics (MD) simulations of neutral and low pH T-domain models in explicit solvent. At low pH, six histidine residues of the protein were protonated. Two independent MD trajectories resulted in partial protein unfolding at low pH, in which similar regions of the protein conformational subspace were explored. Notably, a pH induced unfolding transition was initiated by partial unfolding of helix TH4 followed by unfolding of helix TH1. Helix TH2 repeatedly unfolds in the low pH T-domain model, which is consequently predicted to be disordered by a consensus of disorder prediction algorithms. Protonation of histidines disrupted a hydrophobic core containing a putative transmembrane helix TH8, which is encircled by hydrophobic surfaces of helices TH3, TH5 and TH9. Afterwards, the low pH T-domain model was reorganized into an ensemble of partially unfolded structures with increased solvent exposure of hydrophobic and charged sites. Thus, MD simulations suggest the destabilizing role of protonation of histidines, in the neutral pH conformation in solution, which may facilitate the initial stages of T-domain membrane binding. The simulation at neutral pH samples conformations in the vicinity of the native structure of the protein. However, significant fluctuations of the protein, including unfolding and refolding of α-helices were observed at these simulation time-scales.
Genetic analysis ofTP53gene mutations in exon 4 and exon 8 among esophageal cancer patients in Sudan
Authors: Eltaher Sulafa Mohamed , Idris Abeer Babiker , Mahmoud A. H , Yousif Mawadah Yousif Mohamed , Mohamed Nouh Saad , Hamid Muzamil M. Abdel , Elsiddig Kamal Elzaki , Hassan Mohamed A. , Yousif Galal Mohammed 
Published: March 2019

AbstractBackgroundEsophageal carcinoma (EC) represents the 1strank among all gastrointestinal cancers in Sudan. Despite little publications, there is a deep absence of literature about the molecular pathogenesis of EC considering TP53 gene from Sudanese population.AimsIn this study, we performed the expression analysis on p53 protein level by immunohistochemical staining and examined its overexpression with p53 mutations in exons 4 and 8 among esophageal cancer patients in Sudan.Material and MethodsFixed tissue with 10% buffered formalin was stained by Hematoxlin and Eosin (H&E), Alcian blue-Periodic Acid Schiff (PAS) and Immunohistochemistry stain. PCR-RFLP was used to study the frequencies of p53 codon 72 R/P polymorphism. Conventional PCR and sanger sequencing were applied for exon 4 and exon 8. Then detection and functional analysis of SNPs and mutations were performed using various in bioinformatics tools.ResultNuclear accumulations for p53 protein was detected in all of the esophageal carcinomas examined while no accumulations were observed in normal control sections. Four patients with immune-positive for p53 showed no mutations in p53 gene (exon4 and exon8). The incidence of the homozygous mutant variant Pro/Pro was higher in esophageal cancerous patients comparing to healthy control subject 20(71. 4%) vs. 1(10%), respectively (p=0.0026). In exon 4, no mutation was detected other than NG_017013.2:g. 16397C>G. While in exon 8, g.18783-18784AG>TT, g.18803A>C, g.18860A>C, g.18845A>T and g.18863_ 18864 InsT were observed.Conclusionwe found a significant association between the overexpression of TP53 protein and mutation in exon 4 and 8. A silent mutation P301P was detected in all of examined cases. Two patients who diagnosed with small cell sarcoma have shared the same mutations in exon8. Further studies with large sample size are required to demonstrate the usefulness of these mutations in the screening of EC especially SCCE.
Risky Decision-Making Predicts Dopamine Release Dynamics in Nucleus Accumbens Shell
Authors: Freels Timothy G. , Gabriel Daniel B. K. , Lester Deranda B. , Simon Nicholas W. 
Published: March 2019

AbstractThe risky decision-making task (RDT) measures risk-taking in a rat model by assessing preference between a small, safe reward and a large reward with increasing risk of punishment (mild foot shock). It is well-established that dopaminergic drugs modulate risk-taking; however, little is known about how differences in baseline phasic dopamine signaling drive individual differences in risk preference. Here, we usedin vivofixed potential amperometry in male Long-Evans rats to test if phasic nucleus accumbens shell (NACs) dopamine dynamics are associated with risk-taking. We observed a positive correlation between medial forebrain bundle-evoked dopamine release in the NACs and risky decision-making, suggesting that risk-taking is associated with elevated dopamine sensitivity. Moreover, “risk-taking” subjects were found to demonstrate greater phasic dopamine release than “risk-averse” subjects. Risky decision-making also predicted enhanced sensitivity to nomifensine, a dopamine reuptake inhibitor, quantified as elevated latency for dopamine to clear from the synapse. Importantly, this hyperdopaminergic phenotype was selective for risky decision-making, as delay discounting performance was not predictive of phasic dopamine release or dopamine supply. These data identify phasic NACs dopamine release as a possible therapeutic target for alleviating the excessive risk-taking observed across multiple forms of psychopathology.Significance StatementExcessive risky decision-making is a hallmark of addiction, promoting ongoing drug seeking despite the risk of social, financial, and physical consequences. However, punishment-driven risk-taking is understudied in preclinical models. Here, we examined the relationship between individual differences in risk-taking and dopamine release properties in the rat nucleus accumbens shell, a brain region associated with motivation and decision-making. We observed that high risk taking predicted elevated phasic dopamine release and sensitivity to the dopamine transporter blocker nomifensine. This hypersensitive dopamine system was not observed in rats with high impulsive choice, another behavior associated with substance use disorder. This provides critical information about neurobiological factors underlying a form of decision-making that promotes vulnerability to substance abuse.
DNA damage-specific effects of Tel1/ATM and γH2A/γH2AX on checkpoint signaling inSaccharomyces cerevisiae
Authors: Siler Jasmine , Guo Na , Liu Zhengfeng , Qin Yuhua , Bi Xin 
Published: March 2019

AbstractDNA lesions trigger the activation of DNA damage checkpoints (DDCs) that stop cell cycle progression and promote DNA damage repair.Saccharomyces cerevisiaeTel1 is a homolog of mammalian ATM kinase that plays an auxiliary role in DDC signaling. γH2A, equivalent to γH2AX in mammals, is an early chromatin mark induced by DNA damage that is recognized by a group of DDC and DNA repair factors. We find that both Tel1 and γH2A negatively impact G2/M checkpoint in response to DNA topoisomerase I poison camptothecin independently of each other. γH2A also negatively regulates DDC induced by DNA alkylating agent methyl methanesulfonate. These results, together with prior findings demonstrating positive or no roles of Tel1 and γH2A in DDC in response to other DNA damaging agents such as phleomycin and ionizing radiation, suggest that Tel1 and γH2A have DNA damage-specific effects on DDC. We present data indicating that Tel1 acts in the same pathway as Mre11-Rad50-Xrs2 complex to suppress CPT induced DDC possibly by repairing topoisomerase I-DNA crosslink. On the other hand, we find evidence consistent with the notion that γH2A regulates DDC by mediating the competitive recruitment of DDC mediator Rad9 and DNA repair factor Rtt107 to sites of DNA damage. We propose that γH2A serves to create a dynamic balance between DDC and DNA repair that is influenced by the nature of DNA damage.
Mechanism of pharmacochaperoning in KATP channels revealed by cryo-EM
Authors: Martin Gregory M. , Sung Min Woo , Yang Zhongying , Innes Laura M. , Kandasamy Balamurugan , David Larry L. , Yoshioka Craig , Shyng Show-Ling 
Published: March 2019

AbstractATP-sensitive potassium (KATP) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic β-cells to maintain glucose homeostasis. Mutations that impair channel folding or assembly prevent cell surface expression and cause congenital hyperinsulinism. Structurally diverse KATPinhibitors have been shown to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of KATPchannels bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. We found all three drugs bind within a common pocket in SUR1. Further, we found the N-terminus of Kir6.2 inserted within the central cavity of the SUR1 ABC core, adjacent the drug binding pocket. The findings reveal a common mechanism by which diverse compounds stabilize the Kir6.2 N-terminus within the SUR1 ABC core, allowing it to act as a firm “handle” for the assembly of metastable mutant SUR1-Kir6.2 complexes.
The Developmental Transcriptome forLytechinus variegatusExhibits Temporally Punctuated Gene Expression Changes
Authors: Hogan John D. , Keenan Jessica L. , Luo Lingqi , Hawkins Dakota Y. , Ibn-Salem Jonas , Lamba Arjun , Schatzberg Daphne , Piacentino Michael L. , Zuch Daniel T. , Core Amanda B. , Blumberg Carolyn , Timmermann Bernd , Grau José Horacio , Speranza Emily , Andrade-Narravo Miguel A. , Irie Naoki , Poustka Albert J. , Bradham Cynthia A. 
Published: March 2019

AbstractEmbryonic development is arguably the most complex process an organism undergoes during its lifetime, and understanding this complexity is best approached with a systems-level perspective. The sea urchin has become a highly valuable model organism for understanding developmental specification, morphogenesis, and evolution. As a non-chordate deuterostome, the sea urchin occupies an important evolutionary niche between protostomes and vertebrates.Lytechinus variegatus(Lv) is an Atlantic species that has been well studied, and which has provided important insights into signal transduction, patterning, and morphogenetic changes during embryonic and larval development. The Pacific species,Strongylocentrotus purpuratus(Sp), is another well-studied sea urchin, particularly for gene regulatory networks (GRNs) andcis-regulatory analyses. A well-annotated genome and transcriptome for Sp are available, but similar resources have not been developed for Lv. Here, we provide an analysis of the Lv transcriptome at 11 timepoints during embryonic and larval development. The data indicate that the gene regulatory networks that underlie specification are well-conserved among sea urchin species. We show that the major transitions in variation of embryonic transcription divide the developmental time series into four distinct, temporally sequential phases. Our work shows that sea urchin development occurs via sequential intervals of relatively stable gene expression states that are punctuated by abrupt transitions.
Visual awareness judgments are sensitive to accuracy feedback in stimulus discrimination task
Authors: Siedlecka Marta , Wereszczyński Michał , Paulewicz Borysław , Wierzchoń Michał 
Published: March 2019

AbstractIn this study we tested the hypothesis that perceptual awareness judgments are sensitive to the accuracy feedback about previous behaviour. We used a perceptual discrimination task in which participants reported their stimulus awareness. We created two conditions: No-feedback and Feedback (discrimination accuracy feedback was provided at the end of each trial). The results showed that visual awareness judgments are related to the accuracy of current and previous responses. Participants reported lower stimulus awareness for incorrectly versus correctly discriminated stimuli in both conditions; they also reported lower stimulus awareness in trials preceded by incorrect discrimination responses, compared to trials preceded by correct discrimination. This difference was significantly stronger in the Feedback condition. Moreover, in the Feedback condition we also observed larger post-error slowing for PAS ratings. We discuss the relation between the effects of performance monitoring and visual awareness and interpret the results in the context of current theories of consciousness.