bluuebunny/crossref_metadata_2025_split huggingface dataset:
HbA1c and Risks of All-Cause and Cause-Specific Death in Subjects without Known Diabetes: A Dose-Response Meta-Analysis of Prospective Cohort Studies
Authors: Zhong Guo-Chao , Ye Ming-Xin , Cheng Jia-Hao , Zhao Yong , Gong Jian-Ping 
Published: April 2016

AbstractWhether HbA1c levels are associated with mortality in subjects without known diabetes remains controversial. Moreover, the shape of the dose–response relationship on this topic is unclear. Therefore, a dose–response meta-analysis was conducted. PubMed and EMBASE were searched. Summary hazard ratios (HRs) were calculated using a random-effects model. Twelve studies were included. The summary HR per 1% increase in HbA1c level was 1.03 [95% confidence interval (CI) = 1.01–1.04] for all-cause mortality, 1.05 [95% CI = 1.02–1.07) for cardiovascular disease (CVD) mortality and 1.02 (95% CI = 0.99–1.07) for cancer mortality. After excluding subjects with undiagnosed diabetes, the aforementioned associations remained significant for CVD mortality only. After further excluding subjects with prediabetes, all aforementioned associations presented non-significance. Evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer was found (all Pnon-linearity < 0.05). The dose–response curves were relatively flat for HbA1c less than around 5.7% and rose steeply thereafter. In conclusion, higher HbA1c level is associated with increased mortality from all causes and CVD among subjects without known diabetes. However, this association is driven by those with undiagnosed diabetes or prediabetes. The results regarding cancer mortality should be treated with caution due to limited studies.
Th17 responses and natural IgM antibodies are related to gut microbiota composition in systemic lupus erythematosus patients
Authors: López Patricia , de Paz Banesa , Rodríguez-Carrio Javier , Hevia Arancha , Sánchez Borja , Margolles Abelardo , Suárez Ana 
Published: April 2016

AbstractIntestinal dysbiosis, characterized by a reduced Firmicutes/Bacteroidetes ratio, has been reported in systemic lupus erythematosus (SLE) patients. In this study, in vitro cultures revealed that microbiota isolated from SLE patient stool samples (SLE-M) promoted lymphocyte activation and Th17 differentiation from naïve CD4+ lymphocytes to a greater extent than healthy control-microbiota. Enrichment of SLE-M with Treg-inducing bacteria showed that a mixture of two Clostridia strains significantly reduced the Th17/Th1 balance, whereas Bifidobacterium bifidum supplementation prevented CD4+ lymphocyte over-activation, thus supporting a possible therapeutic benefit of probiotics containing Treg-inducer strains in order to restore the Treg/Th17/Th1 imbalance present in SLE. In fact, ex vivo analyses of patient samples showed enlarged Th17 and Foxp3+ IL-17+ populations, suggesting a possible Treg-Th17 trans-differentiation. Moreover, analyses of fecal microbiota revealed a negative correlation between IL-17+ populations and Firmicutes in healthy controls, whereas in SLE this phylum correlated directly with serum levels of IFNγ, a Th1 cytokine slightly reduced in patients. Finally, the frequency of Synergistetes, positively correlated with the Firmicutes/Bacteroidetes ratio in healthy controls, tended to be reduced in patients when anti-dsDNA titers were increased and showed a strong negative correlation with IL-6 serum levels and correlated positively with protective natural IgM antibodies against phosphorylcholine.
Regnase-1 in microglia negatively regulates high mobility group box 1-mediated inflammation and neuronal injury
Authors: Liu Xiao-Xi , Wang Chen , Huang Shao-Fei , Chen Qiong , Hu Ya-Fang , Zhou Liang , Gu Yong 
Published: April 2016

AbstractExtracellular high mobility group box 1 (HMGB1) has been demonstrated to function as a proinflammatory cytokine and induces neuronal injury in response to various pathological stimuli in central nervous system (CNS). However, the regulatory factor involved in HMGB1-mediated inflammatory signaling is largely unclear. Regulatory RNase 1 (Regnase-1) is a potent anti-inflammation enzyme that can degrade a set of mRNAs encoding proinflammatory cytokines. The present study aims to determine the role of Regnase-1 in the regulation of HMGB1-mediated inflammatory injury in CNS. Cultured microglia and rat brain were treated with recombinant HMGB1 to examine the induction of Regnase-1 expression. Moreover, the role of Regnase-1 in modulating the expression of inflammatory cytokines and neuronal injury was then investigated in microglia by specific siRNA knockdown upon HMGB1 treatment. Results showed that HMGB1 could significantly induce the de novo synthesis of Regnase-1 in cultured microglia. Consistently, Regnase-1 was elevated and found to be co-localized with microglia marker in the brain of rat treated with HMGB1. Silencing Regnase-1 in microglia enhanced HMGB1-induced expression of proinflammatory cytokines and exacerbated neuronal toxicity. Collectively, these results suggest that Regnase-1 can be induced by HMGB1 in microglia and negatively regulates HMGB1-mediated neuroinflammation and neuronal toxicity.
Preventive effects of minocycline in a neurodevelopmental two-hit model with relevance to schizophrenia
Authors: Giovanoli S , Engler H , Engler A , Richetto J , Feldon J , Riva M A , Schedlowski M , Meyer U 
Published: April 2016

AbstractMaternal immune activation can increase the vulnerability of the offspring to develop neuroimmune and behavioral abnormalities in response to stress in puberty. In offspring of immune-challenged mothers, stress-induced inflammatory processes precede the adult onset of multiple behavioral dysfunctions. Here, we explored whether an early anti-inflammatory intervention during peripubertal stress exposure might prevent the subsequent emergence of adult behavioral pathology. We used an environmental two-hit model in mice, in which prenatal maternal administration of the viral mimetic poly(I:C) served as the first hit, and exposure to sub-chronic unpredictable stress during peripubertal maturation as the second hit. Using this model, we examined the effectiveness of the tetracycline antibiotic minocycline (MINO) given during stress exposure to block stress-induced inflammatory responses and to prevent subsequent behavioral abnormalities. We found that combined exposure to prenatal immune activation and peripubertal stress caused significant deficits in prepulse inhibition and increased sensitivity to the psychotomimetic drugs amphetamine and dizocilpine in adulthood. MINO treatment during stress exposure prevented the emergence of these behavioral dysfunctions. In addition, the pharmacological intervention blocked hippocampal and prefrontal microglia activation and interleukin-1β expression in offspring exposed to prenatal infection and peripubertal stress. Together, these findings demonstrate that presymptomatic MINO treatment can prevent the subsequent emergence of multiple behavioral abnormalities relevant to human neuropsychiatric disorders with onset in early adulthood, including schizophrenia. Our epidemiologically informed two-hit model may thus encourage attempts to explore the use of anti-inflammatory agents in the early course of brain disorders that are characterized by signs of central nervous system inflammation during development.
Regulation of prefrontal cortex myelination by the microbiota
Authors: Hoban A E , Stilling R M , Ryan F J , Shanahan F , Dinan T G , Claesson M J , Clarke G , Cryan J F 
Published: April 2016

AbstractThe prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC.
Multidimensional Approach to the Development of a Mandarin Chinese–Oriented Sound Test
Authors: Hung Yu-Chen , Lin Chun-Yi , Tsai Li-Chiun , Lee Ya-Jung 
Published: April 2016

Purpose
Because the Ling six-sound test is based on American English phonemes, it can yield unreliable results when administered to non-English speakers. In this study, we aimed to improve specifically the diagnostic palette for Mandarin Chinese users by developing an adapted version of the Ling six-sound test.

Method
To determine the set of testing sounds, we performed an exhaustive acoustic and statistical analysis in which we considered not only the general acoustic properties but also the order of acquisition and the inter- and intraspeaker variability.

Results

Six phonemes (/u, ə, a, i, tɕ
h
, s/) were selected as the testing items for the Mandarin Chinese sound test because these sounds exhibit a highly compartmentalized frequency specificity, spanning the entire Chinese speech spectrum, as well as a relatively low articulatory variability and can be acquired fairly early.

Conclusion
Through adopting language-dependent modifications, caregivers and professionals should have a more adequate tool to monitor children's auditory access to the full range of Mandarin speech sounds.

Supplemental Material

https://doi.org/10.23641/asha.14963634
Exploring the Utility of a School-Age Narrative Microstructure Index: Proportion of Restricted Utterances
Authors: Jerger Sara , Thorne John C. 
Published: April 2016

PurposeThis research attempted to replicate Hoffman's 2009 finding that the proportion of narrative utterances with semantic or syntactic errors (i.e., ≥ 14% “restricted utterances”) can differentiate school-age children with typical development from those with language impairment with a sensitivity of 83% and specificity of 88%.MethodMethods similar to Hoffman (2009) were used to evaluate an existing set of narratives from 16 age-matched pairs of 8- to 9-year-old children, half with known language impairment. Transcripts were segmented into T-units; a code of [RESTRICTED] was assigned to any utterance with semantic or syntactic errors.ResultsA Welch'sttest for independent samples revealed a statistically significant difference in the mean proportion of restricted utterances between the two groups after accommodation for an outlier with typical development. A cutoff of ≥ 14% restricted utterances replicated Hoffman's (2009) sensitivity but not specificity. Post hoc analysis of specific error types found sensitivity and specificity rates similar to Hoffman's as well as a significant difference in means when using a proportion of sentence–internal morphosyntactic errors.ConclusionResults support further exploration of utterance-level error coding for diagnostic purposes and future development of this approach to meet clinical assessment needs.
Heterotrimeric G-protein shuttling via Gip1 extends the dynamic range of eukaryotic chemotaxis
Authors: Kamimura Yoichiro , Miyanaga Yukihiro , Ueda Masahiro 
Published: April 2016

Significance
Eukaryotic chemotactic cells can recognize chemical gradients over a wide range of concentrations. This ability is physiologically important for numerous biological processes; however, its underlying mechanism is unknown. Here we report that the dynamic range of chemotaxis is extended to higher concentrations by gradient sensing achieved via regulation of trimeric G-protein shuttling between the cytosol and plasma membrane. G protein-interacting protein 1 (Gip1) regulates this intracellular G-protein translocation, which redistributes cytosolic G proteins to the plasma membrane along chemical gradients at high chemoattractant concentrations. This dynamic spatiotemporal regulation of trimeric G protein yields proper processing of receptor-mediated signaling.
PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells
Authors: Chandrakanthan Vashe , Yeola Avani , Kwan Jair C. , Oliver Rema A. , Qiao Qiao , Kang Young Chan , Zarzour Peter , Beck Dominik , Boelen Lies , Unnikrishnan Ashwin , Villanueva Jeanette E. , Nunez Andrea C. , Knezevic Kathy , Palu Cintia , Nasrallah Rabab , Carnell Michael , Macmillan Alex , Whan Renee , Yu Yan , Hardy Philip , Grey Shane T. , Gladbach Amadeus , Delerue Fabien , Ittner Lars , Mobbs Ralph , Walkley Carl R. , Purton Louise E. , Ward Robyn L. , Wong Jason W. H. , Hesson Luke B. , Walsh William , Pimanda John E. 
Published: April 2016

Significance
In this report we describe the generation of tissue-regenerative multipotent stem cells (iMS cells) by treating mature bone and fat cells transiently with a growth factor [platelet-derived growth factor–AB (PDGF-AB)] and 5-Azacytidine, a demethylating compound that is widely used in clinical practice. Unlike primary mesenchymal stem cells, which are used with little objective evidence in clinical practice to promote tissue repair, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner without forming tumors. This method can be applied to both mouse and human somatic cells to generate multipotent stem cells and has the potential to transform current approaches in regenerative medicine.
Long antibody HCDR3s from HIV-naïve donors presented on a PG9 neutralizing antibody background mediate HIV neutralization
Authors: Willis Jordan R. , Finn Jessica A. , Briney Bryan , Sapparapu Gopal , Singh Vidisha , King Hannah , LaBranche Celia C. , Montefiori David C. , Meiler Jens , Crowe James E. 
Published: April 2016

Significance
When HIV neutralizing antibody (Ab) responses occur, they are often mediated by Abs with exceptional levels of somatic mutation. An exception are HIV neutralizing Abs that feature long heavy-chain complementarity-determining region 3 (HCDR3) regions, such as the Ab PG9. Relative to many other HIV broadly neutralizing Abs (bnAbs), PG9 has fewer somatic mutations than most potent bnAbs. Here we used deep-sequencing and computational methods to identify a panel of HCDR3 sequences in HIV-naïve donors that mediated binding and neutralization of HIV by mimicking the bnAb PG9 long HCDR3 region when expressed in the context of the rest of the PG9 antibody sequence. Thus, it may be possible for structure-based vaccine design efforts to engage long HCDR3s available in the HIV-naïve Ab repertoire and elicit a neutralizing response.
Pathogen receptor discovery with a microfluidic human membrane protein array
Authors: Glick Yair , Ben-Ari Ya’ara , Drayman Nir , Pellach Michal , Neveu Gregory , Boonyaratanakornkit Jim , Avrahami Dorit , Einav Shirit , Oppenheim Ariella , Gerber Doron 
Published: April 2016

Significance
In this work, we report, to our knowledge, the first in vitro tool for host–pathogen screening that encompasses thousands of functional insoluble proteins—primarily transmembrane proteins—immobilized within a microfluidic device. We discovered previously unknown protein–pathogen interactions, and then selected interactions were further validated by conventional methods. Considering the tremendous difficulty in discovering pathogen receptors, this in vitro high-throughput approach is extremely important and efficient for receptor discovery and understanding pathogen tropism, with relevance to emerging human diseases.
The effect of gene interactions on the long-term response to selection
Authors: Paixão Tiago , Barton Nicholas H. 
Published: April 2016

Significance
The role of gene interactions in the response to selection has long been a controversial subject; whereas some have claimed they are not relevant for adaptation, others have argued that their long-term effects are of high significance. In this manuscript, we derive simple and general predictions for the effect of gene interactions on the long-term response to selection in two extreme regimes. We show that, when the dynamics of allele frequencies are dominated by genetic drift, the long-term response is surprisingly simple, depending only on the initial components of the trait variance, regardless of the detailed genetic architecture. In the opposite regime, when selection dominates the dynamics of allele frequencies, the long-term response depends only on the genotype−phenotype.
Hall effect in quantum critical charge-cluster glass
Authors: Wu Jie , Bollinger Anthony T. , Sun Yujie , Božović Ivan 
Published: April 2016

Significance
In cuprates, when doping is reduced superconductivity weakens and eventually disappears. The sample becomes “insulating” insofar that resistivity increases as the temperature is lowered, but the conductivity remains high, so the nature of this strange insulating state has been a puzzle. Here, we study the superconductor–insulator transition, improving the control of the doping level by 2 orders of magnitude and the sensitivity in probing transport fluctuations by 3 orders of magnitude. Our data reveal that at the lowest temperatures superconductivity competes with a charge-glass state. We propose that the latter is a glassy version of a charge density wave, and that it originates from strong localization due to charge–lattice coupling.
Population size does not explain past changes in cultural complexity
Authors: Vaesen Krist , Collard Mark , Cosgrove Richard , Roebroeks Wil 
Published: April 2016

SignificanceArchaeologists have long tried to understand why cultural complexity often changed in prehistory. Recently, a series of highly influential formal models have suggested that demography is the key factor. According to these models, the size of a population determines its ability to invent and maintain cultural traits. In this paper, we demonstrate that the models in question are flawed in two important respects: They use questionable assumptions, and their predictions are not supported by the available archaeological and ethnographic evidence. As a consequence, little confidence can be invested in the idea that demography explains the changes in cultural complexity that have been identified by archaeologists. An alternative explanation is required.
Functional network inference of the suprachiasmatic nucleus
Authors: Abel John H. , Meeker Kirsten , Granados-Fuentes Daniel , St. John Peter C. , Wang Thomas J. , Bales Benjamin B. , Doyle Francis J. , Herzog Erik D. , Petzold Linda R. 
Published: April 2016

Significance
In mammals, circadian rhythms are controlled by a network of neurons in the brain. The structure of this network dictates organism-wide behavior and adaptation to the environment. We used a neurotoxin to desynchronize this circadian network and then used tools from information theory to determine which cells communicate to establish synchronization. Our results show that this functional network consists of two densely-connected cores, surrounded by sparsely connected shell regions. These findings represent the first time, to our knowledge, that this network has been examined at single cell resolution and show that the importance of these core network regions is independent of light input.
Polarized localization of voltage-gated Na
+
channels is regulated by concerted FGF13 and FGF14 action
Authors: Pablo Juan Lorenzo , Wang Chaojian , Presby Matthew M. , Pitt Geoffrey S. 
Published: April 2016

Significance
Neurons concentrate voltage-gated sodium channels (VGSCs) in axons while limiting VGSCs in the somatodendritic compartment. This axonal concentration is important for efficient generation of the action potential, but it remains unclear what limits the concentration of VGSCs in the somatodendritic compartment. Here, we report that two highly similar molecules, FGF13 and FGF14, collaborate to maintain proper VGSC localization. FGF13 is a critical mediator of the process that keeps VGSCs low in the somatodendritic compartment, whereas FGF14 is an important regulator of VGSC localization to the axon.
Importance of ocean salinity for climate and habitability
Authors: Cullum Jodie , Stevens David P. , Joshi Manoj M. 
Published: April 2016

Significance
The habitability of the growing number of confirmed exoplanets is a question of wide interest and importance. A key factor determining habitability is planetary climate, which is influenced heavily by the presence of liquid water oceans, and in particular, the heat transported around the planet by these oceans. Here the impact of average ocean salinity, a key property in determining the density of water, on ocean state is investigated. It is shown that oceans that have sufficiently different average salinities to Earth consist of circulations of opposite direction: sinking in the tropics, filling the deep ocean with warm water, and ultimately warming the polar regions. Variations in ocean properties can therefore extend the range of exoplanet habitability.
Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction
Authors: Bavli Danny , Prill Sebastian , Ezra Elishai , Levy Gahl , Cohen Merav , Vinken Mathieu , Vanfleteren Jan , Jaeger Magnus , Nahmias Yaakov 
Published: April 2016

Significance
Microfluidic organ-on-a-chip technology is poised to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Here we demonstrate a sensor-integrated platform permitting real-time tracking of the dynamics of metabolic adaptation to mitochondrial dysfunction. Our approach permits detection of chemical toxicity before any effects on cell or tissue viability can be observed.
Test of the invasive pathogen hypothesis of bumble bee decline in North America
Authors: Cameron Sydney A. , Lim Haw Chuan , Lozier Jeffrey D. , Duennes Michelle A. , Thorp Robbin 
Published: April 2016

SignificanceWild bumble bees are experiencing population declines globally. Causes of declines in North American populations are unclear, although declining species are more frequently infected by the pathogenNosema bombi. A widely accepted hypothesis suggests that contact with European species during domestication led to the introduction of exoticN. bombi. By screening museum specimens, we show thatN. bombiprevalence increased significantly in declining species in the early to mid-1990s, coincident withN. bombioutbreaks in North American commercial stocks. There is no evidence that exoticNosemastrains were introduced from Europe. Regardless of geographic origins, the temporal connection betweenN. bombiepizootics in commercialBombusstocks and increases in wild populations suggests a substantial risk of pathogen transmission with domestication.