bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validating the Syndemic Threat Surrounding Sexual Minority Men's Health in a Population-Based Study With National Registry Linkage and a Heterosexual Comparison
Authors: Bränström Richard , Pachankis John E. 
Published: April 2018

Background:
Research on the syndemic health threats facing sexual minority men suggests that the elevated risk of HIV among this population co-occurs with other psychosocial health disparities. This study aimed to conduct a population-based examination of clinically assessed syndemic predictors of HIV infection among gay and bisexual, compared with heterosexual, men.

Setting and Methods:
The sample comprised adult men in the Stockholm Public Health Cohort. A total of 29,328 (91.9%) self-identified as heterosexual, 535 (1.7%) as gay, and 396 (1.2%) as bisexual. We linked survey responses to national health registry data.

Results:
Gay men had vastly elevated risk of HIV infection (>150 times) compared with heterosexuals. Gay men also had an elevated risk of depression, suicidality, and violent assaults compared with heterosexuals. Bisexual men had 16 times higher risk of being HIV-positive than heterosexual men. The number of psychosocial syndemic conditions was significantly associated with HIV infection among gay men (adjusted odds ratio [AOR] = 1.67; 95% confidence interval [95% CI]: 1.18 to 2.36), but not among bisexual and heterosexual men (AOR = 0.51; 95% CI: 0.07 to 3.59; AOR = 1.92; 95% CI: 0.96 to 3.84). Among gay men, the association between co-occurring syndemic conditions and odds of HIV infection was synergistic (ie, more than additive).

Conclusions:
This study confirms emerging evidence of the syndemic health threats affecting sexual minority men, finds stronger evidence for syndemics among gay compared with bisexual men, and suggests the need for HIV-prevention interventions that comprehensively address the co-occurring, and synergistically perpetuating, disparities affecting this population.
Short Implants: Analysis of 69 Implants Loaded in Mandible Compared With Longer Implants
Authors: Scarano Antonio , Mortellaro Carmen , Brucoli Matteo , Lucchina Alberta Greco , Assenza Bartolomeo , Lorusso Felice 
Published: April 2018

Objectives:
In the last decade, several studies have reported that short implants achieve excellent results with a 2-stage technique. According to the literature, short dental implants have often been used for the replacement of teeth.

Methods and Materials:
A total of 69 short implants (Bone System) were inserted in the posterior mandibular area (41 in males, 28 in females, with a median age of 55 years and an age ranging from 41 to 70 years).

Results:
Mean loss of bone levels at 1 year was 0.20 ± 0.03 mm, mean changes in bone levels for periods longer than 1 year was 0.07 mm. Survival rate (SRR) of short implants was 98.5%.

Conclusion:
This study showed no complications in short implants and they could represent predictable solutions for the rehabilitation of atrophic posterior mandible to avoid complementary surgical procedures.
A focused library synthesis and cytotoxicity of quinones derived from the natural product bolinaquinone
Authors: Ghods Azadeh , Gilbert Jayne , Baker Jennifer R. , Russell Cecilia C. , Sakoff Jennette A. , McCluskey Adam 
Published: April 2018

Bolinaquinone is a natural product that is a structurally complex, cytotoxic sesquiterpene quinone. A scaffold simplification and focused library approach using a microwave-assisted Suzuki coupling gave 32 bolinaquinone analogues with good-to-excellent cytotoxicity profiles. Mono-arylbenzoquinones, Library
A
, were preferentially toxic towards BE2-C (neuroblastoma) cells with growth inhibition (GI
50
) values of 4–12 µM; only the 3,4-dimethoxyphenyl
23
and 3-biphenyl
28
variants were broad-spectrum active—HT29 (colon carcinoma), U87 and SJ-G2 (glioblastoma), MCF-7 (breast carcinoma), A2780 (ovarian carcinoma), H460 (lung carcinoma), A431 (skin carcinoma), Du145 (prostate carcinoma), BE2-C (neuroblastoma), MIA (pancreatic carcinoma) and SMA (spontaneous murine astrocytoma). Library
B
with a second aryl moiety exhibited broad-spectrum cytotoxicity with MCF-7 cells’ GI
50
values of 5.6 ± 0.7 and 5.1 ± 0.5 µM for 2,5-dimethoxy-3-(naphthalene-1-yl)-6-(naphthalene-3-yl)
33
and 2,5-dimethoxy-3-(biaryl-2-yl)-6-(naphthalene-3-yl)
36,
respectively. Similar potencies were also noted with 2,5-dimethoxy-3,6-diphenyl
30
against A2780 (GI
50
= 5.9 ± 0.0 µM) and with 2,5-dimethoxy-3-(biaryl-3-yl)-6-(naphthalene-3-yl)
37
against HT29 (GI
50
= 5.4 ± 0.4 µM), while the 3,4-dimethoxy mono-aryl analogue
23
exhibited good levels of activity against A2780 (GI
50
= 3.8 ± 0.75 µM), the neuroblastoma cell line BE2-C (GI
50
= 3 ± 0.35 µM) and SMA (GI
50
= 3.9 ± 0.54 µM). Introduction of the amino-substituted Library
C
gave 2-(naphthalen-1-yl)-5-(naphthalen-3-yl)-3,6-bis(propylamino)
43,
with excellent activity against HT29 (0.08 ± 0.0 µM), MCF-7 (0.17 ± 0.1 µM), A2780 (0.14 ± 0.1 µM), A431 (0.11 ± 0.0 µM), Du145 (0.16 ± 0.1 µM), BE2-C (0.08 ± 0.0 µM) and MIA (0.1 ± 0.0 µM).
UNC-6/Netrin and its Receptors UNC-5 and UNC-40/DCC Control Growth Cone Polarity, Microtubule Accumulation, and Protrusion
Authors: Gujar Mahekta R. , Sundararajan Lakshmi , Stricker Aubrie , Lundquist Erik A. 
Published: April 2018

AbstractMany axon guidance ligands and their receptors have been identified, but it is still unclear how these ligand-receptor interactions regulate events in the growth cone, such as protrusion and cytoskeletal arrangement, during directed outgrowthin vivo. In this work, we dissect the multiple and complex effects of UNC-6/Netrin on the growth cone. Previous studies showed that inC. elegans, the UNC-6/Netrin receptor UNC-5 regulates growth cone polarity, as evidenced by loss of asymmetric dorsal F-actin localization and protrusion inunc-5mutants. UNC-5 and another UNC-6/Netrin receptor UNC-40/DCC also regulate the extent of protrusion, with UNC-40/DCC driving protrusion and UNC-5 inhibiting protrusion. In this work we analyze the roles of UNC-6/Netrin, UNC-40/DCC, and UNC-5 in coordinating growth cone F-actin localization, microtubule organization, and protrusion that results in directed outgrowth away from UNC-6/Netrin. We find that a previously-described pathway involving the UNC-73/Trio Rac GEF and UNC-33/CRMP that acts downstream of UNC-5, regulates growth cone dorsal asymmetric F-actin accumulation and protrusion.unc-5andunc-33mutants also display excess EBP-2::GFP puncta, suggesting that MT + end accumulation is important in growth cone polarity and/or protrusion.unc-73Rac GEF mutants did not display excess EBP-2::GFP puncta despite larger and more protrusive growth cones, indicating a MT-independent mechanism to polarize the growth cone and to inhibit protrusion, possibly via actin. Finally, we show that UNC-6/Netrin and UNC-40/DCC are required for excess protrusion inunc-5mutants, but not for loss of F-actin asymmetry or MT + end accumulation, indicating that UNC-6/Netrin and UNC-40/DCC are required for protrusion downstream of F-actin asymmetry and MT + end entry. Our data suggest a model in which UNC-6/Netrin polarizes the growth cone via UNC-5, and then regulates a balance of pro- and anti-protrusive forces driven by UNC-40 and UNC-5, respectively, that result in directed protrusion and outgrowth.
The AP-1 complex is essential for fungal growth via its role in secretory vesicle polar sorting, endosomal recycling and cytoskeleton organization
Authors: Martzoukou Olga , Diallinas George , Amillis Sotiris 
Published: April 2018

AbstractThe AP-1 complex is essential for membrane protein traffic via its role in the pinching-off and sorting of secretory vesicles from the trans-Golgi and/or endosomes. While its essentiality is undisputed in metazoa, its role in model simpler eukaryotes seems less clear. Here we dissect the role of AP-1 in the filamentous fungus Aspergillus nidulans and show that it is absolutely essential for growth due to its role in clathrin-dependent maintenance of polar traffic of specific membrane cargoes towards the apex of growing hyphae. We provide evidence that AP-1 is involved in both anterograde sorting of RabERab11-labeled secretory vesicles and RabA/BRab5- dependent endosome recycling. Additionally, AP-1 is shown to be critical for microtubule and septin organization, further rationalizing its essentiality in cells that face the challenge of cytoskeleton-dependent polarized cargo traffic. This work also opens a novel issue on how non-polar cargoes, such as transporters, are sorted to the eukaryotic plasma membrane.
Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots
Authors: Lin Yen-Lung , Gokcumen Omer 
Published: April 2018

AbstractGenomic structural variants (SVs) are distributed nonrandomly across the human genome. These “hotspots” have been implicated in critical evolutionary innovations, as well as serious medical conditions. However, the evolutionary and biomedical features of these hotspots remain incompletely understood. In this study, we analyzed data from 2,504 genomes from the 1000 Genomes Project Consortium and constructed a refined map of 1,148 SV hotspots in human genomes. By studying the genomic architecture of these hotspots, we found that both nonallelic homologous recombination and non-homologous mechanisms act as mechanistic drivers of SV formation. We found that the majority of SV hotspots are within gene-poor regions and evolve under relaxed negative selection or neutrality. However, we found that a small subset of SV hotspots harbor genes that are enriched for anthropologically crucial functions, including blood oxygen transport, olfaction, synapse assembly, and antigen binding. We provide evidence that balancing selection may have maintained these SV hotspots, which include two independent hotspots on different chromosomes affecting alpha and beta hemoglobin gene clusters. Biomedically, we found that the SV hotspots coincide with breakpoints of clinically relevant, largede novoSVs, significantly more often than genome-wide expectations. As an example, we showed that the breakpoints of multiple largede novoSVs, which lead to idiopathic short stature, coincide with SV hotspots. As such, the mutational instability in SV hotpots likely enables chromosomal breaks that lead to pathogenic structural variation formations. Our study contributes to a better understanding of the mutational landscape of the genome and implicates both mechanistic and adaptive forces in the formation and maintenance of SV hotspots.
RNA sequencing (RNA-seq) reveals extremely low levels of reticulocyte-derived globin gene transcripts in peripheral blood from horses (Equus caballus) and cattle (Bos taurus)
Authors: Correia Carolina N. , McLoughlin Kirsten E. , Nalpas Nicolas C. , Magee David A. , Browne John A. , Rue-Albrecht Kevin , Gordon Stephen V. , MacHugh David E. 
Published: April 2018

AbstractRNA-seq has emerged as an important technology for measuring gene expression in peripheral blood samples collected from humans and other vertebrate species. In particular, transcriptomics analyses of whole blood can be used to study immunobiology and develop novel biomarkers of infectious disease. However, an obstacle to these methods in many mammalian species is the presence of reticulocyte-derived globin mRNAs in large quantities, which can complicate RNA-seq library sequencing and impede detection of other mRNA transcripts. A range of supplementary procedures for targeted depletion of globin transcripts have, therefore, been developed to alleviate this problem. Here, we use comparative analyses of RNA-seq data sets generated from human, porcine, equine and bovine peripheral blood to systematically assess the impact of globin mRNA on routine transcriptome profiling of whole blood in cattle and horses. The results of these analyses demonstrate that total RNA isolated from equine and bovine peripheral blood contains very low levels of globin mRNA transcripts, thereby negating the need for globin depletion and greatly simplifying blood-based transcriptomic studies in these two domestic species.
Electrophysiological evidence for cerebellar involvement in higher-order cognitive processing
Authors: Sendhilnathan Naveen , Semework Mulugeta , Goldberg Michael E. , Ipata Anna E. 
Published: April 2018

AbstractAlthough the cerebellum has been traditionally considered to be exclusively involved in motor control and learning, recent anatomical and clinical studies suggest that it may also have a role in cognition. However, no electrophysiological evidence exists to support this claim. Here we studied the activity of simple spikes of hand-movement related Purkinje cells in the mid-lateral cerebellum when monkeys learned to associate a well-learned right or left-hand movement with one of two visual symbolic cues. The cells had distinctly different discharge patterns between an overtrained symbol-hand association and a novel symbol-hand association although the kinematics of the movement did not change between the two conditions. The activity change was not related to the pattern of the visual symbols, the hand making the movement, the monkeys’ reaction times or the novelty of the visual symbols. We suggest that mid-lateral cerebellum is involved in higher-order cognitive processing related to learning a new visuomotor association.One Sentence SummaryHand-movement related Purkinje neurons in midlateral cerebellum, which discharge during an overtrained visuomotor association task, change their activity when the monkey has to associate the same movements with new cues, even though the kinematics of the movements do not change.
Characterisation of subpopulations of chicken mononuclear phagocytes that express TIM4 and the macrophage colony-stimulating factor receptor (CSF1R)
Authors: Hu Tuanjun , wu Zhiguang , Bush Stephen J. , Freem Lucy , Vervelde Lonneke , Summers Kim M. , Balic Adam , Hume David A. , Kaiser Pete 
Published: April 2018

AbstractThe phosphatidylserine receptor, TIM4, encoded by TIMD4, mediates the phagocytic uptake of apoptotic cells. We applied anti-chicken TIM4 monoclonal antibodies, in combination with CSF1R reporter transgenes to dissect the function of TIM4 in chick (Gallus gallus). During development in ovo, TIM4 was present on the large majority of macrophages but expression became more heterogeneous post-hatch. Blood monocytes expressed KUL01, class II MHC and CSF1R-mApple uniformly. Around 50% of monocytes were positive for surface TIM4. They also expressed many other monocyte-specific transcripts at a higher level than TIM4− monocytes. In liver, highly-phagocytic TIM4hi cells shared many transcripts with mammalian Kupffer cells and were associated with uptake of apoptotic cells. Although they expressed CSF1R mRNA, Kupffer cells did not express the CSF1R-mApple transgene, suggesting that additional CSF1R transcriptional regulatory elements are required by these cells. By contrast, CSF1R-mApple was detected in liver TIM4lo and TIM4− cells which were not phagocytic and were more abundant than Kupffer cells. These cells expressed CSF1R, alongside high levels of FLT3, MHCII, XCR1 and other markers associated with conventional dendritic cells (cDC) in mice. In bursa, TIM4 was present on the cell surface of two populations. Like Kupffer cells, bursal TIM4hi phagocytes co-expressed many receptors involved in apoptotic cell recognition. TIM4lo cells appear to be a sub-population of bursal B cells. In overview, TIM4 is associated with phagocytes that eliminate apoptotic cells in the chick. In the liver, TIM4 and CSF1R reporters distinguished Kupffer cells from an abundant population of DC-like cells.
Bacillus licheniformisglobal nitrogen homeostatic regulator TnrA is a direct repressor ofpgsBCAAtranscription in Poly-γ-glutamic acid synthesis
Authors: Cai Dongbo , Chen Yaozhong , Wang Shiyi , Mo Fei , Ma Xin , Chen Shouwen 
Published: April 2018

AbstractPoly-γ-glutamic acid (γ-PGA) is a multifunctional and naturally occurring biopolymer made from D- and L-glutamate as monomers, which is mainly produced byBacillus. Few reports have been focused on the regulation network of γ-PGA synthesis in recent years. In this study, we have demonstrated thatBacillus licheniformisglobal nitrogen homeostatic regulator TnrA is a direct repressor of γ-PGA synthase PgsBCAA in γ-PGA synthesis. First, our results confirmed that TnrA repressed γ-PGA synthesis, deficiency oftnrAled to a 22.03% increase of γ-PGA production, and the γ-PGA yield was decreased by 19.02% in the TnrA overexpression strain. Transcriptional level assay illustrated that the γ-PGA synthase gene clusterpgsBCAAtranscriptional level were increased in thetnrAdeficient strain WXΔtnrA, indicating that γ-PGA synthase PgsBCAA was negatively regulated by TnrA. Furthermore, electrophoretic mobility shift assay (EMSA) and enzyme expression assays confirmed that TnrA directly repressedpgsBCAAexpression by binding topgsBCAApromoter, and the TnrA-binding site “CGTCGTCTTCTGTTACA” in thepgsBCAApromoter was identified by sequence and software analysis. Finally, computer analysis confirmed that the transcription regulations of γ-PGA synthase PgsBCAA by TnrA were highly conserved in other well-studiedBacillusspecies (B.licheniformis,Bacillus subtilisandBacillus amyloliquefaciens). Collectively, our results implied that TnrA was a direct repressor forpgsBCAAexpression in γ-PGA synthesis, and this research provided a novel regulatory mechanism underlying γ-PGA synthesis, and a new approach that deficiency oftnrAincreases γ-PGA production.Importanceγ-PGA is an important biopolymer with many applications, which is mainly produced byBacillusspecies. Glutamic acid is the precursor for γ-PGA synthesis, which is catalyzed by the γ-PGA synthase PgsBCAA. Previously, the expression of PgsBCAA was reported to be regulated by ComA-ComP and DegS-DegU, DegQ and SwrA systems, however, few researches were focused on the regulation network of γ-PGA synthesis in recent years. In our research, the γ-PGA synthase PgsBCAA was confirmed to be negatively regulated by the nitrogen metabolism regulator TnrA, and the TnrA binding site in thepgsBCAApromoter was identified inB. licheniformisWX-02. Furthermore, computer analysis implied that TnrA-mediated regulation effect onpgsBCAAexpression was highly conserved inBacillus. Collectively, our research provided a novel regulatory mechanism underlying γ-PGA synthesis, and a new approach that deficiency oftnrAincreases γ-PGA production.
foxr1is a novel maternal-effect gene in fish that regulates embryonic cell growth viap21andrictor
Authors: Cheung Caroline T. , Patinote Amélie , Guiguen Yann , Bobe Julien 
Published: April 2018

AbstractThe family of forkhead box (Fox) transcription factors regulate gonadogenesis and embryogenesis, but the role offoxr1/foxn5in reproduction is unknown. Evolution offoxr1in vertebrates was examined and the gene found to exist in most vertebrates, including mammals, ray-finned fish, amphibians, and sauropsids. By quantitative PCR and RNA-seq, we found thatfoxr1had an ovarian-specific expression in zebrafish, a common feature of maternal-effect genes. In addition, it was demonstrated usingin situhybridization thatfoxr1was a maternally-inherited transcript that was highly expressed even in early-stage oocytes and accumulated in the developing eggs during oogenesis. We also analyzed the function offoxr1in female reproduction using a zebrafish CRISPR/Cas9 knockout model. It was observed that embryos from thefoxr1-deficient females had a significantly lower survival rate whereby they either failed to undergo cell division or underwent abnormal division that culminated in growth arrest at around the mid-blastula transition and early death. These mutant-derived eggs contained a dramatically increased level ofp21, a cell cycle inhibitor, and reducedrictor, a component of mTOR and regulator of cell survival, which were in line with the observed growth arrest phenotype. Our study shows for the first time thatfoxr1is an essential maternal-effect gene and is required for proper cell division and survival via the p21 and mTOR pathways. These novel findings will broaden our knowledge on the functions of specific maternal factors stored in the developing egg and the underlying mechanisms that contribute to reproductive fitness.Summary sentenceThefoxr1gene in zebrafish is a novel maternal-effect gene that is required for proper cell division in the earliest stage of embryonic development possibly as a transcriptional factor for cell cycle progression regulators,p21andrictor.
High prevalence of S. pyogenes Cas9-specific T cell sensitization within the adult human population – A balanced effector/regulatory T cell response
Authors: Wagner Dimitrios L. , Amini Leila , Wendering Desiree J. , Reinke Petra , Volk Hans-Dieter , Schmueck-Henneresse Michael 
Published: April 2018

Summary ParagraphThe field of gene therapy has been galvanized by the discovery of the highly efficient and adaptable site-specific nuclease system CRISPR/Cas9 from bacteria.1,2Immunity against therapeutic gene vectors or gene-modifying cargo nullifies the effect of a possible curative treatment and may pose significant safety issues.3-5Immunocompetent mice treated with CRISPR/Cas9-encoding vectors exhibit humoral and cellular immune responses against the Cas9 protein, that impact the efficacy of treatment and can cause tissue damage.5,6Most applications aim to temporarily express the Cas9 nuclease in or deliver the protein directly into the target cell. Thus, a putative humoral antibody response may be negligible.5However, intracellular protein degradation processes lead to peptide presentation of Cas9 fragments on the cellular surface of gene-edited cells that may be recognized by T cells. While a primary T cell response could be prevented or delayed, a pre-existing memory would have major impact. Here, we show the presence of a ubiquitous memory/effector T cell response directed towards the most popular Cas9 homolog fromStreptococcus pyogenes(SpCas9) within healthy human subjects. We have characterized SpCas9-reactive memory/effector T cells (TEFF) within the CD4/CD8 compartments for multi-effector potency and lineage determination. Intriguingly, SpCas9-specific regulatory T cells (TREG) profoundly contribute to the pre-existing SpCas9-directed T cell immunity. The frequency of SpCas9-reactive TREGcells inversely correlates with the magnitude of the respective TEFFresponse. SpCas9-specific TREGmay be harnessed to ensure the success of SpCas9-mediated gene therapy by combating undesired TEFFresponsein vivo. Furthermore, the equilibrium of Cas9-specific TEFFand TREGcells may have greater importance inStreptococcuspyogenes-associated diseases. Our results shed light on the T cell mediated immunity towards the much-praised gene scissor SpCas9 and offer a possible solution to overcome the problem of pre-existing immunity.