G-coupled protein receptors (GPCRs) are the ultimate refuge of pharmacology and medicine as more than 40% of all marketed drugs are directly targeting these receptors. Through cell surface expression, they are at the forefront of cellular communication with the outside world. Metabolites among the conveyors of this communication are becoming more prominent with the recognition of them as ligands for GPCRs. HCAR1 is a GPCR conveyor of lactate. It is a class A GPCR coupled to Gαi which reduces cellular cAMP along with the downstream Gβγ signaling. It was first found to inhibit lipolysis, and lately has been implicated in diverse cellular processes, including neural activities, angiogenesis, inflammation, vision, cardiovascular function, stem cell proliferation, and involved in promoting pathogenesis for different conditions, such as cancer. Other than signaling from the plasma membrane, HCAR1 shows nuclear localization with different location-biased activities therein. Although different functions for HCAR1 are being discovered, its cell and molecular mechanisms are yet ill understood. Here, we provide a comprehensive review on HCAR1, which covers the literature on the subject, and discusses its importance and relevance in various biological phenomena.

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and primarily signal through two main effector proteins: G proteins and β-arrestins. Many agonists of GPCRs promote \"biased\" responses, in which different cellular signaling pathways are activated with varying efficacies. The mechanisms underlying biased signaling have not been fully elucidated, with many potential \"hidden variables\" that regulate this behavior. One contributor is \"location bias,\" which refers to the generation of unique signaling cascades from a given GPCR depending upon the cellular location at which the receptor is signaling. Here, we review evidence that GPCRs are expressed at and traffic to various subcellular locations and discuss how location bias can impact the pharmacologic properties and characterization of GPCR agonists. We also evaluate how differences in subcellular environments can modulate GPCR signaling, highlight the physiological significance of subcellular GPCR signaling, and discuss the therapeutic potential of exploiting GPCR location bias.

The classical paradigm of G protein-coupled receptor (GPCR) signaling via G proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised in recent years following the identification of several receptors that engage in sustained signaling responses from subcellular compartments following internalization of the ligand-receptor complex. This phenomenon was initially discovered for the parathyroid hormone (PTH) type 1 receptor (PTH1R), a vital GPCR for maintaining normal calcium and phosphate levels in the body with the paradoxical ability to build or break down bone in response to PTH binding. The diverse biological processes regulated by this receptor are thought to depend on its capacity to mediate diverse modes of cyclic adenosine monophosphate (cAMP) signaling. These include transient signaling at the plasma membrane and sustained signaling from internalized PTH1R within early endosomes mediated by PTH. Here we discuss recent structural, cell signaling, and in vivo studies that unveil potential pharmacological outputs of the spatial versus temporal dimension of PTH1R signaling via cAMP. Notably, the combination of molecular dynamics simulations and elastic network model-based methods revealed how precise modulation of PTH signaling responses is achieved through structure-encoded allosteric coupling within the receptor and between the peptide hormone binding site and the G protein coupling interface. The implications of recent findings are now being explored for addressing key questions on how location bias in receptor signaling contributes to pharmacological functions, and how to drug a difficult target such as the PTH1R toward discovering nonpeptidic small molecule candidates for the treatment of metabolic bone and mineral diseases.

cAMP is the indispensable second messenger regulating cell metabolism and function in response to extracellular hormones and neurotransmitters. cAMP is produced via the activation of G protein-coupled receptors located at both the cell surface and inside the cell. Recently, Tsvetanova et al. explored cAMP generation in distinct locations and the impact on respective cell functions. Using a phospho-proteomic analysis, they provide insight into the unique role of localized cAMP production in cellular phospho-responses.

Results of meta-analyses are potentially valuable for informing environmental policy and practice decisions. However, selective sampling of primary studies through searches exclusively using widely used bibliographic platform(s) could bias estimates of effect sizes. Such search strategies are common in environmental evidence reviews, and if risk of bias can be detected, this would provide the first empirical evidence that comprehensiveness of searches needs to be improved. We compare the impact of using single and multiple bibliographic platform(s) searches vs more comprehensive searches on estimates of mean effect sizes. We used 137 published meta-analyses, based on multiple source searches, analyzing 9388 studies: 8095 sourced from commercially published articles; and 1293 from grey literature and unpublished data. Single-platform and multiple-platform searches missed studies in 100 and 80 of the meta-analyses, respectively: 52 and 46 meta-analyses provided larger-effect estimates; 32 and 28 meta-analyses provided smaller-effect estimates; eight and four meta-analyses provided opposite direction of estimates; and two each were unable to estimate effects due to missing all studies. Further, we found significant positive log-linear relationships between proportions of studies missed and the deviations of mean effect sizes, suggesting that as the number of studies missed increases, deviation of mean effect size is likely to expand. We also found significant differences in mean effect sizes between indexed and non-indexed studies for 35% of meta-analyses, indicating high risk of bias when the searches were restricted. We conclude that the restricted searches are likely to lead to unrepresentative samples of studies and biased estimates of true effects.

Highly expressed genes are commonly located close to the origin of replication of bacterial chromosomes (OriC). This location skew is thought to reflect selective advantages associated with gene dosage effects during the replication cycle. The expression of constitutively expressed genes can vary up to fivefold based on chromosomal location, but it is not clear what level of variation would occur in naturally regulated operons. We tested the magnitude of the chromosome location effect using EF-Tu (tufA, tufB), an abundant protein whose cellular level correlates with, and limits, the maximum growth rate. We translocated the Salmonella tufB operon to four locations across the chromosome. The distance from OriC had only a small effect on growth rate, consistent with this operon having the natural ability to upregulate expression and compensate for reduced gene dosage. In contrast, when the total EF-Tu concentration was limiting for the growth rate (tufA deleted), we observed a strong gene dosage effect when tufB was located further from OriC. However, only a short period of experimental evolution was required before the bacteria adapted to this EF-Tu starvation situation by acquiring genetic changes that increased expression levels from the translocated tufB gene, restoring growth rates. Our findings demonstrate that, at least for the tufB operon, gene dosage is probably not the dominant force selecting for a chromosomal location close to OriC. We suggest that the colocation of highly expressed genes close to OriC might instead be selected because it enhances their coregulation during various growth states, with gene dosage being a secondary benefit.IMPORTANCE A feature of bacterial chromosomes is that highly expressed essential genes are usually located close to the origin of replication. Because bacteria have overlapping cycles of replication, genes located close to the origin will often be present in multiple copies, and this is thought to be of selective benefit where high levels of expression support high growth rate. However, the magnitude of this selective effect and whether other forces could be at play are poorly understood. To study this, we translocated a highly expressed essential operon, tufB, to different locations and measured growth fitness. We found that transcriptional regulation buffered the effects of translocation and that even under conditions where growth rate was reduced, genetic changes that increased the expression of tufB were easily and rapidly selected. We conclude, at least for tufB, that forces other than gene dosage may be significant in selecting for chromosomal location.

Studies published in languages other than English are often neglected when research teams conduct systematic reviews. Literature on how to deal with non-English studies when conducting reviews have focused on the importance of including such studies, while less attention has been paid to the practical challenges of locating and assessing relevant non-English studies. We investigated the factors which might predict the inclusion of non-English studies in systematic reviews in the social sciences, to better understand how, when and why these are included/excluded.
We appraised all Campbell Collaboration systematic reviews (n = 123) published to July 2016, categorising each by its language inclusiveness. We sought additional information from review authors via a questionnaire and received responses concerning 47 reviews. Data were obtained for 17 factors and we explored correlations with the number of non-English studies in the reviews via statistical regression models. Additionally, we asked authors to identify factors that support or hinder the inclusion of non-English studies.
Of 123 reviews, 108 did not explicitly exclude, and of these, 17 included non-English language studies. One factor correlated with the number of included non-English studies across all models: the number of countries in which the members of the review team work (B-value = 0.56; SE B = 0.24; 95% CI = 0.07-1.03; p = 0.02). This indicates that reviews which included non-English studies were more likely to be produced by international review teams. Our survey showed a dominance of researchers from English-speaking countries (52.9%) and review teams consisting only of team members from these countries (65.9%). The most frequently mentioned challenge to including non-English studies was a lack of resources (funding and time) followed by a lack of language resources (e.g. professional translators).
Our findings may indicate a connection between the limited inclusion of non-English studies and a lack of resources, which forces review teams to rely on their limited language skills rather than the support of professional translators. If unaddressed, review teams risk ignoring key data and introduce bias in otherwise high-quality reviews. However, the validity and interpretation of our findings should be further assessed if we are to tackle the challenges of dealing with non-English studies.

The objective of the present study was to determine the publication rate of cancer randomized controlled trial (RCTs) and to analyze the determinants of the publication, as well as to estimate the possible existence of a location and time lag bias. We also described the bibliometric characteristics of the publications.
We conducted an observational study that identified publications resulting from RCTs involving cancer-related drug products. These studies were authorized and registered by the Spanish Agency of Medicines and Medical Devices between 1999 and 2003.
We identified 168 publications of 303 RCTs, resulting in a publication rate of 55.4% after a mean follow-up of 12 years. The only factor associated to the likelihood of nonpublication was the study setting favoring only national RCTs (odds ratio 2.7; 95% confidence interval 1.5-4.8). Type of sponsor did not seem to be associated, although the largest volume of nonpublished trials is international, industry-sponsored. Positive results seemed to be associated to a publication in a higher impact factor journal and a shorter time-to-publication.
About half of the cancer RCTs during the target period have not been published. The national setting is a factor associated to nonpublication, whereas the direction of results determines its dissemination (impact factor and timely publication).

Recent research has demonstrated that involuntary attention improves target identification accuracy for letters using non-predictive peripheral cues, helping to resolve some of the controversy over performance enhancement from involuntary attention. While various cueing studies have demonstrated that their reported cueing effects were not due to response bias to the cue, very few investigations have quantified the extent of any response bias or developed methods of removing bias from observed results in a double judgment accuracy task. We have devised a method to quantify and remove response bias to cued locations in a double judgment accuracy cueing task, revealing the true, unbiased performance enhancement from involuntary and voluntary attention. In a 7-alternative forced choice cueing task using backward masked stimuli to temporally constrain stimulus processing, non-predictive cueing increased target detection and discrimination at cued locations relative to uncued locations even after cue location bias had been corrected.