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Contemporary science has been characterized by an exponential growth in publications and a rise of team science. At the same time, there has been an increase in the number of awarded PhD degrees, which has not been accompanied by a similar expansion in the number of academic positions. In such a competitive environment, an important measure of academic success is the ability to maintain a long active career in science. In this paper, we study workforce trends in three scientific disciplines over half a century. We find dramatic shortening of careers of scientists across all three disciplines. The time over which half of the cohort has left the field has shortened from 35 y in the 1960s to only 5 y in the 2010s. In addition, we find a rapid rise (from 25 to 60% since the 1960s) of a group of scientists who spend their entire career only as supporting authors without having led a publication. Altogether, the fraction of entering researchers who achieve full careers has diminished, while the class of temporary scientists has escalated. We provide an interpretation of our empirical results in terms of a survival model from which we infer potential factors of success in scientific career survivability. Cohort attrition can be successfully modeled by a relatively simple hazard probability function. Although we find statistically significant trends between survivability and an author’s early productivity, neither productivity nor the citation impact of early work or the level of initial collaboration can serve as a reliable predictor of ultimate survivability.

High-fat diet (HFD)-induced obesity is associated with insulin resistance, which may affect brain synaptic plasticity through impairment of insulin-sensitive processes underlying neuronal survival, learning, and memory. The experimental model consisted of 3 month-old C57BL/6J mice fed either a normal chow diet (control group) or a HFD (60% of calorie from fat; HFD group) for 12 weeks. This model was characterized as a function of time in terms of body weight, fasting blood glucose and insulin levels, HOMA-IR values, and plasma triglycerides. IRS-1/Akt pathway was assessed in primary hepatocytes and brain homogenates. The effect of HFD in brain was assessed by electrophysiology, input/output responses and long-term potentiation. HFD-fed mice exhibited a significant increase in body weight, higher fasting glucose- and insulin levels in plasma, lower glucose tolerance, and higher HOMA-IR values. In liver, HFD elicited (a) a significant decrease of insulin receptor substrate (IRS-1) phosphorylation on Tyr608 and increase of Ser307 phosphorylation, indicative of IRS-1 inactivation; (b) these changes were accompanied by inflammatory responses in terms of increases in the expression of NFκB and iNOS and activation of the MAP kinases p38 and JNK; (c) primary hepatocytes from mice fed a HFD showed decreased cellular oxygen consumption rates (indicative of mitochondrial functional impairment); this can be ascribed partly to a decreased expression of PGC1α and mitochondrial biogenesis. In brain, HFD feeding elicited (a) an inactivation of the IRS-1 and, consequentially, (b) a decreased expression and plasma membrane localization of the insulin-sensitive neuronal glucose transporters GLUT3/GLUT4; (c) a suppression of the ERK/CREB pathway, and (d) a substantial decrease in long-term potentiation in the CA1 region of hippocampus (indicative of impaired synaptic plasticity). It may be surmised that 12 weeks fed with HFD induce a systemic insulin resistance that impacts profoundly on brain activity, i.e., synaptic plasticity.

Exercise interventions in individuals with Parkinson's disease incorporate goal-based motor skill training to engage cognitive circuitry important in motor learning. With this exercise approach, physical therapy helps with learning through instruction and feedback (reinforcement) and encouragement to perform beyond self-perceived capability. Individuals with Parkinson's disease become more cognitively engaged with the practice and learning of movements and skills that were previously automatic and unconscious. Aerobic exercise, regarded as important for improvement of blood flow and facilitation of neuroplasticity in elderly people, might also have a role in improvement of behavioural function in individuals with Parkinson's disease. Exercises that incorporate goal-based training and aerobic activity have the potential to improve both cognitive and automatic components of motor control in individuals with mild to moderate disease through experience-dependent neuroplasticity. Basic research in animal models of Parkinson's disease is beginning to show exercise-induced neuroplastic effects at the level of synaptic connections and circuits.

Background Osteoporosis is a complex disease with a strong genetic contribution. A recently published genome-wide association study (GWAS) for estimated bone mineral density (eBMD) identified 1103 independent genome-wide significant association signals. Most of these variants are non-coding, suggesting that regulatory effects may drive many of the associations. To identify genes with a role in osteoporosis, we integrate the eBMD GWAS association results with those from our previous osteoclast expression quantitative trait locus (eQTL) dataset. Results We identify sixty-nine significant cis -eQTL effects for eBMD GWAS variants after correction for multiple testing. We detect co-localisation of eBMD GWAS and osteoclast eQTL association signals for 21 of the 69 loci, implicating a number of genes including CCR5 , ZBTB38 , CPE , GNA12 , RIPK3 , IQGAP1 and FLCN . Summary-data-based Mendelian Randomisation analysis of the eBMD GWAS and osteoclast eQTL datasets identifies significant associations for 53 genes, with TULP4 presenting as a strong candidate for pleiotropic effects on eBMD and gene expression in osteoclasts. By performing analysis using the GARFIELD software, we demonstrate significant enrichment of osteoporosis risk variants among high-confidence osteoclast eQTL across multiple GWAS P value thresholds. Mice lacking one of the genes of interest, the apoptosis/necroptosis gene RIPK3 , show disturbed bone micro-architecture and increased osteoclast number, highlighting a new biological pathway relevant to osteoporosis. Conclusion We utilise a unique osteoclast eQTL dataset to identify a number of potential effector genes for osteoporosis risk variants, which will help focus functional studies in this area.

Scientific authorship has become a contested terrain in contemporary science. Based on a survey of authors across fields, we measure the likelihood of specialist authors (sometimes called \"guest\" authors): people who only made specialized contributions, such as data, materials, or funding; and \"nonauthor collaborators\" (sometimes referred to as \"ghost\" authors): those who did significant work on the project but do not appear as authors, across different research contexts, including field, size of the project team, commercial orientation, impact of publication, and organization of the collaboration. We find that guest and ghost authors are common, with about one-third of publications having at least one specialist author and over half having at least one nonauthor collaborator. We see significant cross-field variations in both overall rates and types of specialist authors and nonauthor collaborators. We find there are generally fewer specialist authors among highly cited papers and more graduate student nonauthor collaborators in single location projects. The results suggest authorship practices vary across fields, and by project characteristics, complicating the use of authorship lists as a basis for evaluation (especially when comparing across fields or types of projects). We discuss implications of these findings for interpreting author lists in the context of science policy.

Alzheimer's disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer's disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.

GABAergic dysfunction is present in the hippocampus in schizophrenia (SZ) and bipolar disorder (BD). The trisynaptic pathway was \"deconstructed\" into various layers of sectors CA3/2 and CA1 and gene expression profiling performed. Network association analysis was used to uncover genes that may be related to regulation of glutamate decarboxylase 67 (GAD₆₇), a marker for this system that has been found by many studies to show decreased expression in SZs and BDs. The most striking change was a down-regulation of GAD₆₇ in the stratum oriens (SO) of CA2/3 in both groups; CA1 only showed changes in the SO of schizophrenics. The network generated for GAD₆₇ contained 25 genes involved in the regulation of kainate receptors, TGF-β and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, IL-1β, (GRIK2/3), TGF-β2, TGF-βR1, histone deacetylase 1 (HDAC1), death associated protein (DAXX), and cyclin D2 (CCND2) were all significantly up-regulated, whereas in BDs, PAX5, Runx2, LEF1, TLE1, and CCND2 were significantly down-regulated. In the SO of CA1 of BDs, where GAD67 showed no expression change, TGF-β and Wnt signaling genes were all up-regulated, but other transcription factors showed no change in expression. In other layers/sectors, BDs showed no expression changes in these GAD₆₇ network genes. Overall, these results are consistent with the hypothesis that decreased expression of GAD₆₇ may be associated with an epigenetic mechanism in SZ. In BD, however, a suppression of transcription factors involved in cell differentiation may contribute to GABA dysfunction.

The LIM-domain containing protein Ajuba and the scaffold protein SQSTM1/p62 regulate signalling of NF-κB, a transcription factor involved in osteoclast differentiation and survival. The ubiquitin-associated domain of SQSTM1/p62 is frequently mutated in patients with Paget’s disease of bone. Here, we report that Ajuba activates NF-κB activity in HEK293 cells, and that co-expression with SQSTM1/p62 inhibits this activation in an UBA domain-dependent manner. SQSTM1/p62 regulates proteins by targeting them to the ubiquitin-proteasome system or the autophagy-lysosome pathway. We show that Ajuba is degraded by autophagy, however co-expression with SQSTM1/p62 (wild type or UBA-deficient) protects Ajuba levels both in cells undergoing autophagy and those exposed to proteasomal stress. Additionally, in unstressed cells co-expression of SQSTM1/p62 reduces the amount of Ajuba present in the nucleus. SQSTM1/p62 with an intact ubiquitin-associated domain forms holding complexes with Ajuba that are not destined for degradation yet inhibit signalling. Thus, in situations with altered levels and localization of SQSTM1/p62 expression, such as osteoclasts in Paget’s disease of bone and various cancers, SQSTM1/p62 may compartmentalize Ajuba and thereby impact its cellular functions and disease pathogenesis. In Paget’s, ubiquitin-associated domain mutations may lead to increased or prolonged Ajuba-induced NF-κB signalling leading to increased osteoclastogenesis. In cancer, Ajuba expression promotes cell survival. The increased levels of SQSTM1/p62 observed in cancer may enhance Ajuba-mediated cancer cell survival.

Objectives Osteoarthritis (OA) is a joint disease with a heritable component. Genetic loci identified via genome-wide association studies (GWAS) account for an estimated 26.3% of the disease trait variance in humans. Currently, there is no method for predicting the onset or progression of OA. We describe the first use of the Collaborative Cross (CC), a powerful genetic resource, to investigate knee OA in mice, with follow-up targeted multi-omics analysis of homologous regions of the human genome. Methods We histologically screened 275 mice for knee OA and conducted quantitative trait locus (QTL) mapping in the complete cohort (> 8 months) and the younger onset sub-cohort (8–12 months). Multi-omic analysis of human genetic datasets was conducted to investigate significant loci. Results We observed a range of OA phenotypes. QTL mapping identified a genome-wide significant locus on mouse chromosome 19 containing Glis3 , the human equivalent of which has been identified as associated with OA in recent GWAS. Mapping the younger onset sub-cohort identified a genome-wide significant locus on chromosome 17. Multi-omic analysis of the homologous region of the human genome (6p21.32) indicated the presence of pleiotropic effects on the expression of the HLA − DPB2 gene and knee OA development risk, potentially mediated through the effects on DNA methylation. Conclusions The significant associations at the 6p21.32 locus in human datasets highlight the value of the CC model of spontaneous OA that we have developed and lend support for an immune role in the disease. Our results in mice also add to the accumulating evidence of a role for Glis3 in OA. Key messages What is already known about this subject? • Genetic factors play a role in OA development, with loci identified via genome-wide association studies (GWAS) estimated to account for 26.3% of the disease trait variance in humans. What does this study add? • We identified two genetic loci in mice associated with the development of spontaneous knee OA. • Regulation of HLA-DPB2 expression by DNAm sites may have a role in the development of knee OA, providing supporting evidence for a potential immune role in the disease. How might this impact clinical practice? • Further investigation into variations in GLIS3 and HLA-DPB2 and their functions may provide new diagnostic tools and potential treatment targets for spontaneous knee OA.

In this paper, we use data from the Carnegie Mellon Survey on industrial R&D to evaluate for the U.S. manufacturing sector the influence of \"public\"(i.e., university and government R&D lab) research on industrial R&D, the role that public research plays in industrial R&D, and the pathways through which that effect is exercised. We find that public research is critical to industrial R&D in a small number of industries and importantly affects industrial R&D across much of the manufacturing sector. Contrary to the notion that university research largely generates new ideas for industrial R&D projects, the survey responses demonstrate that public research both suggests new R&D projects and contributes to the completion of existing projects in roughly equal measure overall. The results also indicate that the key channels through which university research impacts industrial R&D include published papers and reports, public conferences and meetings, informal information exchange, and consulting. We also finnd that, after controlling for industry, the influence of public research on industrial R&D is disproportionately greater for larger firms as well as start-ups.