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Living up to the expectations of the JIBS Decade Award, Goerzen, Asmussen, and Nielsen’s 2013 paper not only introduced the literature on global cities to the international business (IB) community but continues to be generative. In their “Retrospective and a Looking Forward” paper 10 years later, the authors highlight megatrends about people, places and things, and new contexts and alternative perspectives, and they encourage further new ways of thinking about global cities and IB. This commentary expands upon their framework of three overlapping circles of global issues, global organizations, and global locations, by drawing especially from recent experiences in the U.S. and research in economic geography and allied fields. Facing global issues of climate change, human rights, health, housing, and the impacts of digital technologies on work, cities offer prospects of responding to these challenges, a context for multinational enterprises (MNEs) to consider. Against the backdrop of large-scale global migrations of unskilled, mostly contract, workers to global cities in developed economies, recruitment agencies and advocacy groups for migrants are global organizations as important as MNEs. Finally, the fluidity of physical boundaries, as illustrated by city-regions, world regions beyond traditional Western-centric perspectives, and intra-national variations, is key to analyzing global locations.

Summary Pharmacologic therapy is recommended to reduce future fracture risk. We examined osteoporosis medications dispensed to older women after first fracture. Only 23 % received therapy during the first year post-fracture. Prior osteoporosis therapy, a prior osteoporosis diagnosis, and older age were good predictors of post-fracture osteoporosis therapy. Introduction Pharmacologic therapy is recommended after osteoporotic fracture to reduce future fracture risk. The objective of this retrospective study was to examine osteoporosis therapy dispensed to women post-fracture. Methods We identified women ≥50 years old in a large administrative claims database from 2003 to mid-2012 who were continuously enrolled 2 years before (baseline) and 1 year after first osteoporotic fracture. Exclusions were Paget’s disease or malignant neoplasm. Pre- and post-fracture osteoporosis therapies (oral and parenteral) were assessed overall and by fracture site. Results A total of 47,171 women of mean (SD) age of 63 (10) years were eligible; fractures included 8 % hip, 17 % vertebral, 73 % non-hip/non-vertebral, and 3 % multiple fracture sites. Only 18 % received osteoporosis therapy within 90 days and 23 % within 1 year post-fracture. Overall, 19 % of women had a prior osteoporosis diagnosis; 20 % had received osteoporosis therapy during baseline. Of 37,649 (80 %) women without baseline therapy, only 9 % initiated pharmacologic therapy within 1 year. The adjusted odds ratio (OR) of therapy within 1 year post-fracture was significantly greater for women who had received baseline osteoporosis therapy (versus none) and who had vertebral (OR 12.7, 95 % confidence interval (CI) 11.2–14.5), hip (15.2, 12.5–18.7), or non-hip/non-vertebral fracture (34.4, 31.7–37.3). Other significant predictors included pre-fracture osteoporosis diagnosis (1.6, 1.4–1.7) and older age (OR range, 1.3–1.7). Treatment adherence was significantly better among women with baseline osteoporosis diagnosis. Conclusions The substantial post-fracture treatment gap represents an important unmet need for women with osteoporotic fractures. Fracture liaison or adherence programs could lead to improved post-fracture treatment rates.

Despite the fact that urban hukou is understood to be far superior to rural hukou and that rural migrants have strong intention to stay in cities for many years, responses to hukou reforms that increase opportunities to obtain urban hukou have been less than enthusiastic. This article addresses this puzzle by showing how the respective values of rural hukou and urban hukou have changed in recent decades. The access and benefits that are tied to rural hukou-including farming and housing land, compensation for land requisition, and more relaxed birth control-are considered increasingly valuable. Thus, many migrants are opting to straddle and circulate between the city and countryside rather than giving up their rural hukou. Meanwhile, the competitive advantage of urban hukou has declined as China seeks to expand basic public services to all and as the market's role in distri-buting food, housing, and other needs increases. The mismatch between rural migrants' preference for large cities and hukou reforms' focus on medium-sized and small cities and towns also undermines the reforms' effectiveness. From a policy point of view, this article's findings suggest that China's urbanization strategy should take multilocality seriously and should focus on rural migrants' livelihood and well-being in cities, rather than on hukou conversion alone.

The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters—glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids—and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate ‘slow’ (G-protein-coupled receptors) and ‘fast’ (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an ‘associative’ disorder—a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways—and may unify a number of currently competing hypotheses of SCZ pathophysiology.

Toll-like receptors (TLRs) are a family of pattern recognition receptors involved in cardiovascular diseases. Notably, numerous studies have demonstrated that TLR4 activates the expression of several of pro-inflammatory cytokine genes that play pivotal roles in myocardial inflammation, particularly myocarditis, myocardial infarction, ischemia-reperfusion injury, and heart failure. In addition, TLR4 is an emerging target for anti-inflammatory therapies. Given the significance of TLR4, it would be useful to summarize the current literature on the molecular mechanisms and roles of TLR4 in myocardial inflammation. Thus, in this review, we first introduce the basic knowledge of the TLR4 gene and describe the activation and signaling pathways of TLR4 in myocardial inflammation. Moreover, we highlight the recent progress of research on the involvement of TLR4 in myocardial inflammation. The information reviewed here may be useful to further experimental research and to increase the potential of TLR4 as a therapeutic target.

Genetic pleiotropy is abundant across spatially distributed brain characteristics derived from one neuroimaging modality (e.g. structural, functional or diffusion magnetic resonance imaging [MRI]). A better understanding of pleiotropy across modalities could inform us on the integration of brain function, micro- and macrostructure. Here we show extensive genetic overlap across neuroimaging modalities at a locus and gene level in the UK Biobank ( N  = 34,029) and ABCD Study ( N  = 8607). When jointly analysing phenotypes derived from structural, functional and diffusion MRI in a genome-wide association study (GWAS) with the Multivariate Omnibus Statistical Test (MOSTest), we boost the discovery of loci and genes beyond previously identified effects for each modality individually. Cross-modality genes are involved in fundamental biological processes and predominantly expressed during prenatal brain development. We additionally boost prediction of psychiatric disorders by conditioning independent GWAS on our multimodal multivariate GWAS. These findings shed light on the shared genetic mechanisms underlying variation in brain morphology, functional connectivity, and tissue composition. The authors uncover extensive genetic overlap across brain structure, functional connectivity, and brain tissue composition using multivariate methods. Insights gained enhance understanding of brain biology and prediction of psychiatric conditions.

A cross-sectional survey of prevalence was conducted among senior primary school pupils of Siphofaneni area, Eswatini. This area is devoid of potable water, with a newly constructed Lubovane dam and an LUSIP irrigation scheme. The objective of the study was to investigate the distribution of urinary schistosomiasis among Siphofaneni senior primary school pupils. Using simple random sampling, 200 partcipants were enroled from four of six schools in the area. Ten millimetres (10 ml) of urine samples were obtained from each participant and examined for eggs. The intensity of the infection was estimated by calculating the total number of eggs present in 10 ml urine. Out of 200 participants, 45% (n = 91) were males, and 55% (n = 109) were females. The mean age for participants was 13 years, and almost half (47%, n = 94) were in Grade 5. Overall, the prevalence of infection was 16% (32/200). More than half (59%, 19/32) of the Schistosomiasis cases were from females. Positive and significant associations were observed between the number of eggs (χ =170.9) and the presence of red blood cells (χ =49.2) at = 0.001. In conclusion, the prevalence of Schistosomiasis is high among pupils enrolled in Siphofaneni area primary schools that needs comprehensive treatment and education to prevent from infection.

Mdm2 is a critical negative regulator of the tumor suppressor protein p53. Mdm2 is an E3 ligase whose overexpression leads to functional inactivation of p53. Mdm2 protein stability is regulated by several mechanisms including RING (Really Interesting New Gene) domain-mediated autoubiquitination. Here we report biochemical identification of NEDD4-1 as an E3 ligase for Mdm2 that contributes to the regulation of Mdm2 protein stability in cells. NEDD4-1 was identified from Jurkat cytosolic fractions using an enzyme-dead Mdm2 mutant protein as a substrate for in vitro E3 ligase assays. We show that lysates from Nedd4-1 knockout (KO) mouse embryonic fibroblasts (MEFs) have significantly diminished E3 ligase activity toward Mdm2 compared with lysates from wild-type (WT) MEFs. Recombinant NEDD4-1 promotes Mdm2 ubiquitination in vitro in a concentration- and time-dependent manner. In cells, NEDD4-1 physically interacts with Mdm2 via the RING domain of Mdm2. Overexpression of NEDD4-1, but not an enzyme-dead NEDD4-1CS mutant, increases ubiquitination of Mdm2. NEDD4-1 catalyzes the formation of K63-type polyubiquitin chains on Mdm2 that are distinct from K48-type polyubiquitination chains mediated by the Mdm2/MdmX complex. Importantly, K63-type polyubiquitination by NEDD4-1 competes with K48-type polyubiquitination on Mdm2 in cells. As a result, NEDD4-1-mediated ubiquitination stabilizes Mdm2. NEDD4-1 knockdown reduces the t 1/2 (half-life) of endogenous Mdm2 from 20 to 12 min in U2OS cells. Nedd4-1 KO MEFs manifest increased p53 levels and activity, a more robust DNA damage response and increased G1 arrest compared with WT MEFs. Similarly, NEDD4-1 knockdown in WT-p53-bearing cells increases basal p53 levels and activity in an Mdm2-dependent manner, causes stronger p53 responses to DNA damage and results in p53-dependent growth inhibition compared with corresponding NEDD4-1-proficient control cells. This study identifies NEDD4-1 as a novel component of the p53/Mdm2 regulatory feedback loop that controls p53 activity during stress responses.

Epithelial-to-mesenchymal transition (EMT) is well known to involve in tumor invasion and metastasis. Src homology region 2 domain-containing phosphatase 1 (SHP-1) functions as a potent tumor suppressor and also acts as a negative regulator of p-STAT3 Tyr705 oncogenic signaling. However, little is known about the molecular mechanism(s) through which SHP-1 regulates EMT during hepatocellular carcinoma (HCC) progression. Here we first reported that endogenous SHP-1 protein levels were significantly downregulated in cells with mesenchymal characteristics and negatively correlated with p-STAT3 Tyr705 and vimentin but positively correlated with E-cadherin. SHP-1 overexpression abolished transforming growth factor-β1 (TGF-β1)-induced p-STAT3 Tyr705 and EMT, as well inhibited migration and invasion but further rescued by signal transducer and activator of transcription factor 3 (STAT3) overexpression. Depletion of SHP-1 could induce a more increase in TGF-β1-induced p-STAT3 Tyr-705 and EMT characteristics, further supporting the mechanism that suppression of TGF-β1-induced EMT is dependent on SHP-1-mediated STAT3 inactivation. Constitutively overexpressed SHP-1 tyrosine phosphatase activity by D61A-mutated SHP-1 markedly reduced TGF-β1-induced p-STAT3 Tyr705 and EMT features but was not altered by C453S catalytic-dead mutant SHP-1. Consequently, SHP-1 acted as a powerful suppressor in preventing EMT by exerting its tyrosine phosphatase activity that directly downregulated p-STAT3 Tyr705 . Most notably, we discovered a novel SHP-1 agonist SC-43 better than sorafenib to exert more potent anti-EMT effects in vitro as well as anti-metastatic growth in vivo . In conclusion, SHP-1 is a potent suppressor of HCC EMT and metastasis, thus highlighting that SC-43–SHP-1 axis may serve as a potential therapeutic target that antagonized p-STAT3 Tyr705 and thereby prevented HCC EMT and metastasis.