Dynamic analysis of two-link flexible manipulator considering the link length ratio and the payload

Dynamic modeling and analysis of flexible manipulators play an essential role in optimizing mechanical design parameters and control law of real robot systems. In this paper, a nonlinear dynamic model of a manipulator is formulated based on the Finite Element Method. To analyze the dynamic behavior effectively, a numerical simulation scheme is proposed by taking full advantages of MATLAB and SIMULINK toolboxes. In this manner, the effect of varying payload and link length ratio of the manipulator to its elastic displacement is dynamically taken into account. The simulation results show that the payload and length link ratio have significant influences on the elastic displacements of the system. In particular, a proper spectrum of the link length ratio, in which the flexural displacement of the end point of the manipulator is smallest, is demonstrated. To this end, the proposed methodology could be used further to select optimal geometric parameters for the links of new robot designs

Presence of anaplastic lymphoma kinase in inflammatory breast cancer

Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPK\uce\ub2 in pre-clinical models of IBC. To evaluate the clinical relevance of ALK in IBC, analysis of 25 IBC patient tumors using the FDA approved diagnostic test for ALK genetic abnormalities was performed. These studies revealed that 20/25 (80%) had either increased ALK copy number, low level ALK gene amplification, or ALK gene expression, with a prevalence of ALK alterations in basal-like IBC. One of 25 patients was identified as having an EML4-ALK translocation. The generality of gains in ALK copy number in basal-like breast tumors with IBC characteristics was demonstrated by analysis of 479 breast tumors using the TGCA data-base and our newly developed 79 IBC-like gene signature. The small molecule dual tyrosine kinase cMET/ALK inhibitor, Crizotinib (PF- 02341066/Xalkori\uc2\uae, Pfizer Inc), induced both cytotoxicity (IC50= 0.89 \uce\ubcM) and apoptosis, with abrogation of pALK signaling in IBC tumor cells and in FC-IBC01 tumor xenograft model, a new IBC model derived from pleural effusion cells isolated from an ALK+IBC patient. Based on these studies, IBC patients are currently being evaluated for the presence of ALK genetic abnormalities and when eligible, are being enrolled into clinical trials evaluating ALK targeted therapeutics. \uc2\ua9 2013 Robertson et al

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Identification of transcription factors interacting with the oxytocin gene promoter

Oxytocin (OT) and the related hormone vasopressin (AVP) are both expressed in the hypothalamus but are never co-expressed in the same neurons. The OT and AVP genes are believed to derive from one common gene by gene duplication and both genes are adjacent to each other on the chromosome in all species studied. Because of the lack of suitable cell lines expressing the OT gene, scientists have taken advantage of the availability of promoter sequences of numerous species to overcome this deficit. Alignment of the OT promoters available revealed stretches of high homology and further analysis of these stretches revealed that they are binding sites for the nuclear receptor superfamily of transcription factors such as the estrogen receptor (ER), retinoic acid receptor (RAR) and the thyroid hormone receptor (TR). Here, I identify that the orphan receptors, chicken ovalbumin up-stream promoter transcription factor II (COUP-TFII), ErbA-related factor 2 (Ear-2) and retinoid orphan receptor alpha1 (RORalphal) as potential regulators of the OT gene promoter.In contrast to the positive effect of the ER, RAR and TR on the OT promoter, COUP-TFII and Ear-2 have a negative effect on the human OT promoter. The effects of COUP-TFs on the OT promoter are two-fold; they are able to silence or actively repress basal promoter activity and secondly, inhibit the activation by other nuclear receptors via a mechanism of competitive binding. Two additive DNA elements were identified to mediate the effect of COUP-TFII and Ear-2. The first one is a direct repeat of the AGGTCA motif spaced by zero nucleotide (DR0) that is embedded in the OT/estrogen response element (OT/ERE). The second element, located downstream of the OT/ERE, consists of three AGGTCA motifs each spaced by four nucleotides. Inhibition of the estrogenic induction only requires the DR0 whereas both elements are required for full silencing of basal activity. DNaseI footprinting and gel shift assays show that recombinant COUP-TFII and Ear-2 are able to bind to the DR0 and the downstream repeats. Mutations that affect the ability of COUP-TFII and Ear-2 to bind to these elements also affect their activity in transient transfection studies. The importance of COUP-TFII and Ear-2 in the regulation of OT gene expression is supported by their expression in the epithelial layer of the rat parturient uterus. The uterus is a known site of OT expression where a dynamic regulation of OT is observed. (Abstract shortened by UMI.

The Transmission Mechanism of Russian Central Banks Countercyclical Monetary Policy since 2011: Evidence from the Interest Rate Pass-Through

The study is an investigation of the nature of the Russian interest rate pass-through from February 2011 to November 11, 2016. The empirical results reveal a relatively low short-run interest pass-through of 0.662937 and an incomplete long-run interest rate pass-through of 0.826353. The bounds test results indicate no long-term relationship between countercyclical monetary policy and market rates. These empirical findings suggest that the Russian Central Bank has not been very effective in formulating and implementing its countercyclical monetary policy. In light of the formidable political and economic challenges faced by the Russian Federation over this sample period, the results are hardly surprising

Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models

Inflammatory breast cancer (IBC) is a unique and deadly disease with unknown drivers. We hypothesized the inflammatory environment contributes to the IBC phenotype. We used an in vitro co-culture system to investigate interactions between normal and polarized macrophages (RAW 264.7 cell line), bone-marrow derived mesenchymal stem cells (MSCs), and IBC cells (SUM 149 and MDA-IBC3). We used an in vivo model that reproduces the IBC phenotype by co-injecting IBC cells with MSCs into the mammary fat pad. Mice were then treated with a macrophage recruitment inhibitor, anti-CSF1. MSC and macrophages grown in co-culture produced higher levels of pro-tumor properties such as enhanced migration and elevated IL-6 secretion. IBC cells co-cultured with educated MSCs also displayed enhanced invasion and mammosphere formation and blocked by anti-IL-6 and statin treatment. The treatment of mice co-injected with IBC cells and MSCs with anti-CSF1 inhibited tumor associated macrophages and inhibited pSTAT3 expression in tumor cells. Anti-CSF1 treated mice also exhibited reduced tumor growth, skin invasion, and local recurrence. Herein we demonstrate reciprocal tumor interactions through IL-6 with cells found in the IBC microenvironment. Our results suggest IL-6 is a mediator of these tumor promoting influences and is important for the IBC induced migration of MSCs