ARRB1 suppresses the activation of hepatic macrophages via modulating endoplasmic reticulum stress in lipopolysaccharide-induced acute liver injury

Acute liver injury (ALI) caused by multiple inflammatory responses is a monocyte-/macrophage-mediated liver injury that is associated with high morbidity and mortality. Liver macrophage activation is a vital event that triggers ALI. However, the mechanism of liver macrophage activation has not been fully elucidated. This study examined the role of β-arrestin1 (ARRB1) in wild-type (WT) and ARRB1-knockout (ARRB1-KO) mouse models of ALI induced by lipopolysaccharide (LPS), and ARRB1-KO mice exhibited more severe inflammatory injury and liver macrophage activation compared to WT mice. We found that LPS treatment reduced the expression level of ARRB1 in Raw264.7 and THP-1 cell lines, and mouse primary hepatic macrophages. Overexpression of ARRB1 in Raw264.7 and THP-1 cell lines significantly attenuated LPS-induced liver macrophage activation, such as transformation in cell morphology and enhanced expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), while downregulation of ARRB1 by small interfering RNA and ARRB1 deficiency in primary hepatic macrophages both aggravated macrophage activation. Moreover, overexpression of ARRB1 suppressed LPS-induced endoplasmic reticulum (ER) stress in liver macrophages, and inhibition of ER stress impeded excessive hepatic macrophage activation induced by downregulation of ARRB1. Our data demonstrate that ARRB1 relieves LPS-induced ALI through the ER stress pathway to regulate hepatic macrophage activation and that ARRB1 may be a potential therapeutic target for ALI.

Farnesyl pyrophosphate is a new danger signal inducing acute cell death

Cell death is a vital event in life. Infections and injuries cause lytic cell death, which gives rise to danger signals that can further induce cell death, inflammation, and tissue damage. The mevalonate (MVA) pathway is an essential, highly conserved and dynamic metabolic pathway. Here, we discover that farnesyl pyrophosphate (FPP), a metabolic intermediate of the MVA pathway, functions as a newly identified danger signal to trigger acute cell death leading to neuron loss in stroke. Harboring both a hydrophobic 15-carbon isoprenyl chain and a heavily charged pyrophosphate head, FPP leads to acute cell death independent of its downstream metabolic pathways. Mechanistically, extracellular calcium influx and the cation channel transient receptor potential melastatin 2 (TRPM2) exhibit essential roles in FPP-induced cell death. FPP activates TRPM2 opening for ion influx. Furthermore, in terms of a mouse model constructing by middle cerebral artery occlusion (MCAO), FPP accumulates in the brain, which indicates the function of the FPP and TRPM2 danger signal axis in ischemic injury. Overall, our data have revealed a novel function of the MVA pathway intermediate metabolite FPP as a danger signal via transient receptor potential cation channels.

Patterns and Differentials of Onset of Menstruation among School Girls in Chittagong Metropolitan Area of Bangladesh

Onset of menstruation is the biological and physical indicator, which is one of the important components of female reproductive characteristics. Considering its importance in the context of reproductive health and fertility, the aim of this study is to determine the mean age at menarche and also to investigate the patterns and differentials of such an important vital event of the randomly selected girls aged 9-15 years from the schools of Chittagong metropolitan area. The results of this study show that the overall mean menarcheal age of the selected girls is only 11.75±0.97 years with significant variations by their background characteristics. The co-efficient of variation (8.3%) indicates that there exists extreme heterogeneity in menarcheal age of the respondents. Co-efficient of skewness (β1=0.15) and excess of kurtosis (γ2=0.35) reflect that the shape characteristics of age at menarche is positively skewed and leptokurtic. The mean age at menarche is computed as relatively low (11.37 years) among the respondents residing in the metropolitan areas. The mean age at menarche is found the highest (12.01 years) among the underweight and the lowest among overweight (11.43 years) girls. The results from the life table technique show that unexpectedly 1.2% girls likely to attain menarche only within age of 9.67 years. The value of spread (s=16 months) shows extreme heterogeneity in menarcheal age. The values of trimean of onset of menstruation for underweight, normal and overweight girls are found 11.83, 11.58 and 11.41 years respectively. The Chittagong Univ. J. Sci. 40(1) : 178-199, 2019

The Historical Evolution оf the Population оf Ukraine in the Light of the Theory of Demographic Transition

The main results of scientific investigations of long-time trends in population dynamics and population replacement in deep retrospect for Ukraine are presented. Perceptions of the transformational changes in the structure of population of Ukraine are expanding — both for the statistical era and for the population nonstatistical era of national history. Th e investigation is based on the author’s reconstructions of historical series of demographic dynamics in Ukraine, which for the fi rst time made it possible to reconstruct the real trajectory of population trends in regions of Ukraine for the long time period (since beginning of Common Era). Th e transformation of population replacement in our country in the con- text of the theories of demographic modernization and comparison with similar changes in other European countries is investigated.Novelty: For the fi rst time, it is clear that the overall trend in the numerical effi ciency of our country has been ambiguous for thousands of years, especially in the past. Th e periods of perturbation (wars, famines, epidemics, natural disas- ters) made the trend undulatory; over the second millennium, annual growth rates have fallen 150 times below zero. Th e results of the study allowed for the fi rst time to carry out correct periodization of the demographic and epidemiological transitions: it is scientifi cally estab- lished that the demographic transition has been going on since the mid-1890s, and epide- miological — since the mid-1920s. In the course it was established that demographic deve- lopment of Ukraine continues in both the well-known tendencies of demographic transition and under the infl uence of national diff erences. Th e Ukrainian way of modernization in the twentieth century was very dramatic — our country has been described as one of the coun- tries with the largest loss of population. The peculiarity of the dynamics of demographic modernization in Ukraine in the twentieth century lies primarily in the fact that it has a de- formed intermittent nature due to the multimillion-dollar hecatomb of human victims, and in recent times there has been demodernization of the processes of reproduction of the popu- lation of our country. Key words: population, vital event, reconstruction, population growth, historical series, demographic modernization, Ukraine.

Conditional Deletion of Foxg1 Alleviates Demyelination and Facilitates Remyelination via the Wnt Signaling Pathway in Cuprizone-Induced Demyelinated Mice

The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system (CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells (OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone (CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type (WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3β, a key regulatory kinase in the Wnt pathway, regulates the ability of β-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763, a selective inhibitor of GSK-3β activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3β, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.

Non-communicable diseases are the leading cause of mortality in rural Birbhum, West Bengal, India: a sex-stratified analysis of verbal autopsies from a prospective cohort, 2012–2017

ObjectivesThere is a dearth of data on causes of death in rural India, which impedes identification of public health priorities to guide health interventions. This study aims to offer insights from verbal autopsies, to understand the pattern and distribution of causes of death in a rural area of Birbhum District, West Bengal, India.DesignCauses of death data were retrieved from a prospective vital event surveillance system.SettingThe Birbhum Population Project, a Health and Demographic Surveillance System, West Bengal, India.ParticipantsBetween January 2012 and December 2017, all deaths were recorded.Main outcome measuresTrained Surveyors tracked all deaths prospectively and used a previously validated verbal autopsy (VA) tool to record causes of death. Experienced physicians reviewed completed VA forms, and assigned cause of death using the 10th version of International Classification of Diseases. In addition to cause-specific mortality fraction, cause-specific crude death rate (CDR) among males and females were estimated.ResultsA total of 2320 deaths (1348 males and 972 females) were recorded. An estimated CDR was 708/100 000. Over half of all deaths (1176 deaths, 50.7%) were attributed to non-communicable diseases (NCDs), with nearly 30% of all deaths attributed to circulatory system disorders; whereas 24.2% and 3.9% deaths were due to cerebrovascular diseases and ischaemic heart disease, respectively. Equal percent (13%) of males died from external causes and from infectious and parasitic diseases, and 11% died from respiratory system-related diseases. Among females, 12% died from infectious and parasitic diseases. Among children aged 0–4 years, 50% of all male deaths and 45% of all female deaths were attributed to conditions in the perinatal period.ConclusionsNCDs are the leading cause of death among adults in a select population of rural Birbhum, India. Health programmes for rural India should prioritise plans to mitigate deaths due to NCDs.

Risk factors for young people not in education, employment or training (NEET) using the Scottish Longitudinal Study

BackgroundThe high level of young people not in education, employment or training (NEET) has been an important long-standing issue in Scotland. The experience of being NEET has long term detrimental effects. Main AimIdentify risk factors that could inform interventions aimed at reducing the number of NEETs. MethodsWe use the Scottish Longitudinal Study (SLS) which provides a 5.3% representative sample of Scotland’s population based around the Censuses of 1991, 2001 and 2011. The SLS includes Vital Event data, Census data for the SLS sample and also those living in the same household and, since 2007, school census data. This allows us to study two cohorts of 16-19 year olds (the ages used in Scotland when considering NEET status) over a period of 10 years: those 6-9 years old at the time of the 1991 Census to the 2001 Census when they were 16-19 years old those 6-9 years old at the time of the 2001 Census to the 2011 Census when they were 16-19 years old We used logistic regression to investigate whether NEET status is associated with individual, family and household characteristics measured 10 years previously and later data including school qualification, school behaviour, areal characteristics and teenage pregnancy. ResultsThese analyses found several factors were associated with the likelihood of being NEET for both cohorts, including having no qualifications, teenage pregnancy and living in an area where there was a relatively high level of NEETs (100% census data). For the later cohort, school census data were available and school behaviour were important factors, whereas household characteristics at childhood were important factors for the earlier cohort. ConclusionA number of factors are associated with NEET but those closer in time to the NEET ages of 16-19 appear to be more important than childhood factors.

Automatic coding of occupation and cause-of-death records

The Digitising Scotland project aims to digitise 24 million Scottish vital event records of births, marriages and deaths from 1856 to 1973. To use these records effectively for large-scale research they must not only be made machine-readable, but also coded in a form suitable for statistical analysis. The digitised birth, marriage, and death certificates include textual descriptions of occupations and causes of death. Our aim is to map these descriptions to standard HISCO and ICD-10 codes. It is impractical to have experts code all the records manually, so we treat the problem as a text classification task and apply machine learning techniques. A proportion of the records will be manually coded and used to train the system. More recent records are already coded and these can also be used for training. Following earlier work by [Kirby et al] and [Carson et al] we are experimenting with Bayesian classifiers for this task. By combining exact matching for texts that have been seen in the training data and Bayes for the rest, we get an accuracy in cross-validation of 92% for causes of death and 94-97% for occupations.We are investigating methods to improve this, including automatic spelling correction and synonym detection, use of age and sex information, and (for causes of death) the presence of co-occurring causes.We are also investigating the value of coarser-grained but more reliable coding, and reporting second- and third-choice codes. This is work in progress, and the final paper will consider whether the improvements we are making are sufficient to produce useful data for further research. We will also make recommendations about further manual annotation to provide training data covering the whole timespan of the records.

Unique health identifiers for universal health coverage

Identifying everyone residing in a country, especially the poor, is an indispensable part of pursuing universal health coverage (UHC). Having information on an individuals’ financial protection is also imperative for measuring the progress of UHC. This paper examines different ways of instituting a system of unique health identifiers that can lead toward achieving UHC, particularly in relation to utilizing universal civil registration and national unique identification number systems. Civil registration is a fundamental function of the government that establishes a legal identity for individuals and enables them to access essential public services. National unique identification numbers assigned at birth registration can further link their vital event information with data collected in different sectors, including in finance and health. Some countries use the national unique identification number as the unique health identifier, such as is done in South Korea and Thailand. In other countries, a unique health identifier is created in addition to the national unique identification number, but the two numbers are linked; Slovenia offers an example of this arrangement. The advantages and disadvantages of the system types are discussed in the paper. In either approach, linking the health system with the civil registration and national identity management systems contributed to advancing effective and efficient UHC programs in those countries.