Transcriptional regulation of the glucoamylase-encoding gene under endoplasmic reticulum stress in Aspergillus niger

The ability of many filamentous fungi, such as Aspergillus niger, to secret a high level of homologous proteins has led to their consideration as hosts for the production of heterologous proteins. However, the levels of some secreted heterologous proteins have often been low. Although many strategies have been developed to improve the level of secreted heterologous proteins, further studies into the remaining bottlenecks are required. One common strategy used to improve secreted protein production from filamentous fungi is to express the target protein under the control of a highly-induced native promoter. One major bottleneck in the secretion of heterologous proteins is caused by the folding of proteins within the lumen of the endoplasmic reticulum (ER). Recent studies have shown that expressing some heterologous proteins could subject A. niger to ER-stress. In this study, A. niger was subjected to different environmental conditions and ER stress responses were examined under each of these environmental conditions to further investigate the regulation of the gene encoding glucoamylase (glaA). Treating A. niger with dithiothreitol (OTT), a reducing agent that causes the formation of unfolded proteins, caused the down-regulation of transcription of the glaA but not the gene encoding the non-secreted protein y-actin. The OTT-treated fungal cells also showed evidence of induction of the UPR because expression of bipA was up-regulated and splicing of hacA, the gene encoding the transcription factor responsible for induction of the Unfolded Protein Response (UPR), occurs allowing the production of an active HacA protein. This is the first study to show clearly by nuclear run-on studies that the transcriptional down-regulation effect occurs at the level of transcription, rather than mRNA stability, and is found to be mediated through the promoter of the glaA gene (PglaA) in a region more than 1.192 kb upstream of the translational start. As a preliminary attempt to investigate if the transcriptional downregulation effect was mediated through HacA (i.e. part of the UPR), the ER stress was induced through antisense technology to lower the level of POI in the ER of A. niger. Although the transcription of glaA was attenuated in that strain of A. niger, UPR was not evident, suggesting that the transcriptional down-regulation mechanism is controlled differently from the UPR. Furthermore, activation of the ER-Associated Degradation (ERAO) mechanism in OTT-treated A. niger cultures was demonstrated by detecting transcriptional up-regulation of the putative gene encoding the RpnG, a homologue of the yeast Rpn7p subunit of the 26S proteasome

Geoquímica del rango volcánico alcalino del eoceno medio-superior, parte sur de las montañas centrales de Alborz, norte de Irán

The Ziaran volcanic Belt (ZVB), North of Iran contains a number of intra-continental alkaline volcanic range situated on South part of central Alborz Mountains, formed along the localized extensional basins developed in relation with the compressional regime of Eocene. The mid-upper Eocene volcanic suite comprises the extracted melt products of adiabatic decompression melting of the mantle that are represented by small volume intra-continental plate volcanic rocks of alkaline volcanism and their evaluated Rocks with compositions representative of mantle-derived, primary (or near-primary) melts. Trace element patterns with significant enrichment in LILE, HFSE and REEs, relative to Primitive Mantle. Chondrite-normalized of rare earth elements and enrichment in incompatible elements and their element ratios (e. g. LREE/HREE, MREE/HREE, LREE/MREE) shown these element modelling indicates that the magmas were generated by comparably variable degrees of partial melting of garnet lherzolite and a heterogeneous asthenospheric, OIB mantle sources.El cinturón volcánico de Ziaran (ZVB), al norte de Irán, contiene una serie de cordilleras volcánicas alcalinas intracontinentales situadas en la parte sur de las montañas centrales de Alborz, formadas a lo largo de las cuencas extensionales localizadas desarrolladas en relación con el régimen de compresión del Eoceno. La suite volcánica del Eoceno medio superior comprende los productos de fusión extraídos de la fusión por descompresión adiabática del manto que están representados por rocas volcánicas de placa intracontinental de pequeño volumen de vulcanismo alcalino y sus rocas evaluadas con composiciones representativas de las rocas derivadas del manto, primarias (o cercanas). -primaria) se derrite. Patrones de oligoelementos con enriquecimiento significativo en LILE, HFSE y REE, en relación con Primitive Mantle. Condrita normalizada de elementos de tierras raras y enriquecimiento en elementos incompatibles y sus proporciones de elementos (por ejemplo, LREE / HREE, MREE / HREE, LREE / MREE) que muestra el modelado de estos elementos indica que los magmas se generaron por grados comparativamente variables de fusión parcial de granate lherzolita y fuentes de manto OIB astenosféricas heterogéneas

Geoquímica del rango volcánico alcalino del eoceno medio-superior, parte sur de las montañas centrales de Alborz, norte de Irán

The Ziaran volcanic Belt (ZVB), North of Iran contains a number of intra-continental alkaline volcanic range situated on South part of central Alborz Mountains, formed along the localized extensional basins developed in relation with the compressional regime of Eocene. The mid-upper Eocene volcanic suite comprises the extracted melt products of adiabatic decompression melting of the mantle that are represented by small volume intra-continental plate volcanic rocks of alkaline volcanism and their evaluated Rocks with compositions representative of mantle-derived, primary (or near-primary) melts. Trace element patterns with significant enrichment in LILE, HFSE and REEs, relative to Primitive Mantle. Chondrite-normalized of rare earth elements and enrichment in incompatible elements and their element ratios (e. g. LREE/HREE, MREE/HREE, LREE/MREE) shown these element modelling indicates that the magmas were generated by comparably variable degrees of partial melting of garnet lherzolite and a heterogeneous asthenospheric, OIB mantle sources.El cinturón volcánico de Ziaran (ZVB), al norte de Irán, contiene una serie de cordilleras volcánicas alcalinas intracontinentales situadas en la parte sur de las montañas centrales de Alborz, formadas a lo largo de las cuencas extensionales localizadas desarrolladas en relación con el régimen de compresión del Eoceno. La suite volcánica del Eoceno medio superior comprende los productos de fusión extraídos de la fusión por descompresión adiabática del manto que están representados por rocas volcánicas de placa intracontinental de pequeño volumen de vulcanismo alcalino y sus rocas evaluadas con composiciones representativas de las rocas derivadas del manto, primarias (o cercanas). -primaria) se derrite. Patrones de oligoelementos con enriquecimiento significativo en LILE, HFSE y REE, en relación con Primitive Mantle. Condrita normalizada de elementos de tierras raras y enriquecimiento en elementos incompatibles y sus proporciones de elementos (por ejemplo, LREE / HREE, MREE / HREE, LREE / MREE) que muestra el modelado de estos elementos indica que los magmas se generaron por grados comparativamente variables de fusión parcial de granate lherzolita y fuentes de manto OIB astenosféricas heterogéneas

Geoquímica del rango volcánico alcalino del eoceno medio-superior, parte sur de las montañas centrales de Alborz, norte de Irán

El cinturón volcánico de Ziaran (ZVB), al norte de Irán, contiene una serie de cordilleras volcánicas alcalinas intracontinentales situadas en la parte sur de las montañas centrales de Alborz, formadas a lo largo de las cuencas extensionales localizadas desarrolladas en relación con el régimen de compresión del Eoceno. La suite volcánica del Eoceno medio superior comprende los productos de fusión extraídos de la fusión por descompresión adiabática del manto que están representados por rocas volcánicas de placa intracontinental de pequeño volumen de vulcanismo alcalino y sus rocas evaluadas con composiciones representativas de las rocas derivadas del manto, primarias (o cercanas). -primaria) se derrite. Patrones de oligoelementos con enriquecimiento significativo en LILE, HFSE y REE, en relación con Primitive Mantle. Condrita normalizada de elementos de tierras raras y enriquecimiento en elementos incompatibles y sus proporciones de elementos (por ejemplo, LREE / HREE, MREE / HREE, LREE / MREE) que muestra el modelado de estos elementos indica que los magmas se generaron por grados comparativamente variables de fusión parcial de granate lherzolita y fuentes de manto OIB astenosféricas heterogéneas

The Petrology of Ziyran Volcanic Belt (ZVB) Eocene Volcanic Rocks

The Ziyaran Volcanic Belt (ZVB) is located in the southern part of central Alborz and in the Ziyaran area. The geology of this layer includes various kinds of stone units. In the north, they are the reminder of Cenozoic, quaternary deposits, and in the western part, the exposure stone units are mostly Precambrian and Paleozoic deposits and in the south-eastern part of the studied area, the stones belong to the Mesozoic era and specifically, the sediments belong to the Jurassic era are exposed. Also, the basic volcanic rocks that belong to the Eocene period are located in the Ziyaran area, in the western part of Taleqan County and in the Alborz state. This study aimed to evaluate the petrology of Ziyaran Volcanic Belt (ZVB) Eocene volcanic rocks. For this purpose, which is mostly focused on the study of Cretaceous stones in the central Alborz zone, sampling of the stones in the intended area was performed with the survey and field methods and for 120 samples. After the preparation of the thin layer from the well and without alteration samples, they were examined with petrography and petrology tests. The results of the petrology studies of the volcanic rocks of the Ziyaran area expressed that the basic volcanic rocks in the intermediate area with the intermediate- upper chemical composition of Eocene Alkaline Phosphatase (ALP) located in the central zone of Alborz heights, with lithology composition of Alkali olivine basalts and Andesite

The Petrology of Ziyran Volcanic Belt (ZVB) Eocene Volcanic Rocks

The Ziyaran Volcanic Belt (ZVB) is located in the southern part of central Alborz and in the Ziyaran area. The geology of this layer includes various kinds of stone units. In the north, they are the reminder of Cenozoic, quaternary deposits, and in the western part, the exposure stone units are mostly Precambrian and Paleozoic deposits and in the south-eastern part of the studied area, the stones belong to the Mesozoic era and specifically, the sediments belong to the Jurassic era are exposed. Also, the basic volcanic rocks that belong to the Eocene period are located in the Ziyaran area, in the western part of Taleqan County and in the Alborz state. This study aimed to evaluate the petrology of Ziyaran Volcanic Belt (ZVB) Eocene volcanic rocks. For this purpose, which is mostly focused on the study of Cretaceous stones in the central Alborz zone, sampling of the stones in the intended area was performed with the survey and field methods and for 120 samples. After the preparation of the thin layer from the well and without alteration samples, they were examined with petrography and petrology tests. The results of the petrology studies of the volcanic rocks of the Ziyaran area expressed that the basic volcanic rocks in the intermediate area with the intermediate- upper chemical composition of Eocene Alkaline Phosphatase (ALP) located in the central zone of Alborz heights, with lithology composition of Alkali olivine basalts and Andesite

General and abdominal adiposity and hypertension in eight world regions: a pooled analysis of 837 population-based studies with 7•5 million participants

Background: Adiposity can be measured using BMI (which is based on weight and height) as well as indices of abdominal adiposity. We examined the association between BMI and waist-to-height ratio (WHtR) within and across populations of different world regions and quantified how well these two metrics discriminate between people with and without hypertension. Methods: We used data from studies carried out from 1990 to 2023 on BMI, WHtR and hypertension in people aged 20–64 years in representative samples of the general population in eight world regions. We graphically compared the regional distributions of BMI and WHtR, and calculated Pearson's correlation coefficients between BMI and WHtR within each region. We used mixed-effects linear regression to estimate the extent to which WHtR varies across regions at the same BMI. We graphically examined the prevalence of hypertension and the distribution of people who have hypertension both in relation to BMI and WHtR, and we assessed how closely BMI and WHtR discriminate between participants with and without hypertension using C-statistic and net reclassification improvement (NRI). Findings: The correlation between BMI and WHtR ranged from 0·76 to 0·89 within different regions. After adjusting for age and BMI, mean WHtR was highest in south Asia for both sexes, followed by Latin America and the Caribbean and the region of central Asia, Middle East and north Africa. Mean WHtR was lowest in central and eastern Europe for both sexes, in the high-income western region for women, and in Oceania for men. Conversely, to achieve an equivalent WHtR, the BMI of the population of south Asia would need to be, on average, 2·79 kg/m2 (95% CI 2·31–3·28) lower for women and 1·28 kg/m2 (1·02–1·54) lower for men than in the high-income western region. In every region, hypertension prevalence increased with both BMI and WHtR. Models with either of these two adiposity metrics had virtually identical C-statistics and NRIs for every region and sex, with C-statistics ranging from 0·72 to 0·81 and NRIs ranging from 0·34 to 0·57 in different region and sex combinations. When both BMI and WHtR were used, performance improved only slightly compared with using either adiposity measure alone. Interpretation: BMI can distinguish young and middle-aged adults with higher versus lower amounts of abdominal adiposity with moderate-to-high accuracy, and both BMI and WHtR distinguish people with or without hypertension. However, at the same BMI level, people in south Asia, Latin America and the Caribbean, and the region of central Asia, Middle East and north Africa, have higher WHtR than in the other regions. Funding: UK Medical Research Council and UK Research and Innovation (Innovate UK)

Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 population-representative studies with 141 million participants

Background: Diabetes can be detected at the primary health-care level, and effective treatments lower the risk of complications. There are insufficient data on the coverage of treatment for diabetes and how it has changed. We estimated trends from 1990 to 2022 in diabetes prevalence and treatment for 200 countries and territories. Methods: We used data from 1108 population-representative studies with 141 million participants aged 18 years and older with measurements of fasting glucose and glycated haemoglobin (HbA1c), and information on diabetes treatment. We defined diabetes as having a fasting plasma glucose (FPG) of 7·0 mmol/L or higher, having an HbA1c of 6·5% or higher, or taking medication for diabetes. We defined diabetes treatment as the proportion of people with diabetes who were taking medication for diabetes. We analysed the data in a Bayesian hierarchical meta-regression model to estimate diabetes prevalence and treatment. Findings: In 2022, an estimated 828 million (95% credible interval [CrI] 757–908) adults (those aged 18 years and older) had diabetes, an increase of 630 million (554–713) from 1990. From 1990 to 2022, the age-standardised prevalence of diabetes increased in 131 countries for women and in 155 countries for men with a posterior probability of more than 0·80. The largest increases were in low-income and middle-income countries in southeast Asia (eg, Malaysia), south Asia (eg, Pakistan), the Middle East and north Africa (eg, Egypt), and Latin America and the Caribbean (eg, Jamaica, Trinidad and Tobago, and Costa Rica). Age-standardised prevalence neither increased nor decreased with a posterior probability of more than 0·80 in some countries in western and central Europe, sub-Saharan Africa, east Asia and the Pacific, Canada, and some Pacific island nations where prevalence was already high in 1990; it decreased with a posterior probability of more than 0·80 in women in Japan, Spain, and France, and in men in Nauru. The lowest prevalence in the world in 2022 was in western Europe and east Africa for both sexes, and in Japan and Canada for women, and the highest prevalence in the world in 2022 was in countries in Polynesia and Micronesia, some countries in the Caribbean and the Middle East and north Africa, as well as Pakistan and Malaysia. In 2022, 445 million (95% CrI 401–496) adults aged 30 years or older with diabetes did not receive treatment (59% of adults aged 30 years or older with diabetes), 3·5 times the number in 1990. From 1990 to 2022, diabetes treatment coverage increased in 118 countries for women and 98 countries for men with a posterior probability of more than 0·80. The largest improvement in treatment coverage was in some countries from central and western Europe and Latin America (Mexico, Colombia, Chile, and Costa Rica), Canada, South Korea, Russia, Seychelles, and Jordan. There was no increase in treatment coverage in most countries in sub-Saharan Africa; the Caribbean; Pacific island nations; and south, southeast, and central Asia. In 2022, age-standardised treatment coverage was lowest in countries in sub-Saharan Africa and south Asia, and treatment coverage was less than 10% in some African countries. Treatment coverage was 55% or higher in South Korea, many high-income western countries, and some countries in central and eastern Europe (eg, Poland, Czechia, and Russia), Latin America (eg, Costa Rica, Chile, and Mexico), and the Middle East and north Africa (eg, Jordan, Qatar, and Kuwait). Interpretation: In most countries, especially in low-income and middle-income countries, diabetes treatment has not increased at all or has not increased sufficiently in comparison with the rise in prevalence. The burden of diabetes and untreated diabetes is increasingly borne by low-income and middle-income countries. The expansion of health insurance and primary health care should be accompanied with diabetes programmes that realign and resource health services to enhance the early detection and effective treatment of diabetes. Funding: UK Medical Research Council, UK Research and Innovation (Research England), and US Centers for Disease Control and Prevention

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance