Assignment of orthologous relationships among mammalian alpha-globin genes by examining flanking regions reveals a rapid rate of evolution

In order to study the relationships among mammalian alpha-globin genes, we have determined the sequence of the 3' flanking region of the human alpha 1 globin gene and have made pairwise comparisons between sequenced alpha-globin genes. The flanking regions were examined in detail because sequence matches in these regions could be interpreted with the least complication from the gene duplications and conversions that have occurred frequently in mammalian alpha-like globin gene clusters. We found good matches between the flanking regions of human alpha 1 and rabbit alpha 1, human psi alpha 1 and goat I alpha, human alpha 2 and goat II alpha, and horse alpha 1 and goat II alpha. These matches were used to align the alpha-globin genes in gene clusters from different mammals. This alignment shows that genes at equivalent positions in the gene clusters of different mammals can be functional or nonfunctional, depending on whether they corrected against a functional alpha-globin gene in recent evolutionary history. The number of alpha-globin genes (including pseudogenes) appears to differ among species, although highly divergent pseudogenes may not have been detected in all species examined. Although matching sequences could be found in interspecies comparisons of the flanking regions of alpha- globin genes, these matches are not as extensive as those found in the flanking regions of mammalian beta-like globin genes. This observation suggests that the noncoding sequences in the mammalian alpha-globin gene clusters are evolving at a faster rate than those in the beta-like globin gene clusters. The proposed faster rate of evolution fits with the poor conservation of the genetic linkage map around alpha-globin gene clusters when compared to that of the beta-like globin gene clusters. Analysis of the 3' flanking regions of alpha-globin genes has revealed a conserved sequence approximately 100-150 bp 3' to the polyadenylation site; this sequence may be involved in the expression or regulation of alpha-globin genes.      

Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast.

The endoplasmic reticulum (ER) of the yeast Saccharomyces cerevisiae contains of proteolytic system able to selectively degrade misfolded lumenal secretory proteins. For examination of the components involved in this degradation process, mutants were isolated. They could be divided into four complementation groups. The mutations led to stabilization of two different substrates for this process. The mutant classes were called ''der'' for ''degradation in the ER''. DER1 was cloned by complementation of the der1-2 mutation. The DER1 gene codes for a novel, hydrophobic protein, that is localized to the ER. Deletion of DER1 abolished degradation of the substrate proteins. The function of the Der1 protein seems to be specifically required for the degradation process associated with the ER. The depletion of Der1 from cells causes neither detectable growth phenotypes nor a general accumulation of unfolded proteins in the ER. In DER1-deleted cells, a substrate protein for ER degradation is retained in the ER by the same mechanism which also retains lumenal ER residents. This suggests that DER1 acts in a process that directly removes protein from the folding environment of the ER.     

Zinc and cadmium hyperaccumulation by Thlaspi caerulescens from metalliferous and nonmetalliferous sites in the Mediterranean area: implications for phytoremediation

Growth, tolerance and zinc and cadmium hyperaccumulation of Thlaspi caerulescens populations from three metal contaminated soils and three normal soils were compared under controlled conditions. Individuals of six populations were cultivated on five soils with increasing concentrations of zinc (50–25000 μg g⁻¹) and cadmium (1–170 μg g⁻¹). There was no mortality of normal soil populations in the four metal-contaminated soils, but plant growth was reduced to half that of populations from metal-contaminated soils. However, in noncontaminated soil, the growth of individuals from normal soils was greater than that of individuals from metal-contaminated soils. Individuals from normal soils concentrated three times more zinc in the aboveground biomass than those from metal-contaminated soils, but the latter accumulated twice as much cadmium. We conclude that populations of T. caerulescens from both normal and metal-contaminated soils are interesting material for phytoextraction of zinc and cadmium, but to optimize the process of phytoextraction it is necessary to combine the extraction potentials of both type of populations.     

Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity

Nucleotide-binding domain leucine-rich repeat proteins (NLRs) play a key role in immunity and disease through their ability to modulate inflammation in response to pathogen-derived and endogenous danger signals. Here, we identify the requirements for activation of NLRP1, an NLR protein associated with a number of human pathologies, including vitiligo, rheumatoid arthritis, and Crohn disease. We demonstrate that NLRP1 activity is dependent upon ASC, which associates with the C-terminal CARD domain of NLRP1. In addition, we show that NLRP1 activity is dependent upon autolytic cleavage at Ser(1213) within the FIIND. Importantly, this post translational event is dependent upon the highly conserved distal residue His(1186). A disease-associated single nucleotide polymorphism near His(1186) and a naturally occurring mRNA splice variant lacking exon 14 differentially affect this autolytic processing and subsequent NLRP1 activity. These results describe key molecular pathways that regulate NLRP1 activity and offer insight on how small sequence variations in NLR genes may influence human disease pathogenesis.     

利用AFLP遗传连锁图定位大麦苗期对叶锈病的部分抗性基因

借助大麦染色体ＡＦＬＰ标记遗传连锁图和ＭａｐＱＴＬＶ３．０作图软件,对大麦叶病的数量抗性基因进行了定位分析,明确了大麦部分抗性品种Ｖａｄａ对叶锈病的潜育期由分别位于染色体１、２、６、７上离短臂末端７９ｃＭ、１８６ｃＭ、５８ｃＭ和１１７ｃＭ处的４个数量抗性基因所控制。     

Sex differences in the immune response to acute COVID-19 respiratory tract infection

Determine if sex differences exist in clinical characteristics and outcomes of adults hospitalized for coronavirus disease 2019 (COVID-19) in a US healthcare system. Case series study. Sequentially hospitalized adults admitted for COVID-19 at two tertiary care academic hospitals in New Orleans, LA, between 27 February and 15 July 2020. Measures included demographics, comorbidities, presenting symptoms, and laboratory results. Outcomes included intensive care unit admission (ICU), invasive mechanical ventilation (IMV), and in-hospital death. We included 776 patients (median age 60.5 years; 61.4% women, 75% non-Hispanic Black). Rates of ICU, IMV, and death were similar in both sexes. In women versus men, obesity (63.8 vs 41.6%, P < 0.0001), hypertension (77.6 vs 70.1%, P = 0.02), diabetes (38.2 vs 31.8%, P = 0.06), chronic obstructive pulmonary disease (COPD, 22.1 vs 15.1%, P = 0.015), and asthma (14.3 vs 6.9%, P = 0.001) were more prevalent. More women exhibited dyspnea (61.2 vs 53.7%, P = 0.04), fatigue (35.7 vs 28.5%, P = 0.03), and digestive symptoms (39.3 vs 32.8%, P = 0.06) than men. Obesity was associated with IMV at a lower BMI (> 35) in women, but the magnitude of the effect of morbid obesity (BMI ≥ 40) was similar in both sexes. COPD was associated with ICU (adjusted OR (aOR), 2.6; 95%CI, 1.5–4.3) and IMV (aOR, 1.8; 95%CI, 1.2–3.1) in women only. Diabetes (aOR, 2.6; 95%CI, 1.2–2.9), chronic kidney disease (aOR, 2.2; 95%CI, 1.3–5.2), elevated neutrophil-to-lymphocyte ratio (aOR, 2.5; 95%CI, 1.4–4.3), and elevated ferritin (aOR, 3.6; 95%CI, 1.7–7.3) were independent predictors of death in women only. In contrast, elevated D-dimer was an independent predictor of ICU (aOR, 7.3; 95%CI, 2.7–19.5), IMV (aOR, 6.5; 95%CI, 2.1–20.4), and death (aOR, 4.5; 95%CI, 1.2–16.4) in men only. This study highlights sex disparities in clinical determinants of severe outcomes in COVID-19 patients that may inform management and prevention strategies to ensure gender equity.     

Visual Impairment as a Function of Visual Acuity in Both Eyes and Its Impact on Patient Reported Preferences

Purpose

To assess the impact of VA loss on patient reported utilities taking both eyes into account compared to taking only the better or the worse eye into account.

Methods

In this cross-sectional study 1085 patients and 254 controls rated preferences with the generic health-related (EQ-5D; n = 868) and vision-specific (Vision and Quality of Life Index (VisQoL); n = 837) multi-attribute utility instruments (MAUIs). Utilities were calculated for three levels of VA in the better and worse eyes, as well as for 6 different vision states based on combinations of the better and worse eye VA.

Results

Using the VisQoL, utility scores decreased significantly with deteriorating vision in both the better and worse eyes when analysed separately. When stratified by the 6 vision states, VisQoL utilities decreased as VA declined in the worse eye despite stable VA in the better eye. Differences in VisQoL scores were statistically significant for cases where the better eye had no vision impairment and the worse seeing fellow eye had mild, moderate or severe vision impairment. In contrast, the EQ-5D failed to capture changes in better or worse eye VA, or any of the six vision states.

Conclusions

Calculating utilities based only on better eye VA or using a generic MAUI is likely to underestimate the impact of vision impairment, particularly when the better eye has no or little VA loss and the worse eye is moderately to severely visually impaired. These findings have considerable implications for the assessment of overall visual impairment as well as economic evaluations within eye health.     

TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia

Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD‐TDP). Recently, a genome‐wide association study identified the first FTLD‐TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD‐TDP risk. Intriguingly, the most significant association was in FTLD‐TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD‐TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B‐specific antibody for investigation of this protein. Enzyme‐linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over‐expression. However, over‐expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N‐glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD‐TDP risk.