Flavonol triglycosides containing galactose in tea.

The isolation and structural elucidation of new quercetin and kaempferol triglycosides from Camellia sinensis is described. Their structures were determined as quercetin and kaempferol 3-glucosyl(1----3) rhamnosyl(1----6)galactosides. The content of quercetin glucosylrhamnosylgalactoside ranged between 0 and 87 mg per 100 g, and that of the kaempferol homologue between 0 and 119 mg per 100 g dry wt.     

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.     

Big flies, small repeats: the "Thr-Gly" region of the period gene in Diptera

The region of the clock gene period (per) that encodes a repetitive tract of threonine-glycine (Thr-Gly) pairs has been compared between Dipteran species both within and outside the Drosophilidae. All the non- Drosophilidae sequences in this region are short and present a remarkably stable picture compared to the Drosophilidae, in which the region is much larger and extremely variable, both in size and composition. The accelerated evolution in the repetitive region of the Drosophilidae appears to be mainly due to an expansion of two ancestral repeats, one encoding a Thr-Gly dipeptide and the other a pentapeptide rich in serine, glycine, and asparagine or threonine. In some drosophilids the expansion involves a duplication of the pentapeptide sequence, but in Drosophila pseudoobscura both the dipeptide and the pentapeptide repeats are present in larger numbers. In the nondrosophilids, however, the pentapeptide sequence is represented by one copy and the dipeptide by two copies. These observations fulfill some of the predictions of recent theoretical models that have simulated the evolution of repetitive sequences.      

Evolutionary origin of human and primate malarias: evidence from the circumsporozoite protein gene

We have analyzed the conserved regions of the gene coding for the circumsporozoite protein (CSP) in 12 species of Plasmodium, the malaria parasite. The closest evolutionary relative of P. falciparum, the agent of malignant human malaria, is P. reichenowi, a chimpanzee parasite. This is consistent with the hypothesis that P. falciparum is an ancient human parasite, associated with humans since the divergence of the hominids from their closest hominoid relatives. Three other human Plasmodium species are each genetically indistinguishable from species parasitic to nonhuman primates; that is, for the DNA sequences included in our analysis, the differences between species are not greater than the differences between strains of the human species. The human P. malariae is indistinguishable from P. brasilianum, and P. vivax is indistinguishable from P. simium; P. brasilianum and P. simium are parasitic to New World monkeys. The human P. vivax-like is indistinguishable from P. simiovale, a parasite of Old World macaques. We conjecture that P. malariae, P. vivax, and P. vivax-like are evolutionarily recent human parasites, the first two at least acquired only within the last several thousand years, and perhaps within the last few hundred years, after the expansion of human populations in South America following the European colonizations. We estimate the rate of evolution of the conserved regions of the CSP gene as 2.46 x 10(-9) per site per year. The divergence between the P. falciparum and P. reichenowi lineages is accordingly dated 8.9 Myr ago. The divergence between the three lineages leading to the human parasites is very ancient, about 100 Myr old between P. malariae and P. vivax (and P. vivax-like) and about 165 Myr old between P. falciparum and the other two.      

Excitation of System I and System II in Photosynthesis as a Possible Control Mechanism of Glycolate Metabolism in the Blue-Green Alga Anacystis nidulans

Photosynthetic enhancement studies performed at 619 nm (excitation of Systems I and II) and at 446 nm (mainly excitation of System I) revealed an 18% photosynthetic enhancement simultaneously with a 31% reduction in glycolate excretion. This observation supports the hypothesis that some glycolate may be consumed in an oxidation process associated with System I when System II is poorly excited and the supply of electrons from the water splitting process of photosynthesis is low.     

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.

     

Evolutionary origins of taste buds: phylogenetic analysis of purinergic neurotransmission in epithelial chemosensors

Taste buds are gustatory endorgans which use an uncommon purinergic signalling system to transmit information to afferent gustatory nerve fibres. In mammals, ATP is a crucial neurotransmitter released by the taste cells to activate the afferent nerve fibres. Taste buds in mammals display a characteristic, highly specific ecto-ATPase (NTPDase2) activity, suggesting a role in inactivation of the neurotransmitter. The purpose of this study was to test whether the presence of markers of purinergic signalling characterize taste buds in anamniote vertebrates and to test whether similar purinergic systems are employed by other exteroceptive chemosensory systems. The species examined include several teleosts, elasmobranchs, lampreys and hagfish, the last of which lacks vertebrate-type taste buds. For comparison, Schreiner organs of hagfish and solitary chemosensory cells (SCCs) of teleosts, both of which are epidermal chemosensory end organs, were also examined because they might be evolutionarily related to taste buds. Ecto-ATPase activity was evident in elongate cells in all fish taste buds, including teleosts, elasmobranchs and lampreys. Neither SCCs nor Schreiner organs show specific ecto-ATPase activity, suggesting that purinergic signalling is not crucial in those systems as it is for taste buds. These findings suggest that the taste system did not originate from SCCs but arose independently in early vertebrates.