Susceptibility to glaucoma: differential comparison of the astrocyte transcriptome from glaucomatous African American and Caucasian American donors

Background  

Epidemiological and genetic studies indicate that ethnic/genetic background plays an important role in susceptibility to primary open angle glaucoma (POAG). POAG is more prevalent among the African-descent population compared to the Caucasian population. Damage in POAG occurs at the level of the optic nerve head (ONH) and is mediated by astrocytes. Here we investigated differences in gene expression in primary cultures of ONH astrocytes obtained from age-matched normal and glaucomatous donors of Caucasian American (CA) and African American (AA) populations using oligonucleotide microarrays.     

MSP1(19) miniproteins can serve as targets for invasion inhibitory antibodies in Plasmodium falciparum provided they contain the correct domains for cell surface trafficking

Antibodies from malaria-exposed individuals can agglutinate merozoites released from Plasmodium schizonts, thereby preventing them from invading new erythrocytes. Merozoite coat proteins attached to the plasma membrane are major targets for host antibodies and are therefore considered important malaria vaccine candidates. Prominent among these is the abundant glycosylphosphatidylinositol (GPI)-anchored merozoite surface protein 1 (MSP1) and particularly its C-terminal fragment (MSP1₁₉) comprised of two epidermal growth factor (EGF)-like modules. In this paper, we revisit the role of agglutination and immunity using transgenic fluorescent marker proteins. We describe expression of heterologous MSP1₁₉'miniproteins' on the surface of Plasmodium   falciparum merozoites. To correctly express these proteins, we determined that GPI-anchoring and the presence of a signal sequence do not allow default export of proteins from the endoplasmic reticulum to merozoite surface and that extra sequence elements are required. The EGFs are insufficient for correct trafficking unless they are fused to additional residues that normally reside upstream of this fragment. Antibodies specifically targeting the surface-expressed miniprotein can inhibit erythrocyte invasion in vitro despite the presence of endogenous MSP1. Using a line expressing a green fluorescent protein–MSP1 fusion protein, we demonstrate that one mode of inhibition by antibodies targeting the MSP1₁₉ domain is the rapid agglutinating of merozoites prior to erythrocyte attachment.     

Maturation of female common snook Centropomus undecimalis: implications for managing protandrous fishes

The assumption for hermaphroditic fish species that mature individuals of the terminal sex arise directly from mature individuals of the primary sex has led to the use of sex ratios as a proxy for age at maturity (A₅₀). The timing of transition and deficient energy reserves, however, can result in a delay between transition and spawning. To test the assumption of female maturity and investigate the relationship between maturation and energy reserves, common snook, Centropomus undecimalis, a protandrous hermaphrodite, were collected from rivers, estuaries, inlets and offshore habitats on the east coast of Florida during 2010–2015. Immature females were observed every month, with lowest proportions during the peak spawning months of July and August. When calculated based on sex ratio, A₅₀ (8.1 years) overestimated the age at which 50% of the female population was, in fact, mature (4.1–4.9 years). Best-fit models indicate that mesenteric fat index (I_F) and hepato-somatic index (I_H) were significantly affected by gonad phase, month and size and weakly by habitat. In post hoc analysis, immature female I_F did not differ significantly from developing and regenerating females, but immature female I_H was significantly lower than that for all mature phases except animals in the regressing phase. Although immature females may have sufficient energy in terms of fat, it appears that energy is not allocated to reproductive processes, as evidenced by lower I_H. Nonetheless, approximately 95% of females were spawning-capable during peak spawning months, suggesting that the energy threshold at which immature females reach maturity is met by most females each spawning cycle.     

A proposed mechanism of thermophily in facultative thermophiles

Glyceraldehyde-3-phosphate dehydrogenase in crude extracts of $\text{Bacillus coagulans}$ KU, a facultative thermophile, showed marked thermolability whether the cells were grown at mesophilic or thermophilic temperature. When extracts were brought to a given ionic strength by the addition of salt and then heat treated, it was possible to confer heat resistance well in excess of the thermophilic growth temperature. Disc electrophoresis is indicative that portions of the profiles are quite different between extracts of cells grown at 37° and 55°. Based on the data, a mechanism of thermophily is postulated that is different from any thus far proposed for thermophilic microorganisms.     

Localization of the human gene for the El alpha subunit of branched chain keto acid dehydrogenase (BCKDHA) to chromosome 19q13.1----q13.2

The gene encoding the El alpha subunit of branched chain keto acid dehydrogenase (BCKDHA) was mapped to human chromosome region 19q13.1----q13.2 using 3H-labeled cDNA hybridized in situ to human chromosomes.     

Third generation of matrix metalloprotease inhibitors: Gain in selectivity by targeting the depth of the S1′ cavity

Following the disappointment of clinical trials with early broad-spectrum synthetic inhibitors of matrix metalloproteases (MMPs), the field is now resurging with a new focus on the development of more selective inhibitors. Compounds able to fully discriminate between different members of the MMP family are sorely needed for therapeutic applications. Chemical efforts over the past years have led to very few selective inhibitors of MMPs. The over-exploitation of the hydroxamate function, or other strong zinc-binding groups, might be responsible for this failure. By resorting to weaker zinc-chelating groups, like phosphoryl or carboxylic groups, inhibitors with improved selectivity profiles have been developed. However, the most encouraging results have been obtained with compounds that avoid targeting the zinc but gain their affinity from plunging deeper into the MMP S₁′ cavity. Analyses of the crystal structures of MMP-13 and MMP-8 complexes with such compounds provide novel insights for the design of more selective inhibitors for other members of the MMP family.     

Plasmodium falciparum‐encoded exported hsp70/hsp40 chaperone/co‐chaperone complexes within the host erythrocyte

Malaria parasites modify their host cell, the mature human erythrocyte. We are interested in the molecules mediating these processes, and have recently described a family of parasite‐encoded heat shock proteins (PfHsp40s) that are targeted to the host cell, and implicated in host cell modification. Hsp40s generally function as co‐chaperones of members of the Hsp70 family, and until now it was thought that human Hsp70 acts as the PfHsp40 interaction partner within the host cell. Here we revise this hypothesis, and identify and characterize an exported parasite‐encoded Hsp70, referred to as PfHsp70‐x. PfHsp70‐x is exported to the host erythrocyte where it forms a complex with PfHsp40s in structures known as J‐dots, and is closely associated with PfEMP1. Interestingly, Hsp70‐x is encoded only by parasite species that export the major virulence factor EMP1, implying a possible role for Hsp70‐x in EMP1 presentation at the surface of the infected erythrocyte. Our data strongly support the presence of parasite‐encoded chaperone/co‐chaperone complexes within the host erythrocyte, which are involved in protein traffic through the host cell. The host–pathogen interaction within the infected erythrocyte is more complex than previously thought, and is driven notonly by parasite co‐chaperones, but also by the parasite‐encoded chaperone Hsp70‐x itself.     

Defection by plants in the yucca–yucca moth association: a test of the cheater plant hypothesis for Yucca treculeana

In mutualisms, an underlying conflict of interests may select for defection from providing benefits. In the obligate mutualism between yuccas and yucca moths, where pollination service and seeds for pollinator larvae are traded, it has been suggested that some individuals in a population of Y. baccata may defect by preventing pollinator egg or larvae from development. We tested this hypothesis in Y. treculeana , another species suggested to contain cheater plants. Five specific predictions were tested during two years of study. A prediction that a surplus of plants without pollinator larvae should be present was met. Predicted existence of two distinct fruit morphs was rejected, and none of several highly variable morphological traits were linked to presence/absence of larvae. Predicted excess of intact seeds in the fruits of plants without larvae was not found; in fact, such plants produced fewer seeds, contrary to the hypothesis. A suggestion that inverse frequency-dependent fitness could explain the pattern was rejected. Contrary to prediction, distribution of larvae of a closely related cheater yucca moth was positively associated with pollinator larvae, even though it would not be affected by the proposed killing mechanism. The results together provide strong support against the existence of cheater plants in Y. treculeana .     

Sex and dosing-time dependencies in irinotecan-induced circadian disruption

Circadian disruption accelerates malignant growth; thus, it should be avoided in anticancer therapy. The circadian disruptive effects of irinotecan, a topoisomerase I inhibitor, was investigated according to dosing time and sex. In previous work, irinotecan achieved best tolerability following dosing at zeitgeber time (ZT) 11 in male and ZT15 in female mice, whereas worst toxicity corresponded to treatment at ZT23 and ZT3 in male and female mice, respectively. Here, irinotecan (50 mg/kg intravenous [i.v.]) was delivered at the sex-specific optimal or worst circadian timing in male and female B6D2F1 mice. Circadian disruption was assessed with rest-activity, body temperature, plasma corticosterone, and liver mRNA expressions of clock genes Rev-erbα, Per2, and Bmal1. Baseline circadian rhythms in rest-activity, body temperature, and plasma corticosterone were more prominent in females as compared to males. Severe circadian disruption was documented for all physiology and molecular clock endpoints in female mice treated at the ZT of worst tolerability. Conversely, irinotecan administration at the ZT of best tolerability induced slight alteration of circadian physiology and clock-gene expression patterns in female mice. In male mice, irinotecan produced moderate alterations of circadian physiology and clock-gene expression patterns, irrespective of treatment ZT. However, the average expression of Rev-erbα, Per2, and Bmal1 were down-regulated 2- to 10-fold with irinotecan at the worst ZT, while being minimally or unaffected at the best ZT, irrespective of sex. Corticosterone secretion increased acutely within 2?h with a sex-specific response pattern, resulting in a ZT-dependent phase-advance or -delay in both sex. The mRNA expressions of irinotecan clock-controlled metabolism genes Ce2, Ugt1a1, and Top1 were unchanged or down-regulated according to irinotecan timing and sex. This study shows that the circadian timing system represents an important toxicity target of irinotecan in female mice, where circadian disruption persists after wrongly timed treatment. As a result, the mechanisms underling cancer chronotherapeutics are expectedly more susceptible to disruption in females as compared to males. Thus, the optimal circadian timing of chemotherapy requires precise determination according to sex, and should involve the noninvasive monitoring of circadian biomarkers.