Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir

Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result. Circulating virus remained CCR5 tropic in 60/62 patients, 51 of whom experienced an HIV RNA reduction from baseline of >1 log(10) copies/ml, indicating that CXCR4-using variants were not rapidly selected despite CCR5-specific drug pressure. In two patients, viral load declined during treatment and CXCR4-using virus was detected at day 11. No pretreatment factor predicted the emergence of CXCR4-tropic virus during maraviroc therapy in these two patients. Phylogenetic analysis of envelope (Env) clones from pre- and posttreatment time points indicated that the CXCR4-using variants probably emerged by outgrowth of a pretreatment CXCR4-using reservoir, rather than via coreceptor switch of a CCR5-tropic clone under selection pressure from maraviroc. Phylogenetic analysis was also performed on Env clones from a third patient harboring CXCR4-using virus prior to treatment. This patient was enrolled due to a sample labeling error. Although this patient experienced no overall reduction in viral load in response to treatment, the CCR5-tropic components of the circulating virus did appear to be suppressed while receiving maraviroc as monotherapy. Importantly, in all three patients, circulating virus reverted to predominantly CCR5 tropic following cessation of maraviroc.     

Pseudotrisomy 13 syndrome: use of homozygosity mapping to target candidate genes

Pseudotrisomy 13 syndrome is characterised by holoprosencephaly with or without polydactyly, but with a normal karyotype. The genetic cause of this syndrome remains unclear, but it is thought to be autosomal recessive. In order to identify possible candidate genes, we identified regions of homozygosity in the DNA of an affected foetus, which was the seventh pregnancy of a healthy non-consanguineous Cook Island Maori couple; this ethnic group derives from a small founder population. Several large regions of homozygosity were identified using a high density array. We excluded two candidate genes that lay within these regions, and suggest that Pseudotrisomy 13 syndrome might not be monogenic and that a larger cohort of patients should be analysed using high density dosage/SNP arrays as well as whole exome sequencing in order to clarify the genetic underpinning of this rare syndrome.     

Water-Soluble Ruthenium Complexes Bearing Activity Against Protozoan Parasites

Parasitic illnesses are major causes of human disease and misery worldwide. Among them, both amebiasis and Chagas disease, caused by the protozoan parasites, Entamoeba histolytica and Trypanosoma cruzi, are responsible for thousands of annual deaths. The lack of safe and effective chemotherapy and/or the appearance of current drug resistance make the development of novel pharmacological tools for their treatment relevant. In this sense, within the framework of the medicinal inorganic chemistry, metal-based drugs appear to be a good alternative to find a pharmacological answer to parasitic diseases. In this work, novel ruthenium complexes [RuCl₂(HL)(HPTA)₂]Cl₂ with HL = bioactive 5-nitrofuryl containing thiosemicarbazones and PTA?=?1,3,5-triaza-7-phosphaadamantane have been synthesized and fully characterized. PTA was included as co-ligand in order to modulate complexes aqueous solubility. In fact, obtained complexes were water soluble. Their activity against T. cruzi and E. histolytica was evaluated in vitro. [RuCl₂(HL4)(HPTA)₂]Cl₂ complex, with HL4?=?N-phenyl-5-nitrofuryl-thiosemicarbazone, was the most active compound against both parasites. In particular, it showed an excellent activity against E. histolytica (half maximal inhibitory concentration (IC₅₀)?=?5.2 μM), even higher than that of the reference drug metronidazole. In addition, this complex turns out to be selective for E. histolytica (selectivity index (SI) >38). The potential mechanism of antiparasitic action of the obtained ruthenium complexes could involve oxidative stress for both parasites. Additionally, complexes could interact with DNA as second potential target by an intercalative-like mode. Obtained results could be considered a contribution in the search for metal compounds that could be active against multiple parasites.     

The adaptive capacity of fishery management systems for confronting climate change impacts on marine populations

Global climate change will affect the abundance, distribution, and life history timing of many exploited marine populations, but specific changes are difficult to predict. Management systems in which harvest strategies and tactics are flexible in responding to unpredictable biological changes are more likely to succeed in maintaining productive populations. We explore the adaptability of fisheries management systems in relation to oceanic warming rates by asking how two important management characteristics vary with temperature changes for >500 stocks. (1) Harvest control rules, a framework for altering fishing pressure in response to changes in the abundance of targeted species (primarily due to fishing), may provide the capacity for harvest policies to change in response to climate-driven abundance declines also. (2) Seasonal openings with flexible dates that involve in-season monitoring may allow managers to better respond to possible changes in the timing of life-history periods like spawning to prevent fishing seasons falling out of sync with species’ phenology. Harvest control rules were widely used across industrialized fisheries including in regions that experienced relatively high oceanic warming rates, but after controlling for regional factors we found no association between ocean warming and the use of harvest control rules. Flexible-date seasonal openings were rare compared to fixed-date seasonal openings, but tended to occur in areas with the greatest warming rates while fisheries without seasonal closures tended to occur in areas with the least observed temperature changes. We found no consistent evidence of recent ocean warming effects on the current biomass or exploitation rates relative to management targets of 241 assessed marine populations. Together, these results suggest that the oceanic areas expected to have the greatest climate impacts on populations do at least tend to contain fisheries that demonstrate the potential for adaptability to unpredictable climate impacts.     

Bacteriocinogenic properties and in vitro probiotic potential of enterococci from Tunisian dairy products

The aim of this study was to isolate new bacteriocinogenic strains with putative probiotic potential from various Tunisian fermented milks. A total of 44 Gram-positive catalase-negative isolates were colony-purified and screened for antimicrobial activity. Of inhibitory isolates, four were identified as Enterococcus durans and one as Enterococcus faecalis using 16S rRNA gene sequence. The five strains were sensitive to penicillin G, all aminoglycosides tested, to the vancomycin, tetracycline, and chloramphenicol, and E. durans 42G and E. faecalis 61B were resistant to erythromycin. The antimicrobial substances were sensitive to proteolytic enzymes and had good biochemical stability. E. durans 61A showed a good resistance to gastric and small intestinal secretions, but were more sensitive to the duodenal conditions. Considering the safety and the stability under simulated gastrointestinal tract, it appears that the bacteriocinogenic strain E. durans 61A is a good candidate for its application as novel probiotic strain in the food industry.     

KIFC3 promotes mitotic progression and integrity of the central spindle in cytokinesis

Kinesin-14 motor proteins play a variety of roles during metaphase and anaphase. However, it is not known whether members of this family of motors also participate in the dramatic changes in mitotic spindle organization during the transition from telophase to cytokinesis. We have identified the minus-end-directed motor, KIFC3, as an important contributor to central bridge morphology at this stage. KIFC3’s unique motor-dependent localization at the central bridge allows it to congress microtubules, promoting efficient progress through cytokinesis. Conversely, when KIFC3 function is perturbed, abscission is delayed, and the central bridge is both widened and extended. Examination of KIFC3 on growing microtubules in interphase indicates that it caps microtubules released from the centrosome, both in the region of the centrosome and in the cell periphery. In line with other kinesin-14 family members, KIFC3 may guide free microtubules to their destination at the bridge and/or may slide and crosslink central bridge microtubules in order to stage the cells for abscission.     

The physiological role of reversible methionine oxidation

Sulfur-containing amino acids such as cysteine and methionine are particularly vulnerable to oxidation. Oxidation of cysteine and methionine in their free amino acid form renders them unavailable for metabolic processes while their oxidation in the protein-bound state is a common post-translational modification in all organisms and usually alters the function of the protein. In the majority of cases, oxidation causes inactivation of proteins. Yet, an increasing number of examples have been described where reversible cysteine oxidation is part of a sophisticated mechanism to control protein function based on the redox state of the protein. While for methionine the dogma is still that its oxidation inhibits protein function, reversible methionine oxidation is now being recognized as a powerful means of triggering protein activity. This mode of regulation involves oxidation of methionine to methionine sulfoxide leading to activated protein function, and inactivation is accomplished by reduction of methionine sulfoxide back to methionine catalyzed by methionine sulfoxide reductases. Given the similarity to thiol-based redox-regulation of protein function, methionine oxidation is now established as a novel mode of redox-regulation of protein function. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.     

Genetic Deletion of Mst1 Alters T Cell Function and Protects against Autoimmunity

Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4⁺ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1^−/− B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1^−/− CD4⁺ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4⁺ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.     

Associations between Disease Awareness and Health-Related Quality of Life in a Multi-Ethnic Asian Population

Background

Health related quality of life (HRQoL) is an important dimension of individuals'' well-being, and especially in chronic diseases like diabetes and hypertension. The objective of this study was to evaluate the contributions of disease process, comorbidities, medication or awareness of the disease to HRQoL in diabetes mellitus, hypertension and dyslipidemia.

Methods

This was a cross-sectional study of 3514 respondents from the general community in Singapore, assessed for HRQoL, disease and comorbid conditions through self-report, clinical and laboratory investigations. HRQoL was assessed using SF-36 health survey version 2. For each condition, participants were categorized as having 1) no disease, 2) undiagnosed, 3) diagnosed, not taking medication, and 4) diagnosed, taking medication. Analysis used one-way ANOVA and multiple linear regression.

Results

Diagnosed disease was associated with lower physical health component summary (PCS) scores across all three conditions. After adjustment for comorbidities, this association remained significant only for those not on medication in diabetes (−2.7±1.2 points, p = 0.03) and dyslipidemia (−1.3±0.4 points, p = 0.003). Diagnosed hypertension (no medication −2.6±0.9 points, p = 0.002; medication −1.4±0.5 points, p = 0.004) and dyslipidemia (no medication −0.9±0.4 points, p = 0.03; medication −1.9±0.5 points, p<0.001) were associated with lower mental health component summary (MCS) scores. Undiagnosed disease was associated with higher MCS in diabetes (2.4±1.0 points, p = 0.01) and dyslipidemia (0.8±0.4 points, p = 0.045), and PCS in hypertension (1.2±0.4 points, p = 0.004).

Conclusions

Disease awareness was associated with lower HRQoL across the diseases studied, with PCS associations partially mediated by comorbidities. Equally importantly, undiagnosed disease was not associated with HRQoL deficits, which may partly explain why these individuals do not seek medical care.