Although anti‐retroviral treatments have significantly slowed down the spread of the HIV‐1 pandemic, approximately 2 million new infections occur every year. The majority of new infections are in ...sub‐Saharan Africa where rates of infection are much higher in women than men. Young women are disproportionately affected and have higher susceptibility to HIV‐1. The complex interactions between HIV‐1 and the female genital tract (FGT) and the mechanisms regulating susceptibility in women remain incompletely understood. In this review, we focus on the current understanding of the acute events that occur in the FGT following HIV‐1 exposure with a particular focus on the effect of endogenous and exogenous sex hormones on HIV‐1 susceptibility. We highlight the contribution of the recent transcriptomic and proteomic studies in providing new insights.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Generating stable antibodies is an important goal in the development of antibody‐based drugs. Often, thermal stability is assumed predictive of overall stability. To test this, we used different ...internally created antibodies and first studied changes in antibody structure as a function of pH, using the dye ANS. Comparison of the pH50 values, the midpoint of the transition from the high‐pH to the low‐pH conformation, allowed us for the first time to rank antibodies based on their pH stability. Next, thermal stability was probed by heating the protein in the presence of the dye Sypro Orange. A new data analysis method allowed extraction of all three antibody unfolding transitions and showed close correspondence to values obtained by differential scanning calorimetry. T1%, the temperature at which 1% of the protein is unfolded, was also determined. Importantly, no correlations could be found between thermal stability and pH50, suggesting that to accurately quantify antibody stability, different measures of protein stability are necessary. The experimental data were further analyzed using a machine‐learning approach with a trained model that allowed the prediction of biophysical stability using primary sequence alone. The pH stability predictions proved most successful and were accurate to within pH ±0.2.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cardiac arrest in pregnancy is rare. It has a reported incidence of approximately 1 in 30000 pregnancies worldwide and occurs prehospitally with rates of around 3 in every 100000 live births within ...the developed world. The management of maternal cardiac arrest is complicated by the anatomical and physiological changes of pregnancy, its rarity and clinician unfamiliarity. The presentation and the prehospital environment can make for an incredibly challenging, stressful and highly emotive scene. One aspect of maternal cardiac arrest management is the perimortem cesarean section, a surgical procedure that is potentially lifesaving for both mother and child. Although rarely reported in the field it is possible to successfully perform the procedure. This report details the emergent prehospital treatment of a 41-year-old woman pregnant with her first child of 30 weeks gestation. It describes a case of maternal cardiac arrest, her resuscitation and the undertaking of a prehospital perimortem cesarean section resulting in a neurologically intact infant survivor.
ABSTRACT
Tripartite motif protein 22 (TRIM22) is a novel interferon‐induced protein that potently inhibits the replication of evolutionarily diverse viruses, including HIV‐1. Altered TRIM22 ...expression is also associated with diseases, such as multiple sclerosis, cancer, and autoimmunity. The factors that influence TRIM22 expression and antiviral activity are largely unknown. In this study, we adopted an evolution‐guided functional approach to identify potential genetic determinants of TRIM22 function. Evolutionary analysis of TRIM22 from mammals spanning >100 million years demonstrated that TRIM22 evolution has been shaped by ancient and variable positive selection. We showed that positive selection is operating on multiple TRIM22 residues that cluster in putative functional regions and that some are predicted to be functionally damaging. Interestingly, the second most prevalent TRIM22 SNP in humans (rs1063303) is located at one of these positively selected sites. We showed that the frequency of rs1063303:G>C varies up to 10‐fold between ethnicities and that in some ethnicities SNP rs1063303:G>C is being actively maintained in the population. The SNP rs1063303:G>C variant also had an inverse functional impact where it increased TRIM22 expression and decreased the antiviral activity of TRIM22. Taken together, our data characterize the extensive genetic variation in TRIM22 and identify rs1063303:G>C as a highly prevalent SNP that influences its function.
We adopted an evolution‐guided functional approach to identify potential genetic determinants of TRIM22 function. We showed that positive selection is operating on multiple residues that cluster in putative functional regions and are predicted to be functionally damaging. Our data characterize the extensive genetic variation in TRIM22 and identify rs1063303:G>C as a highly prevalent SNP that influences its function.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The pseudo‐global‐warming (PGW) methodology provides an efficient means to investigate the response of a weather or climate event under an imposed climate change signal. In the traditional PGW ...implementation, this signal is represented through climate‐change “deltas” constructed using monthly averages of global climate model (GCM) output over decadal or longer periods during the past and future. The implications of alternative formulations of such deltas were explored herein. Diurnally varying (DV) deltas were compared to the time‐constant (TC) deltas used in the traditional PGW implementation; this was done to test the potential effect of future changes in the diurnal cycles of temperature, humidity, and winds. Deltas created using 10‐year averages were compared to those using 30‐year averages, to examine the effects of the time‐averaging period in the delta construction. Finally, the common practice of additionally averaging across multiple GCMs to form a composite delta was also considered. Using simulations of three different historical convective storm events, it was shown that each of these PGW delta formulations results in differences in simulation metrics such as total accumulated rainfall, and convective intensity, but major and/or unambiguous differences were not always found. It is recommended that users of the PGW approach carefully consider all implications of delta formulation on their particular problem.
Plain Language Summary
The climate modeling approach is known as “pseudo‐global warming” has essentially remained unchanged since its inception. We explore the sensitivity of this approach to how the initial and boundary conditions are constructed, specifically, to how the climate‐change signal is introduced into these conditions. Discernable differences were found in model simulations exploring this sensitivity, but the differences were ambiguous. The recommendation is that users of this approach carefully consider all implications of how the climate change signal is added.
Key Points
Sensitivity to how the climate‐change signal ("deltas") is formulated in the pseudo‐global warming (PGW) methodology is explored
Diurnally varying deltas were compared to the time‐constant deltas used in the traditional PGW implementation
Each PGW delta formulation results in differences in simulation metrics, but major, unambiguous differences were not found
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A 10% Mo/Si−Ti catalyst was tested for ethane oxidative dehydrogenation (ODH) activity using either O2 or N2O as the oxidant. Ethane ODH activity was tested at contact times varying from 0.46 to 1.0 ...mg min/cm−3. N2O gives superior ethylene selectivities at a given ethane conversion outperforming oxygen at all contact times tested. Ethylene selectivities decrease with contact time at a far slower rate when using N2O as the oxidant. X-ray photoelectron spectroscopy (XPS) experiments demonstrate that molybdenum in the catalyst is fully oxidized to Mo(VI) during ethane ODH using O2, whereas the reduction state decreases to an average of +5.8 when using N2O as the oxidant. Temperature-programmed oxidation experiments of pre-reduced 10% Mo/Si−Ti were carried out at different temperature ramp rates. The activation energy of re-oxidation when using N2O is 98 kJ/mol, whereas that of O2 is 41 kJ/mol leading to a re-oxidation rate at least 1700 times faster when O2 is the oxidant. This difference in rates accounts for the less oxidized state of molybdenum during ethane ODH with N2O and explains the behavior observed during reaction experiments.
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IJS, KILJ, NUK, PNG, UL, UM
A mechanism for the acquisition of high-level echinocandin resistance in Candida glabrata was investigated. FKS mutants were constructed to: determine whether clinically significant micafungin ...resistance requires a hot-spot mutation in FKS1 and a premature stop codon in FKS2, as was observed in a clinical isolate; select for variants with reduced susceptibility and locate mutations in FKS genes; and assess the roles of FKS1 and FKS2.
A panel of FKS mutants was constructed using micafungin-susceptible parents by site-directed mutagenesis. Drug susceptibility, gene expression and glucan synthase activities were compared between mutants. Mutations acquired by selection were identified by DNA sequence analysis of FKS genes from selected variants. Single FKS deletants were constructed and their phenotypes examined.
Introduction of the hot-spot mutation in FKS1 alone conferred an intermediate reduction in susceptibility, and the premature stop codon in FKS2 alone had no effect on susceptibility, while severely reduced susceptibility equivalent to that of the clinical isolate required both mutations. Exposure of susceptible strains to micafungin yielded variants with an intermediate reduction in susceptibility that possessed a hot-spot mutation in FKS1. Further exposure to micafungin yielded variants with severely reduced susceptibility that acquired various single mutations in FKS2. The phenotypes of Δfks1 and Δfks2 mutants indicate that the two FKS genes are functionally redundant, while deletion of both FKS1 and FKS2 conferred synthetic lethality.
In the laboratory mutants of C. glabrata, clinically significant reduced susceptibility to micafungin required single nucleotide changes in both FKS1 and FKS2, and both genes encoded β-1,3-glucan synthase catalytic subunits.
Nitrogen containing nano-structured carbon catalysts were grown on Fe/Al₂O₃ and Ni/Al₂O₃ supports using acetonitrile pyrolysis. The post-pyrolysis samples were tested for activity in the oxygen ...reduction reaction (ORR) and oxidative dehydrogenation (ODH) reaction. Samples were characterized using BET, XPS and TEM. The samples grown over iron containing supports gave the highest activity in both reactions. There was a strong correlation between ODH and ORR activity suggesting the possibility of a common active site between reactions with the quinone/hydroquinone group being a possible candidate. XPS analysis supported this hypothesis showing that catalysts with a higher percentage of oxygen in the form of quinones tend to have the highest ORR and ODH activity. XPS analysis also demonstrated that samples with higher pyridinic nitrogen content, which is a marker for edge plane exposure and may be a part of the ORR active site, gave higher ORR and ODH activity. TEM images confirm that samples with high pyridinic nitrogen content tend to form structures with higher edge plane exposure. Because the active site, regardless of its identity, likely lies on the graphitic edge plane, this leaves the possibility that a common active site is not necessary to explain the correlation between ODH and ORR activity. Graphical Abstract Nitrogen containing, nano-structured carbon catalysts were shown to exhibit a correlation between the activities of oxidative dehydrogenation and electrocatalytic oxygen reduction reactions. graphic removed
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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