Immunity to viruses requires an array of critical cellular proteins that include IFN regulatory factor 3 (IRF3). Consequently, most viruses that infect vertebrates encode proteins that interfere with ...IRF3 activation. This review describes the cellular pathways linked to IRF3 activation and where those pathways are targeted by human viral pathogens. Moreover, key regulatory pathways that control IRF3 are discussed. Besides viral infections, IRF3 is also involved in resistance to some bacterial infections, in anticancer immunity, and in anticancer therapies involving DNA damage agents. A recent finding shows that IRF3 is needed for T cell effector functions that are involved in anticancer immunity and also in T cell autoimmune diseases. In contrast, unregulated IRF3 activity is clearly not beneficial, considering it is implicated in certain interferonopathies, in which heightened IRF3 activity leads to IFN-β-induced disease. Therefore, IRF3 is involved largely in maintaining health but sometimes contributing to disease.
•Positive judgments of ambiguous faces had strong fMRI activation in the CO network.•Accompanied by a second, late peak following final decision on emotional valence.•Supports the initial negativity ...hypothesis, showing positivity is a controlled process.•CO network activation reflects reporting of valence decision late in the trial.
Cortical task control networks, including the cingulo-opercular (CO) network play a key role in decision-making across a variety of functional domains. In particular, the CO network functions in a performance reporting capacity that supports successful task performance, especially in response to errors and ambiguity. In two studies testing the contribution of the CO network to ambiguity processing, we presented a valence bias task in which masked clearly and ambiguously valenced emotional expressions were slowly revealed over several seconds. This slow reveal task design provides a window into the decision-making mechanisms as they unfold over the course of a trial. In the main study, the slow reveal task was administered to 32 young adults in the fMRI environment and BOLD time courses were extracted from regions of interest in three control networks. In a follow-up study, the task was administered to a larger, online sample (n = 81) using a more extended slow reveal design with additional unmasking frames. Positive judgments of surprised faces were uniquely accompanied by slower response times and strong, late activation in the CO network. These results support the initial negativity hypothesis, which posits that the default response to ambiguity is negative and positive judgments are associated with a more effortful controlled process, and additionally suggest that this controlled process is mediated by the CO network. Moreover, ambiguous trials were characterized by a second CO response at the end of the trial, firmly placing CO function late in the decision-making process.
Zika virus (ZIKV), a mosquito-transmitted flavivirus responsible for sporadic outbreaks of mild and febrile illness in Africa and Asia, reemerged in the last decade causing serious human diseases, ...including microcephaly, congenital malformations, and Guillain-Barré syndrome. Although genomic and phylogenetic analyses suggest that genetic evolution may have led to the enhanced virulence of ZIKV, experimental evidence supporting the role of specific genetic changes in virulence is currently lacking. One sequence motif, VNDT, containing an N-linked glycosylation site in the envelope (E) protein, is polymorphic; it is absent in many of the African isolates but present in all isolates from the recent outbreaks. In the present study, we investigated the roles of this sequence motif and glycosylation of the E protein in the pathogenicity of ZIKV. We first constructed a stable full-length cDNA clone of ZIKV in a novel linear vector from which infectious virus was recovered. The recombinant ZIKV generated from the infectious clone, which contains the VNDT motif, is highly pathogenic and causes lethality in a mouse model. In contrast, recombinant viruses from which the VNDT motif is deleted or in which the N-linked glycosylation site is mutated by single-amino-acid substitution are highly attenuated and nonlethal. The mutant viruses replicate poorly in the brains of infected mice when inoculated subcutaneously but replicate well following intracranial inoculation. Our findings provide the first evidence that N-linked glycosylation of the E protein is an important determinant of ZIKV virulence and neuroinvasion.
The recent emergence of Zika virus (ZIKV) in the Americas has caused major worldwide public health concern. The virus appears to have gained significant pathogenicity, causing serious human diseases, including microcephaly and Guillain-Barré syndrome. The factors responsible for the emergence of pathogenic ZIKV are not understood at this time, although genetic changes have been shown to facilitate virus transmission. All isolates from the recent outbreaks contain an N-linked glycosylation site within the viral envelope (E) protein, whereas many isolates of the African lineage virus lack this site. To elucidate the functional significance of glycosylation in ZIKV pathogenicity, recombinant ZIKVs from infectious clones with or without the glycan on the E protein were generated. ZIKVs lacking the glycan were highly attenuated for the ability to cause mortality in a mouse model and were severely compromised for neuroinvasion. Our studies suggest glycosylation of the E protein is an important factor contributing to ZIKV pathogenicity.
Increased global industrial activity has exposed humans to a wide variety of chemical substances some of which, called ‘endocrine-disrupting chemicals’ (EDCs) or ‘endocrine disruptors’, can disrupt ...the endocrine system in the body. The ovarian follicle is a very fragile micro-environment where interactions between hormones, growth factors, the oocyte and its surrounding somatic cells are essential to generate a fully competent oocyte. In vitro experiments suggest that EDCs can disturb this finely tuned balance, but very scarse in vivo data are available to confirm this assumption. Therefore, we have investigated if the presence of EDCs in human follicular fluid is a risk factor for the developmental competence of an in vivo exposed oocyte. Furthermore, because of the limited access to human follicular fluid, we verified if follicular fluid contamination can be predicted based on EDC levels in serum.
METHODS
Follicular fluid (n = 40) and serum (n = 20) samples from women undergoing assisted reproductive technology (ART) were analyzed by means of gas chromatography combined with mass spectrometry to examine the presence of different EDCs, such as polychlorinated biphenyls, polybrominated diphenyl ethers and organochlorine pesticides. Statistical models were used to investigate the relation between the characteristics and ART results of the patients and the contamination status of their follicular fluid and to assess the capacity of serum samples to predict follicular fluid contamination.
RESULTS
Chlorinated biphenyl 153 (72 ± 44 and 201 ± 106 pg/ml) and p,p′-DDE (392 ± 348 and 622 ± 406 pg/ml) were the compounds found in the highest concentrations in follicular fluid and serum samples, respectively. A new variable principal component 1, representing the overall contamination status of the follicular fluid samples, is strongly associated with fertilization rate (P < 0.00001) and the proportion of high-quality embryos relative to the amount of retrieved oocytes (P < 0.05), even when the analysis is adjusted for age, estradiol concentration, BMI, fertilization procedure and male subfertility as explanatory variables. The strong correlations between the EDC concentrations in serum and follicular fluid (r ≥ 0.93) allowed us to build regression models, which accurately predict EDC concentrations in the follicular fluid based on serum samples.
CONCLUSIONS
An overall higher EDC contamination in the follicular micro-environment was associated with a decreased fertilization rate and consequently with a lower chance of an oocyte to develop into a high-quality embryo. In addition, EDC concentrations in serum were reliable predictors of the contamination status of the follicular micro-environment.
The aim. To determinate the influence of the duration of artificial circulation and ischemic time on the structure of complications with one-time combined correction of lesions of two or three heart ...valves and myocardial revascularization and the possibility of their avoidance.
Materials and methods. The work is based on a comparative analysis of the results of one-step multivalvular correction combined with coronary artery bypass grafting (CABG) in 93 patients, which was performed at the National Amosov Institute of Cardiovascular Surgery from 2014 to 2021. Depending on the tactical approaches and the sequence of surgical manipulations, the patients were divided into three groups. Group I included patients who underwent heart valve correction first and then CABG with the use of cardioplegia (n = 42), group II patients underwent CABG first and then valve correction with the use of cardioplegia (n = 36), and group III patients underwent off-pump CABG first and then correction of the heart valves (n = 15). The groups differed significantly in terms of ischemic time and artificial circulation.
Results. The use of different approaches to achieve high-quality protection of the myocardium during ischemia and to minimize the impact of artificial circulation on the body by improving conditions and reducing ischemic time in the correction of multivalvular lesions and CABG showed significant advantages of the method of off-pump bypass.
Conclusions. Correction of combined valvular and coronary pathology in patients with cardioplegic arrest increases the ischemic time above the critical point, which affects the occurrence of specific complications, especially acute heart failure, which significantly worsens the immediate results of surgery. Complications that occurred in the postoperative period in patients with the correction of valvular defects combined with CABG were due to prolonged cardiovascular failure. The technique proposed in the study group with off-pump bypass surgery was more effective than in groups where bypass was performed with the use of cardioplegic cardiac arrest. This technique requires more time to perform and is more technically complex, but can significantly reduce myocardial ischemic time, which, in turn, significantly reduces the incidence of heart failure and postoperative complications.
Assessing brain activity during rest has become a widely used approach in developmental neuroscience. Extant literature has measured resting brain activity both during eyes-open and eyes-closed ...conditions, but the difference between these conditions has not yet been well characterized. Studies, limited to fMRI and EEG, have suggested that eyes-open versus -closed conditions may differentially impact neural activity, especially in visual cortices.
Spontaneous cortical activity was recorded using MEG from 108 typically developing youth (9-15 years-old; 55 female) during separate sessions of eyes-open and eyes-closed rest. MEG source images were computed, and the strength of spontaneous neural activity was estimated in the canonical delta, theta, alpha, beta, and gamma bands, respectively. Power spectral density maps for eyes-open were subtracted from eyes-closed rest, and then submitted to vertex-wise regression models to identify spatially specific differences between conditions and as a function of age and sex.
Relative alpha power was weaker in the eyes-open compared to -closed condition, but otherwise eyes-open was stronger in all frequency bands, with differences concentrated in the occipital cortex. Relative theta power became stronger in the eyes-open compared to the eyes-closed condition with increasing age in frontal cortex. No differences were observed between males and females.
The differences in relative power from eyes-closed to -open conditions are consistent with changes observed in task-based visual sensory responses. Age differences occurred in relatively late developing frontal regions, consistent with canonical attention regions, suggesting that these differences could be reflective of developmental changes in attention processes during puberty. Taken together, resting-state paradigms using eyes-open versus -closed produce distinct results and, in fact, can help pinpoint sensory related brain activity.
Emotionally salient cues are detected more readily, remembered better, and evoke greater visual cortical responses compared with neutral stimuli. The current study used concurrent EEG-fMRI recordings ...to identify large-scale network interactions involved in the amplification of visual cortical activity when viewing aversively conditioned cues. To generate a continuous neural signal from pericalcarine visual cortex, we presented rhythmic (10/sec) phase-reversing gratings, the orientation of which predicted the presence (CS+) or absence (CS−) of a cutaneous electric shock (i.e., the unconditioned stimulus). The resulting single trial steady-state visual evoked potential (ssVEP) amplitude was regressed against the whole-brain BOLD signal, resulting in a measure of ssVEP-BOLD coupling. Across all trial types, ssVEP-BOLD coupling was observed in both primary and extended visual cortical regions, the rolandic operculum, as well as the thalamus and bilateral hippocampus. For CS+ relative to CS− trials during the conditioning phase, BOLD-alone analyses showed CS+ enhancement at the occipital pole, superior temporal sulci, and the anterior insula bilaterally, whereas ssVEP-BOLD coupling was greater in the pericalcarine cortex, inferior parietal cortex, and middle frontal gyrus. Dynamic causal modeling analyses supported connectivity models in which heightened activity in pericalcarine cortex for threat (CS+) arises from cortico-cortical top–down modulation, specifically from the middle frontal gyrus. No evidence was observed for selective pericalcarine modulation by deep cortical structures such as the amygdala or anterior insula, suggesting that the heightened engagement of pericalcarine cortex for threat stimuli is mediated by cortical structures that constitute key nodes of canonical attention networks.
Reporting the second of two targets within a stream of distracting words during rapid serial visual presentation (RSVP) is impaired when the targets are separated by a single distractor word, a ...deficit in temporal attention that has been referred to as the attentional blink (AB). Recent conceptual and empirical work has pointed to pre-target brain states as potential mediators of the AB effect. The current study examined differences in pre-target electrophysiology between correctly and incorrectly reported trials, considering amplitude and phase measures of alpha oscillations as well as the steady-state visual evoked potential (ssVEP) evoked by the RSVP stream. For incorrectly reported trials, relatively lower alpha-band power and greater ssVEP inter-trial phase locking were observed during extended time periods preceding presentation of the first target. These results suggest that facilitated processing of the pre-target distracter stream indexed by reduced alpha and heightened phase locking characterizes a dynamic brain state that predicts lower accuracy in terms of reporting the second target under strict temporal constraints. Findings align with hypotheses in which the AB effect is attributed to neurocognitive factors such as fluctuations in pre-target attention or to cognitive strategies applied at the trial level.
Semiconductor quantum dots of the A
B
group and organic semiconductors have been widely studied and applied in optoelectronics. This study aims to combine CdTe quantum dots and perylene-based dye ...molecules into advanced nanostructure system targeting to improve their functional properties. In such systems, new electronic states, a mixture of Wannier-Mott excitons with charge-transfer excitons, have appeared at the interface of CdTe quantum dots and the perylene dye. The nature of such new states has been analyzed by absorption and photoluminescence spectroscopy with picosecond time resolution. Furthermore, aggregation of perylene dye on the CdTe has been elucidated, and contribution of Förster resonant energy transfer has been observed between aggregated forms of the dye and CdTe quantum dots in the hybrid CdTe-perylene nanostructures. The studied nanostructures have strongly quenched emission of quantum dots enabling potential application of such systems in dissociative sensing.
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