Novel Substituted Azoloazines with Anticoagulant Activity.

Hypercytokinemia, or cytokine storm, often complicates the treatment of viral and bacterial infections, including COVID-19, leading to the risk of thrombosis. However, the use of currently available direct anticoagulants for the treatment of COVID-19 patients is limited due to safety reasons. Therefore, the development of new anticoagulants remains an urgent task for organic and medicinal chemistry. At the same time, new drugs that combine anticoagulant properties with antiviral or antidiabetic activity could be helpfull in the treatment of COVID-19 patients, especially those suffering from such concomitant diseases as arterial hypertension or diabetes. We have synthesized a number of novel substituted azoloazines, some of which have previously been identified as compounds with pronounced antiviral, antibacterial, antidiabetic, antiaggregant, and anticoagulant activity. Two compounds from the family of 1,2,4-triazolo[1,5-a]pyrimidines have demonstrated anticoagulant activity at a level exceeding or at least comparable with that of dabigatran etexilate as the reference compound. 7,5-Di(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine has shown the highest ability to prolong the thrombin time, surpassing this reference drug by 2.2 times. This compound has also exhibited anticoagulant activity associated with the inhibition of thrombin (factor IIa). Moreover, the anticoagulant effect of this substance becomes enhanced under the conditions of a systemic inflammatory reaction.

Effects of childhood institutionalization on semantic processing and its neural correlates persist into adolescence and adulthood.

Individuals raised in institutionalized care settings are more likely to demonstrate developmental deficits than those raised in biological families. One domain that is vulnerable to the impoverished environments characteristic of some institutionalized care facilities is language development. We used EEG to assess ERPs and source-localized event-related spectral perturbations (ERSPs) associated with semantic processing at different levels of picture-word conflict and low versus high word frequency. Additionally, we assessed behavioral language ability (a synonyms task) and IQ. Participants (N = 454) were adolescents and adults with a history of institutionalized care (N = 187) or raised in biological families (N = 267), both recruited from secondary educational settings to approximately match the groups on age and education. Results indicate that individuals with a history of institutionalization are less accurate at judging whether semantic information in a spoken word matches an image. Additionally, those with a history of institutionalization show reduced cognitive control of conflict and more reactive N400 ERPs and beta ERSPs when handling picture-word conflict, especially in the left hemisphere. Frontal theta is related to semantic and conflict processing; however, in this study it did not vary with institutionalization.

Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury.

The problem of lung damage originating from excessive inflammation and cytokine release during various types of infections remains relevant and stimulates the search for highly effective and safe drugs. The biological activity of the latter may be associated with the regulation of hyperactivation of certain immune cells and enzymes. Here, we propose the design and synthesis of amino derivatives of 4,6- and 5,7-diaryl substituted pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines as promising double-acting pharmacophores inhibiting IL-6 and NO. The anti-inflammatory activity of 14 target compounds was studied on isolated primary murine macrophages after LPS stimulation. Seven compounds were identified to inhibit the synthesis of nitric oxide and interleukin 6 at a concentration of 100 µM. The most active compounds are micromolar inhibitors of IL-6 secretion and NO synthesis, showing a minimal impact on innate immunity, unlike the reference drug dexamethasone, along with acceptable cytotoxicity. Evaluation in an animal model of acute lung injury proved the protective activity of compound 6e, which was supported by biochemical, cytological and morphological markers.

Pseudocyclic Form of 4-Hydroxypyrrolidine-2-carboxanilide Podands with Trioxyethylene Chain: Modeling, Conformational Search, and NMR Analysis.

The 4-hydroxypyrrolidine-2-carboxanilide podand salt demonstrates catalytic activity in asymmetric Biginelli reaction. The systematic search for prevalent conformational state of the cation was carried out by computer simulations in combination with one- and two-dimensional NMR experiments. For that purpose, we proposed a novel algorithm for the generation and selection of conformers based on molecular dynamics and clustering in the space of principal components. The search had found an important trend of the podand to form a pseudocyclic structure with a horseshoe-shaped conformation of the oligooxyethylene fragment. This conformation is stabilized by different types of intramolecular hydrogen bonds between the acidic and basic centers of the two 4-hydroxypyrrolidine-2-carboxanilide residuals (branches). The proposed approach had made it possible to identify the major structural factors, providing a correlation between the calculated and experimental chemical shifts of hydrogen atoms in the 1H NMR spectra of the protonated podand.

Early institutionalized care disrupts the development of emotion processing in prosody.

Millions of children worldwide are raised in institutionalized settings. Unfortunately, institutionalized rearing is often characterized by psychosocial deprivation, leading to difficulties in numerous social, emotional, physical, and cognitive skills. One such skill is the ability to recognize emotional facial expressions. Children with a history of institutional rearing tend to be worse at recognizing emotions in facial expressions than their peers, and this deficit likely affects social interactions. However, emotional information is also conveyed vocally, and neither prosodic information processing nor the cross-modal integration of facial and prosodic emotional expressions have been investigated in these children to date. We recorded electroencephalograms (EEG) while 47 children under institutionalized care (IC) (n = 24) or biological family care (BFC) (n = 23) viewed angry, happy, or neutral facial expressions while listening to pseudowords with angry, happy, or neutral prosody. The results indicate that 20- to 40-month-olds living in IC have event-related potentials (ERPs) over midfrontal brain regions that are less sensitive to incongruent facial and prosodic emotions relative to children under BFC, and that their brain responses to prosody are less lateralized. Children under IC also showed midfrontal ERP differences in processing of angry prosody, indicating that institutionalized rearing may specifically affect the processing of anger.

Altered neural processing of emotional words in adults with a history of institutionalization: Evidence from the emotional Stroop task.

We investigated neural correlates of traumatic experience related to the lack of family care in adults with a history of institutionalization (IC) using the Emotional Stroop paradigm. The goals of our study were twofold: we investigated whether adults with IC history (n = 24; Mage  = 22.17, SD = 6.7) demonstrate atypical processing of emotionally salient words in general, and whether they exhibit selective processing bias toward family related words compared to adults raised in biological families (BFC; n = 28; Mage  = 22.25, SD = 4.9). Results demonstrated significant differences in accuracy but not response times between groups on the behavioral level, indicating that the IC group was overall less accurate in identifying the color of the font. Contrary to our prediction, there were no significant differences between neural response to family related versus unrelated words in the IC and BFC groups. The absence of group differences can be explained by the selection of stimuli, which were associated with family rather than institutional history. The IC group showed a larger N280-380 component in response to negative words compared to the BFC group, and larger negativity in the right parietal area in response to positive words in the same time window. Results demonstrate that institutional history is marked by altered emotional processing in the subpopulation of institutional care-leavers, but the footprint is not specific to traumatic experience and extends from general sensitivity to emotional words.

Male pseudohermaphroditism: A case study of 46,XY disorder of sexual development using whole-exome sequencing.

The study shows that whole-exome sequencing is a promising approach to detect novel variants-and gene candidates in DSD, that, as a future direction, may improve the diagnostic gene panels for this heterogeneous disorder.

New technique of dissection of internal mammary vessels for breast reconstruction.

BACKGROUND: Although internal mammary vessels are considered the best recipients for free flap breast reconstruction, they present the notable drawback of limited accessibility. The aim of this study was to develop a minimally invasive surgical technique for the dissection of internal mammary vessels as recipients for breast reconstruction. METHODS: From 2008 to 2018, we performed 32 unilateral microsurgical breast reconstructions (mean patient age: 40.1±8.7 years; range, 23-58 years). As internal mammary vessels were exclusively used as recipients, they were dissected using a technique of minimally invasive video-assisted thoracoscopic surgery (VATS) developed in our hospital. RESULTS: The mean surgery time was 5.4±0.55 hours (range, 4.5-6.5 hours), and the mean duration of VATS dissection of internal mammary vessels was 20.6±2.9 minutes (range, 16-27 minutes). Of the specific complications associated with VATS, we only observed reductions in forced expiratory volume in the first second of >15% in 3 patients (9.4%), 10-15% in 8 patients (25%), and <10% in 21 patients (65.63%). We did not have any cases of significant bleeding or postoperative infection in this series of patients. With regard to aesthetic complications, we observed 1 and 2 cases of total necrosis and partial necrosis of the deep inferior epigastric perforator (DIEP) flap, respectively and 2 cases of partial necrosis of supercharged transverse rectus abdominis muscle flap. CONCLUSIONS: Endoscopic dissection of internal mammary vessels is a simple and feasible technique. When performed by experienced surgeons, it is a fast procedure that is associated with low rate of complications.

Language Development of Children Raised in Institutional Settings: Behavioral and Neurophysiological Findings.

The current study investigated language development of children residing in institutional care (IC) in Russia, compared to peers raised by biological family care (BFC). We used standardized behavioral testing (Preschool Language Scale-5, McArthur CDI), and an event-related potential picture-word matching paradigm. Children in IC significantly underperformed on the measures of receptive and expressive language development, with larger deficits in expressive domain. ERP findings indicated that children in IC did not demonstrate significant N400 effect in response to semantic violations; there were no significant group differences in semantic processing between IC and the BFC groups. In the late time window of 400-600 ms, phonologically legal pseudowords elicited an ERP component with the positive amplitude in the IC group, resembling P300 ERP component, whereas the BFC group showed the expected N400 effect. The findings point to less efficient lexical processing in the IC group. To the best of our knowledge, this study is the first to investigate both the behavioral and neuropsychological aspects of language development, focusing on phonological and lexical-semantic processing, in children who currently live in IC.

An Event-Related Potentials Study of Executive Functioning in Adults With a History of Institutionalization.

The current study investigated the long-term effects of institutionalization on the inhibitory control of young adults raised in orphanages using the color-word Stroop task. We examined whether young adults raised in institutions (IC group; n = 24; M = 22.17 years, SD = 6.7) would demonstrate poorer behavioral performance and atypical neural response to incongruent stimuli compared to their peers raised in biological families (Biological Family Care, BFC group; n = 28; M = 22.25 years, SD = 4.9). Accuracy analysis revealed that all participants were less accurate in the incongruent condition, however, no group differences were found. Reaction time analysis showed that the institutional care (IC) group was overall slower than the BFC. No significant differences in neural response to stimuli incongruence were identified. The absence of group differences in the interference condition can be explained by the low complexity of the Stroop task in the current study. The IC group showed a reduced P3 event-related potential component on both the congruent and incongruent trials. Findings suggest general attention difficulties in this population, rather than inhibitory control deficits.

Cohesion of Cortical Language Networks During Word Processing Is Predicted by a Common Polymorphism in the SETBP1 Gene.

The etiological mechanisms of the genetic underpinnings of developmental language disorder (DLD) are unknown, in part due to the behavioral heterogeneity of the disorder's manifestations. In this study, we explored an association between the SETBP1 gene (18q21.1), revealed in a genome-wide association study of DLD in a geographically isolated population, and brain network-based endophenotypes of functional intracortical coherence between major language-related brain areas. We analyzed electroencephalogram (EEG) data from thirty-nine children (twenty-three with, sixteen without DLD) aged 7.17-15.83 years acquired during an auditory picture-word matching paradigm. Variation at a single nucleotide polymorphism in the intronic region of the SETBP1 gene, rs8085464, explained 19% of the variance in intracortical network cohesion (p = .00478). This suggests that the development of these brain networks might be partially associated with the variation in SETBP1.

Auditory Mismatch Negativity Response in Institutionalized Children.

The attunement of speech perception/discrimination to the properties of one's native language is a crucial step in speech and language development at early ages. Studying these processes in young children with a history of institutionalization is of great interest, as being raised in institutional care (IC) may lead to lags in language development. The sample consisted of 82 children, split into two age groups. The younger age group (<12 months) included 17 children from the IC and 17 children from the biological-family-care (BFC) group. The older group (>12 months) consisted of 23 children from the IC group, and 25 children from the BFC group. A double-oddball paradigm with three consonant-vowel syllables was used, utilizing native (Russian) and foreign (Hindi) languages. A Mismatch Negativity (MMN) component was elicited within a 125-225 ms time window in the frontal-central electrode. Findings demonstrate the absence of MMN effect in the younger age group, regardless of the living environment. Children in the older group are sensitive to native deviants and do not differentiate foreign language contrasts. No significant differences were observed between the IC and BFC groups for children older than 12 months, indicating that children in the IC have typical phonological processing. The results show that the MMN effect is not registered in Russian speaking children before the age of 12 months, regardless of their living environment. At 20 months of age, institutionally reared children show no evidence of delays in phonetic development despite a limited experience of language.

Implicit learning in attractiveness evaluation: The role of conformity and analytical processing.

We address the question how people's opinion and features of information interact in the process of indirect social influence. Implicit learning was considered as a mechanism for conformity in social perception. We carried out 2 experiments using a hidden covariation detection paradigm. In a learning phase, participants memorized a set of female photographs presented together with their attractiveness ratings. The ratings correlated with the hairstyle of the photographed women. The participants who did not consciously detect this correlation demonstrated a systematic bias toward the correlation when evaluating the new stimulus persons. Information about the source of the ratings in the learning phase (other people's opinions or nonsocial sources) did not modulate learning. Learning was not observed when participants critically evaluated the ratings during the memorization phase. The study shows that (a) conformity may be based not only on reinforcement learning mechanism (as was previously suggested) but also on unsupervised implicit learning; (b) implicit learning occurs automatically irrespective of the context (social or not); and (c) a critical attitude toward learned material may prevent implicit learning from being manifested in a test phase. We conclude that indirect social influence may be affected by people's opinion toward the provided information. The study contributes to both implicit learning and social perception research. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effects of early social deprivation on epigenetic statuses and adaptive behavior of young children: A study based on a cohort of institutionalized infants and toddlers.

Early social deprivation (i.e., an insufficiency or lack of parental care) has been identified as a significant adverse early experience that may affect multiple facets of child development and cause long-term outcomes in physical and mental health, cognition and behavior. Current research provides growing evidence that epigenetic reprogramming may be a mechanism modulating these effects of early adversities. This work aimed to investigate the impact of early institutionalization-the immersion in an extreme socially depriving environment in humans-on the epigenome and adaptive behavior of young children up to 4 years of age. We conducted a cross-sectional study involving two comparison groups: 29 children raised in orphanages and 29 children raised in biological families. Genome-wide DNA methylation profiles of blood cells were obtained using the Illumina MethylationEPIC array; the level of child adaptive functioning was assessed using the Vineland Adaptive Behavior Scales-II. In comparison to children raised in families, children residing in orphanages had both statistically significant deficits in multiple adaptive behavior domains and statistically significant differences in DNA methylation states. Moreover, some of these methylation states may directly modulate the behavioral deficits; according to preliminary estimates, about 7-14% of the deviation of adaptive behavior between groups of children may be determined by their difference in DNA methylation profiles. The duration of institutionalization had a significant impact on both the adaptive level and DNA methylation status of institutionalized children.

Language Outcomes in Adults with a History of Institutionalization: Behavioral and Neurophysiological Characterization.

Impoverished early care environments are associated with developmental deficits in children raised in institutional settings. Despite the accumulation of evidence regarding deficits in general cognitive functioning in this population, less is known about the impact of institutionalization on language development at the level of brain and behavior. We examined language outcomes in young adults and adolescents raised in institutions (n = 23) as compared to their socioeconomic status and age peers raised in biological families (n = 24) using a behavioral language assessment and linguistic event-related potentials (ERPs). Controlling for intelligence, adults with a history of institutionalization demonstrated deficits in lexical and grammatical development and spelling. Analyses of ERP data revealed significant group differences in the dynamic processing of linguistic stimuli. Adults with a history of institutionalization displayed reduced neural sensitivity to violations of word expectancy, leading to reduced condition effects for temporo-spatial factors that tentatively corresponded to the N200, P300/N400, and phonological mismatch negativity. The results suggest that language is a vulnerable domain in adults with a history of institutionalization, the deficits in which are not explained by general developmental delays, and point to the pivotal role of early linguistic environment in the development of the neural networks involved in language processing.

Multicomponent sonochemical synthesis of podands.

An efficient sonochemical methodology is described for the synthesis of new podands containing substituted dihydropyrimidines.