The cyclotide T20K inhibits the proliferation of human immune cells and is currently in clinical trials for multiple sclerosis. Here, we provide novel functional data and mechanistic insights into structure–activity relationships of T20K. Analogs with partial or complete reduction of the cystine knot had loss of function in proliferation experiments. Similarly, an acyclic analog of T20K was inactive in lymphocyte bioassays. The lack of activity of non-native peptide analogs appears to be associated with the ability of cyclotides to interact with and penetrate cell membranes, since cellular uptake studies demonstrated fast fractional transfer only of the native peptide into the cytosol of human immune cells. Therefore, structural differences between cyclic and linear native folded peptides were investigated by NMR to elucidate structure–activity relationships. Acyclic T20K had a less rigid backbone and considerable structural changes in loops 1 and 6 compared to the native cyclic T20K, supporting the idea that the cyclic cystine knot motif is a unique bioactive scaffold. This study provides evidence that this structural motif in cyclotides governs bioactivity, interactions with and transport across biological membranes, and the structural integrity of these peptides. These observations could be useful to understand the structure–activity of other cystine knot proteins due to the structural conservation of the cystine knot motif across evolution and to provide guidance for the design of novel cyclic cysteine-stabilized molecules.

The main aim of the study was to empirically investigate and understand the effects that autonomy has on job satisfaction and job performance in Bosnia and Herzegovina. The empirical data was obtained from a questionnaire of 242 people living and working in Bosnia and Herzegovina. Once the data was collected, data analysis was conducted to assure validity and reliability through items’ loadings and Cronbach’s Alpha values.Furthermore, the scales were tested for convergent validity through partial least-square path modelling using SmartPLS 3 software. The results indicated that the effects of autonomy on job performance and job satisfaction were significant and had positive relationship.

Speech detection threshold (SDT) depends on audibility alone, whereas speech recognition threshold (SRT) requires the stimuli to be heard and identified. The aim of the study was to determine the difference between SDT and SRT, and to analyze the correlation between pure tone thresholds and speech thresholds. Difference between SDT and SRT was ≤ 12 dB in majority of cases (p = .018). SDT was strongly correlated with the best pure tone threshold. Pearson correlation coefficient was the highest in “Inverted U” shape (r = .99). There was strong correlation between SRT and PTA (500-2000), PTA (500-4000), and PTA (500-1000), especially in Rising configuration (r = .997, r = .992 r = .989, respectively), as well as, between SRT and frequency of 1000 Hz (r = .989). SRT is in the highest correlation with PTA (500, 1000, 2000 Hz) and with the hearing threshold at frequency of 1000 Hz.

Aim of this paper was to determine the frequency of congenital anomalies in a sample of newborns of Tuzla Canton and as well as their distribution according to gender, mother’s age and marital distance category. Research was undertaken using the retrospective analysis on the Clinic for Gynecology and Obstetrics of University Clinical Center in Tuzla. By analyzing medical documentation of 17223 newborns, we determined the frequency of congenital anomalies of 5.24%. Highest frequency of congenital anomalies was found in the newborns whose mothers are older than 35. It was found that the frequency of congenital anomalies in the observed population is within the range of variation of this parameter with data from the literature.

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update on NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

The main objective of the study was to determine the developmental abilities of preschool children before and after six months of speech therapy treatment, and to examine the impact of the time of initiation of speech therapy treatment on the developmental abilities of children. The sample consisted of 35 children (20 male children and 15 female children), and all respondents reported early intervention due to speech and language difficulties. The age of the respondents ranged from 25 to 60 months. After conducting interviews with parents, taking anamnestic data, professional speech therapy diagnosticobservational procedure and determining speech-language disorders, the children underwent speech therapy treatment. After six months, a final assessment was made and the results showed statistically significant progress in all variables describing developmental abilities in children. The predictor “Time of treatment initiation” also had a statistically significant impact on all tested variables of developmental abilities of preschool children. The results showed that speech therapy treatment enables significant progress in all developmental areas in children, i.e. that progress in one development area follows the development of other areas.

This manuscript aims to propose a new extension of the EDAS method, adapted for usage with single-valued neutrosophic numbers. By using single-valued neutrosophic numbers, the EDAS method can be more efficient for solving complex problems whose solution requires assessment and prediction, because truth- and falsity-membership functions can be used for expressing the level of satisfaction and dissatisfaction about an attitude. In addition, the indeterminacy-membership function can be used to point out the reliability of the information given with truth- and falsity-membership functions. Thus, the proposed extension of the EDAS method allows the use of a smaller number of complex evaluation criteria. The suitability and applicability of the proposed approach are presented through three illustrative examples.

To develop and validate new Juvenile Arthritis Disease Activity Score 10 (JADAS10) and clinical JADAS10 (cJADAS10) cutoffs to separate the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with oligoarthritis and with rheumatoid factor–negative polyarthritis, based on subjective disease assessment by the treating pediatric rheumatologist.

The aim of this study was to determine the antioxidant activity, total phenolics, total flavonoid, proanthocyanidins, and anthocyanins content of eight berry species, namely serviceberry, gooseberry, blackberry, black chokeberry, bilberry, red currant, black currant, and cornelian cherry harvested in the regions of Sarajevo and Tuzla, Bosnia and Herzegovina. The antioxidant activity was determined by a battery of in vitro tests including DPPH radical assay, FRAP assay, ABTS assay, and phosphomolybdate test for total antioxidant capacity. Total phenolics, total flavonoids, and proanthocyanidins ranged from 0.834 to 6.921 mg TAE (tannic acid equivalents), 0.081–0.673 mg of quercetin, and 0.162–3.247 mg of catechin per gram of fresh fruit, respectively. The water extract of fruits had considerable levels of tested constituents and antioxidant activity, with the highest results obtained for black chokeberry. The multivariate clustering analysis showed that water extracts of analyzed species of berries belong to four distinct types in terms of their antioxidants levels and antioxidant activity. Furthermore, these results support the opinion that employment of multiple antioxidant tests is indeed required for adequate in vitro assessment of antioxidant capacity. Results also emphasized the need for a more detailed evaluation of the fruit species with good antioxidant potential (relative to standards), such as cornelian cherry and gooseberry, which are abundant yet not frequently consumed in Bosnia and Herzegovina.

Background Environmental exposures such as smoking are widely recognized risk factors in the emergence of lung diseases including lung cancer and acute respiratory distress syndrome (ARDS). However, the strength of environmental exposures is difficult to measure, making it challenging to understand their impacts. On the other hand, some COVID-19 patients develop ARDS in an unfavorable disease progression and smoking has been suggested as a potential risk factor among others. Yet initial studies on COVID-19 cases reported contradictory results on the effects of smoking on the disease – some suggest that smoking might have a protective effect against it while other studies report an increased risk. A better understanding of how the exposure to smoking and other environmental factors affect biological processes relevant to SARS-CoV-2 infection and unfavorable disease progression is needed. Approach In this study, we utilize mutational signatures associated with environmental factors as sensors of their exposure level. Many environmental factors including smoking are mutagenic and leave characteristic patterns of mutations, called mutational signatures, in affected genomes. We postulated that analyzing mutational signatures, combined with gene expression, can shed light on the impact of the mutagenic environmental factors to the biological processes. In particular, we utilized mutational signatures from lung adenocarcinoma (LUAD) data set collected in TCGA to investigate the role of environmental factors in COVID-19 vulnerabilities. Integrating mutational signatures with gene expression in normal tissues and using a pathway level analysis, we examined how the exposure to smoking and other mutagenic environmental factors affects the infectivity of the virus and disease progression. Results By delineating changes associated with smoking in pathway-level gene expression and cell type proportions, our study demonstrates that mutational signatures can be utilized to study the impact of exogenous mutagenic factors on them. Consistent with previous findings, our analysis showed that smoking mutational signature (SBS4) is associated with activation of cytokine-mediated signaling pathways, leading to inflammatory responses. Smoking related changes in cell composition were also observed, including the correlation of SBS4 with the expansion of goblet cells. On the other hand, increased basal cells and decreased ciliated cells in proportion were associated with the strength of a different mutational signature (SBS5), which is present abundantly but not exclusively in smokers. In addition, we found that smoking increases the expression levels of genes that are up-regulated in severe COVID-19 cases. Jointly, these results suggest an unfavorable impact of smoking on the disease progression and also provide novel findings on how smoking impacts biological processes in lung.

This study explored how women breast cancer survivors who underwent radical mastectomy experienced stress and adversity and managed their diagnosis and treatment. This study is based on semi-structured and in-depth interviews with a convenience sample of 22 participants. Qualitative analysis and discussion groups were conducted in the participant’s homes over 18 months. Thematic analysis resulted in four overarching categories that illustrated how being a woman was challenged and restructured from the participants’ personal experiences. The participants’ coping strategies were primarily reflected in their spirituality, optimism, the embrace of healthy lifestyles, and pink ribbon activism.