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BackgroundThreonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891).MethodsMechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC).ResultsBAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro. Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent.ConclusionsDual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.

This study undertakes a comprehensive bibliometric analysis of publications pertaining to the external public debt management system. The paper aims to study the evolution of scholarly discourse surrounding the external public debt management domain, highlighting contributions, methodologies, and collaborative networks within the field. The methodology encompasses a multivariate approach, incorporating extensive searches across the three major scientometric databases: Google Scholar (PoP), Scopus (in-built Scopus tools, SciVal), and Web of Science (in-built WoS instruments). The bibliometric analysis extends to contextual, evolutionary, and spatial dimensions, allowing for a comprehensive understanding of the identified clusters. The ensuing clusters serve as a roadmap, categorizing publications based on their contextual relevance, evolutionary trajectory, and spatial focus, which enhances the identification of key works in the field, facilitating a nuanced understanding of the current state of external public debt management research. The synthesis of findings from the content-contextual block emphasizes a primary orientation toward understanding the dynamic interplay between external public debt management and economic development. Furthermore, the contextual-temporal block identifies four distinct stages in the evolution of research focus, highlighting the shifting emphasis over time. A discernible pattern of heightened research activity in external public debt management across various countries in recent decades is revealed through spatiotemporal analysis. The interdisciplinary nature of this field is underscored by the dominance of economics, econometrics, finance, business, management, and accounting in dedicated research.

One of the tools of economic policy of any country is efficient public debt management, which influences and determines the dynamics of key macroeconomic indicators. The study aims to assess how public debt management affects Ukraine’s macroeconomic development. The analyzed period includes data of 2015–2021. Econometric modeling is used to establish the existence of causal relationships between the dynamics of public debt and changes in key macroeconomic indicators using the Granger causality test and VAR (Vector Autoregression) model. The obtained results demonstrate that during the study period, the strongest links existed between the public debt and GDP, debt servicing and Ukraine’s total state budget expenditures, public debt and consumer price index, real effective exchange rate index of the hryvnia to the US dollar, and political stability index. At the same time, the calculations proved that public debt does not have a significant impact on foreign direct investment and the level of imports of goods and services. The proposed model allows for forecasts for future periods and can be used in developing public debt management policy.

Hereditary breast/ovarian cancer (HBOC) syndrome is caused by the inheritance of monoallelic germline BRCA1/2 gene mutations. If BRCA1/2 mutation carriers are identified before the disease develops, effective actions against HBOC can be taken, including intensive screening, risk-reducing mastectomy and salpingo-oophorectomy, and risk-reducing medications. The Italian National Prevention Plan mandates the creation of regional BRCA genetic testing programmes. So far, however, only informal data have been reported on their implementation. We have designed a study aimed at evaluating the results of a population-based programme for risk assessment and genetic counselling and testing for BRCA1/2-related HBOC that is underway in the Emilia-Romagna region (northern Italy). The programme—which is entirely free—includes basic screening with an estimate of the likelihood of carrying a BRCA1/2 mutation using a familial risk assessment tool, a closer examination of women with suspected risk increase, an assessment of the need for further genetic counselling and, if needed, genetic testing and risk-reducing interventions. In this paper, the design of the programme and the protocol of the study are presented. The study has an observational, historical cohort design. Eligible are the women found to be at an increased risk of HBOC (profile 3 women). The main objectives are (i) to determine the precision of the programme in measuring the level of risk of HBOC for profile 3 women; (ii) to determine the characteristics of profile 3 women and their association with the risk management strategy chosen; (iii) to compare the age at onset, histologic type, tumour stage, molecular subtype, and prognosis of breast/ovarian cancers observed in the cohort of profile 3 women with the features of sporadic cancers observed in the general female population; (iv) to determine the level and the determinants of adherence to recommendations; and (v) to determine the appropriateness and timing of risk-reducing surgery and medications. Investigating the quality and results of the programme is necessary because the best practices in risk assessment and genetic counselling and testing for BRCA1/2-related cancer and the challenges they encounter should be identified and shared. The study has the potential to provide sound empirical evidence for the factors affecting the effectiveness of this type of service.

AbstractThe present study aimed to evaluate the genetic diversity and differentiation of Pinus nigra Arnold, the European black pine, populations located in protected forested areas in three countries from the Balkan and Mediterranean region: Bulgaria, Greece, and Cyprus. Totally, 175 DNA samples from P. nigra plants collected from eight populations in these countries were analyzed using three SRAP primer pairs. The applied SRAP markers demonstrated high-resolution power, resulting in the identification of an average of 215 ± 67 polymorphic loci per SRAP primer pair. The analysis of molecular variance (AMOVA) showed that 82% of the observed variation was due to intra-population variation, while 18% was due to inter-population variation. The overall analysis of the population structure suggested low (Fst ≤ 0.01) intra-country differentiation for the populations from Bulgaria and Cyprus and moderate (0.15 ≤ Fst ≤ 0.17) inter-country differentiation. On the contrary, high differentiation between the populations (0.06 ≤ Fst ≤ 0.20) and complex genetic structure were characteristic of the three populations from Greece, relatively closely located in the area of the Pindos National Park. Analysis of the population structure also revealed that one of the Pindos populations belonged to the cluster of Bulgarian populations (Fst ≤ 0.01), showing moderate (Fst ≤ 0.11) to high (Fst ≤ 0.20) genetic differentiation from the other analyzed Pindos populations. The further use of SRAP markers for mapping the genetic diversity among P. nigra populations and identification of local populations diverted from the overall phylogeography-driven pattern in the studied region are discussed.

Several specific features and circumstances can characterize Ukraine’s policy of external public debt management, and the results are not always unambiguous. The study aims to assess the effect of external public debt on Ukraine’s economy from 2014 to 2022, a period that includes the Crimea annexation, the onset of the COVID-19 pandemic, and the beginning of the open Russian military aggression. To analyze the contemporary state of public debt and assess the degree of external debt burden’s impact on the country’s economy, a factor analysis technique known as the principal components method was used. Via the STATISTICA.12 software, it was substantiated that the debt situation worsens with the growth of debt burden and solvency indicators as their values approach the thresholds. The application of the Kaiser criterion allowed the selection of the most influential indicators (principal components) for assessing the external debt burden. The eigenvalue of the first component (inflation rate) is 4.48, and it explains 50% of the variance; the second component (production of export-oriented goods) has an eigenvalue of 2.43, explaining 27% of the variance; the third component (government spending on military purposes) has an eigenvalue of 1.24, and it explains 14% of the variance.

Ovarian cancer is among the most prevalent causes of mortality among women. Despite improvements in diagnostic methods, non-specific symptoms and delayed gynecological exams can lead to late-stage ovarian tumor discovery. In this study, the effect of an anti-cancer compound, 3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide (Compound 1), was examined. The impacts of cytotoxicity, apoptosis, and metabolomic changes in ovarian cancer cell lines SK-OV-3 and OVCAR-3, as well as glycosphingolipid (GSL) expression, on cancer stem cells (CSCs), marked as CD49f+, and non-CSCs (CD49f−) were explored. Treatment with Compound 1 reduced the percentage of CSCs compared to non-treated cells (p < 0.001). The functional impact of eight GSLs on CSCs and non-CSCs was examined using flow cytometry. The glycophenotype changed in both cell lines, with increases or decreases in its expression, after the treatment. These findings raise the possibility of specifically targeting CSCs in ovarian cancer therapy. Additionally, treatment with Compound 1 resulted in statistically meaningful increased apoptosis, including both early and late apoptosis (p < 0.001), suggesting a pivotal role in initiating programmed cell death by the apoptotic pathway. The analysis revealed that the metabolic activity of treated cancer cells was lower compared to those of the control group (p < 0.001).

This research is classroom action research (CAR), which aims to improve the quality of students' activity processes in learning and improve students' skills in writing narrative essays using the whole language approach in Indonesian in class IV Madrasah Ibtidaiyah. The research was carried out in two cycles with 27 students in class IV at Madrasah Ibtidaiyah. The instruments used consisted of student observation sheets and student narrative essay writing test sheets. Observation data were analyzed using the average score and score criteria, while test data were analyzed using the average percentage of students' learning completeness. From the research conducted, there was an increase in the activity of students and the test results for writing narrative essays. For student activities in cycle 1, a score of 60 was obtained with good criteria, and in cycle 2, a score of 80 was obtained with good criteria, so the difference in scores between cycle 1 and cycle 2 was 20. For the test results of writing narrative essays in cycle 1, the average value obtained in class was 67.22%, with mastery of learning to write narrative essays classically reaching 37.04%. Meanwhile, cycle 2 received an average grade of 79.8, with mastery of learning to write narrative essays classically reaching 81.5%. Abstrak Penelitian ini merupakan Penelitian Tindakan Kelas (PTK) yang bertujuan untuk meningkatkan kualitas proses aktivitas peserta didik dalam pembelajaran dan meningkatkan keterampilan peserta didik dalam menulis karangan narasi dengan menggunakan pendekatan whole language pada mata pelajaran Bahasa Indonesia di kelas IV Madrasah Ibtidaiyah. Penelitian dilaksanakan dalam 2 siklus dengan subjek penelitian adalah peserta didik kelas IV di Madrasah Ibtidaiyah yang berjumlah 27 orang. Instrumen yang digunakan terdiri atas lembar observasi peserta didik dan lembar tes menulis karangan narasi peserta didik. Data observasi dianalisis dengan menggunakan rata-rata skor dan kriteria skor, sedangkan data tes dianalisis dengan menggunakan rata-rata nilai persentase ketuntasan belajar peserta didik. Hasil penelitian ini menunjukkan adanya peningkatan pada aktivitas peserta didik dan hasil tes menulis karangan narasi. Aktivitas peserta didik pada siklus 1 diperoleh skor 60 dengan kriteria baik dan pada siklus 2 diperoleh skor 80 dengan kriteria baik, selisih skor antara siklus 1 dan siklus 2 adalah 20. Sedangkan hasil tes menulis karangan narasi pada siklus 1 diperoleh nilai rata-rata kelas sebesar 67,22 dengan ketuntasan belajar menulis karangan narasi secara klasikal mencapai 37,04%. Sementara pada siklus 2 mendapat nilai rata-rata kelas 79,8 dengan ketuntasan belajar menulis karangan narasi secara klasikal mencapai 81,5%.

Cerebrovascular disease is a major contributor to subcortical white matter pathology, vascular cognitive impairment (VCI) and dementia. Although the precise pathophysiological mechanisms remain unclear, it is increasingly evident that microglial responses may be critical to the development and progression of cerebrovascular disease and its cognitive consequences. To investigate this further, we assessed microglial reactivity in white matter regions of human post- mortem tissue with pathologically confirmed cerebrovascular injury. In parallel, we implemented a mouse model of VCI induced by bilateral carotid artery stenosis (BCAS) and determined the impact of genetically deleting the microglial immunoreceptor triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial homeostatic and reactive functions. Using immunohistochemistry (IHC) and quantitative polymerase chain reaction (QPCR) we observed increased microglial reactivity and TREM2 expression in our human cohort implicating TREM2 signalling in microglial responses to cerebrovascular. In mice, IHC and flow cytometric analysis revealed Trem2 deficiency blunted microglial reactivity following BCAS (1 month). Transcriptomic analysis of Trem2-/- microglia also demonstrated attenuated induction of gene expression modules associated with inflammation, lysosomal function, lipid processing and metabolic reprogramming following BCAS (data not shown). Importantly, this was associated with greater white matter injury compared to wildtype (WT) counterparts in the absence of overt cognitive changes. Following longer durations of BCAS (6 months), Trem2-/- mice exhibited additional parenchymal and vascular pathologies associated with impairments in spatial learning and memory whilst such changes were largely absent in WT mice. Interestingly, assessment of microglia by IHC demonstrated reduced interaction with white matter cerebrovasculature in Trem2-/- mice. Taken together, these data support a role for microglia in cerebrovascular contributions to cognitive decline and dementia. Therefore, targeting regulators of microglia reactivity may provide means to influence cerebrovascular disease trajectory and associated cognitive changes. While further work is required to delineate the precise function of microglia in this context, our preclinical data suggest TREM2-regulated microglial responses to cerebrovascular insult are important for maintenance of brain health and cognitive resilience. Future work will continue to decipher how TREM2 mediates such resilience with particular focus on interaction with other cell types within the neurogliovascular unit.

Cerebrovascular dysfunction, leading to inadequate brain perfusion and oxygenation, is a major contributor to cognitive decline and dementia. Chronic hypoxia is a putative mechanism of vascular-mediated brain damage, particularly in relation to white matter lesions, as demonstrated by human neuroimaging and histopathology studies. Moreover, increasing evidence suggests that microglia, the primary immune cells of the brain parenchyma, may play a key role in modulating cerebrovascular disease outcomes. Indeed, unpublished work from our lab using a model of chronic cerebral hypoperfusion found greater vascular and white matter abnormalities concomitant with reduced microglial-vascular interactions in mice lacking the microglial immunoreceptor triggering receptor expressed on myeloid cells 2 (TREM2). However, the underlying mechanisms remain incompletely understood. Therefore, this project aims to further investigate whether microglial TREM2 signalling contributes to cerebrovascular resilience, and specifically vasculoprotection, focusing on the context of hypoxia. To address this, we are housing mice at 8%O2 to achieve chronic mild hypoxia (CMH). As corroborated by our studies, CMH induces cerebral microbleeds associated with parenchymal fibrinogen leakage in both grey and white matter regions (Figure 1), and is thus a reductionist approach well-suited for examining microglial mechanisms conferring vasculoprotection. Ongoing studies in young (5-6 months) and aged (15-18 months) cohorts are utilising histology and immunostaining to determine the impact of TREM2 deficiency and ageing on CMH-induced phenotypes, with particular focus on profiling microbleed burden, BBB integrity and interactions between microglia and other cell types within the neurovascular unit. Given that TREM2 is a key regulator of microglial metabolism and lipid processing, future work will utilise flow cytometry and spatial lipidomics to characterise microglia and brain lipid metabolism during CMH, thus providing insight into immunometabolic changes that may underpin microglial vasculoprotection in hypoxia. Findings from these studies will increase our understanding of microglia-vascular interactions, which can ultimately be exploited to promote resilience to cerebrovascular and other hypoxia- related pathologies.

Forecasting external public debt under conditions of uncertainty is important as it allows the country to respond adequately to economic and financial challenges, promotes efficient management of financial resources, formation of a stable financial policy and ensures the country's external debt security, which are critical elements for ensuring economic sustainability and sustainable development. The article's main purpose is to critically analyze and apply existing time-series forecasting methodologies to determine the future values of Ukraine's external public debt in conditions of uncertainty caused by the still unresolved consequences of the COVID-19 pandemic and russia's invasion and full-scale war in Ukraine. Using three forecasting methods, namely trendline extrapolation, exponential smoothing, and autoregressive and moving average models, the paper forecasts the volume of external public debt until 2029 and presents a graphical representation of the debt dynamics from 2011 to 2029. The most pessimistic forecast for the growth of external public debt was revealed when applying the method of data extrapolation based on the trendline. A comparative analysis of the forecast values for the three forecasting methods has revealed common trends in the growth of public debt, as well as the key advantages and disadvantages inherent in each model. Importantly, the article emphasizes the common risks identified in forecasting Ukraine's external debt using time series analysis models, including the problem of achieving only short-term forecasting accuracy and insufficient flexibility taking into account complex and unexpected changes that may arise in conditions of uncertainty and economic instability. The results of the study provide valuable information for policymakers and stakeholders trying to navigate the complexities of managing external public debt under uncertainty.

AbstractThe content of linalyl acetate and the ratio of linalool to linalyl acetate (L/LA ratio) are one of the important parameters that determine the quality of lavender oil. The characterization of a segregating population derived from a self-pollinated Lavandula angustifolia var. Hemus resulted in the identification of a single quantitative trait locus controlling the L/LA ratio (L/LA-QTL) and located on chromosome 8 of the lavender reference genome. The L/LA data analysis demonstrated that plants homozygous for one of the L/LA-QTL alleles had significantly higher linalool content, lower linalyl acetate content and higher L/LA ratio, than the plants which were either heterozygous or homozygous for the other allele. No significant difference was observed for the sum of linalool and linalyl acetate content among these three groups of plants, suggesting that the identified L/LA-QTL is related to an enzyme conversion of linalool to linalyl acetate. The BLAST search revealed that the L/LA-QTL region included a sequence of the LiAAT4 gene of monoterpene acetyltransferase, considered as a candidate gene for the L/LA-QTL locus. Sequence analysis of the LiAAT4 gene of var. Hemus revealed the presence of two alleles differing in two nucleotides and predicted amino acid substitutions. The comparison of the allele configurations of SSR, SRAP and LiAAT4 loci and the L/LA ratio of plants showing recombination in the L/LA-QTL region provided further support that LiAAT4 is a candidate gene underlying the identified L/LA-QTL and controlling the L/LA ratio. The application of molecular markers for the identified L/LA-QTL is discussed.

In the business world, communication over customers must be built properly to make it easier for companies to find out what customers want. Support ticket is one of the business instrument for communication between the customers and the companies. Through a support ticket, customers can respond, complain or ask questions about products with a support team. Increasing the business process of the companies will be increasing the support ticket volume that should be handled by support team. It also has a value for analysis to get business intelligence decision. With that chance, an efficient data processing method is needed to find topics are being discussed by customers. One way that can be used to solve this problem is Topic Modeling. This research uses several parameters the number of topics, alpha value, beta value, iteration, and random seed. With this combination of parameters, the best results based on evaluation of human judgement and topic coherence with 5 topics, an alpha value of 50, a beta value of 0.01, 100 iterations, and 50 random seeds. The five topics interpretation consists of hosting migration, error problems in wordpress, domain email settings and domain transfer, ticketing and transaction processing. The total of 5 topics has a coherence value of 0.507897.

Agen penyebab penyakit Chronic Respiratory Disease (CRD) berasal dari bakteri Mycoplasma gallisepticum yang menginfeksi saluran pernapasan pada ternak unggas seperti ayam, itik, angsa, entok, kalkun, burung dara, dan lain-lain. Faktor yang dapat memperburuk terjadinya infeksi penyakit ini yakni umur ternak, jenis kelamin, stres, dan lingkungan. Infeksi bakteri ini lebih rentan pada ayam yang berumur muda dan ayam betina dibandingkan dengan ayam dewasa dan ayam jantan. Gejala klinis dari penyakit ini yaitu terdengarnya suara ngorok pada ayam di malam hari, keluarnya catarrhal dari rongga hidung, batuk, radang conjunctiva, dan bersin. Masa penyakit CRD berkisar antara 4 - 21 hari dan mudah menular. Metode uji laboratrium untuk mengidentifikasi pemeriksaan terhadap kontaminasi bakteri Mycoplasma gallispeticum di kandang diantarnya uji seroligi seperti HI (Hemaglutination Inhibition Test), RSA (Rapid Serum Aglutination Test), maupun ELISA (Enzyme Linked Immuno Sorbent Assay). Kejadian penyakit CRD hingga saat ini yang masih ditemukan di seluruh wilayah Indonesia menyebabkan kerugian bagi peternak. Kerugian ekonomis akibat penyakit ini dapat diminimalisir dengan pengetahuan peternak akan pentingnya program biosekuriti yang harus diterapkan secara konsisten, serta peningkatan imunitas ternak seperti vaksinasi serta penggunaan antimikroba yang aman dan tidak menimbulkan residu.

U okviru roditeljskih uloga partneri ostvaruju poseban oblik saradnje – koroditeljstvo koji je usmeren na osmišljavanje, upravljanje i realizaciju zajedničke brige o deci. Kvalitet koroditeljskog odnosa značajan je za kvalitet roditeljstva, ali za i razvoj deteta, pre svega u domenu socio-emocionalnog razvoja, bihejvioralnih i relacijskih kompetencija deteta. Longitudinalne studije ukazuju da je kvalitet koroditeljskog odnosa prenatalno dobar prediktor ovog odnosa nakon rođenja deteta. U okviru srpskog govornog područja do sada nisu rađena istraživanja u oblasti koroditeljskih odnosa u prenatalnom periodu, te u skladu sa tim ne postoji adekvatan instrument procene. Uzimajući u obzir značaj istraživanja ove oblasti za razvoj teorije i prakse razvojne psihologije i psihologije porodice prepoznata je potreba za adaptacijom upitnika koji bi služio istraživačima i praktičarima. Cilj ovog rada je da se prikaže faktorska struktura i osnovne psihometrijske karakteristike adaptirane verzije instrumenta Snaga roditeljskog saveza (Parenting alliance measure, Abidin & Konold 1999) na uzorku budućih roditelja. Uzorak je činilo 342 ispitanika, odnosno 171 par koji očekuje prvo dete. Faktorskom analizom izolovana su tri faktora imenovana kao: međusobna podrška koroditelja, obostrana uključenost koroditelja i zajedničke vrednosti koroditelja. Kronbahova alfa za skalu u celini iznosi 0.95, dok za pojedinačne subskale iznosi: 0.89 za subskalu kvalitet međusobne podrške, .89 za subskalu kvalitet obostrane uključenosti roditelja i .77 za subskalu zajedničkih vrednosti koroditelja. Adaptirani upitnik je pokazao dobre metrijske karakteristike, čime je dobijen reprezentativan instrument za procenu prenatalne koroditeljske saradnje.

Nepeta nuda L. is a medicinal plant enriched with secondary metabolites serving to attract pollinators and deter herbivores. Phenolics and iridoids of N. nuda have been extensively investigated because of their beneficial impacts on human health. This study explores the chemical profiles of in vitro shoots and wild-grown N. nuda plants (flowers and leaves) through metabolomic analysis utilizing gas chromatography and mass spectrometry (GC–MS). Initially, we examined the differences in the volatiles’ composition in in vitro-cultivated shoots comparing them with flowers and leaves from plants growing in natural environment. The characteristic iridoid 4a-α,7-β,7a-α-nepetalactone was highly represented in shoots of in vitro plants and in flowers of plants from nature populations, whereas most of the monoterpenes were abundant in leaves of wild-grown plants. The known in vitro biological activities encompassing antioxidant, antiviral, antibacterial potentials alongside the newly assessed anti-inflammatory effects exhibited consistent associations with the total content of phenolics, reducing sugars, and the identified metabolic profiles in polar (organic acids, amino acids, alcohols, sugars, phenolics) and non-polar (fatty acids, alkanes, sterols) fractions. Phytohormonal levels were also quantified to infer the regulatory pathways governing phytochemical production. The overall dataset highlighted compounds with the potential to contribute to N. nuda bioactivity.

Subjects with pathogenic (PV) and likely pathogenic (LPV) FLCN variants have an increased risk of manifesting benign and malignant disorders that are related to Birt–Hogg–Dubé syndrome (BHDS): an autosomal dominantly inherited disorder whose severity can vary significantly. Renal cell carcinoma (RCC) development in BHD (Birt–Hogg–Dubé) patients has a very high incidence; thus, identifying this rare syndrome at early stages and preventing metastatic spread is crucial. Over the last decade, the advancement of Next Generation Sequencing (NGS) and the implementation of multigene panels for hereditary cancer syndromes (HCS) have led to a subsequent focus on additional genes and variants, including those of uncertain significance (VUS). Here, we describe a novel FLCN variant observed in a subject manifesting disorders that were suspected to be related to BHDS and with a family history of multiple cancers.

COMMUNITY EMPOWERMENT RELATED TO WASTE WITH 3R PRINCIPLES IN THE JIMBARAN TRADITIONAL VILLAGE BEACH AREA. The traditional village of Jimbaran is a village located in a coastal area. Jimbaran beach is a tourist destination that has strategic potential and attracts tourists to come to visit. The rapid development of the tourism sector has caused various problems, such as environmental pollution due to waste. Plastic waste is the most common waste. This community service aims to provide a little information and knowledge to the community about how to manage waste with the 3R (Reduce, Reuse dan Recycle) principle to create a clean coastal environment and natural conservationt.

Helichrysum italicum (Roth) G. Don., immortelle, is a plant species used in ethnomedicine and the food industry as a spice added to food, beverages, and bakery products. It has been shown to possess various biological activities, such as antioxidant and antibacterial activity, making it useful as a natural preservative. We investigated the phytochemical profile and biological activity of H. italicum essential oils from wild-grown plant material collected from natural habitats in the Republic of Croatia and Bosnia and Herzegovina. Using high-resolution scanning electron microscopy (SEM), a visual investigation of plant organs (stem, leaf, and flower) was performed, confirming the presence of essential oil reservoirs on the surface of all examined plant organs. Essential oils were isolated by hydrodistillation in the Clevenger apparatus. The chemical composition of the essential oils was determined using the GC-MS analytical technique. Cytotoxic activity tests were performed in vitro on three cell lines: skin (fibroblast), lung, and breast cancer. Using statistical tools, the synergistic and selective effects of H. italicum essential oil on healthy and tumor cells were correlated to chemical composition and cytotoxic activity. The synergistic and antagonistic effects of H. italicum essential oil’s individual components were simulated by testing pure compounds and their mixture of cytotoxic activity on fibroblasts and breast cancer cells. The results confirm that essential oil’s biological activity is much greater than the sum of the effects of its components. The present data are novel contributions to the body of knowledge on the biological activity of this species used in the food industry.

This study attempts to provide a deeper insight into the current genetic status of 12 Bulgarian autochthonous sheep breeds using microsatellite (SSR) markers. A total of 600 individuals from 50 flocks were analyzed using a panel of 13 SSR markers. In total, 228 alleles were found in the studied microsatellite loci. The mean number of alleles, the effective number of alleles, and the polymorphic information content (PIC) values per locus were 17.54, 5.250, and 0.799, respectively. The expected heterozygosity (He) for all breeds ranged from 0.70 to 0.82. The within-population heterozygote deficit (Fis) varied from −0.03 to 0.1, reflecting significant levels for 10 of the 12 breeds. The average genetic differentiation (Fst) was 0.046, revealing a low discrimination between the breeds. The genetic distance, principal coordinate analysis, and the structure analysis showed that two of the studied breeds—Local Stara Zagora/SZ/ and Local Karnobat/MK/—were the most distinct sheep populations. The Bayesian clustering approach suggested poor breed differentiation for the remaining 10 sheep breeds. The results suggest that proper management strategies and specific breeding policies need to be implemented in Bulgaria to avoid the intermixing of breeds and to reduce the erosion of breed purity observed in some breeds.

Penelitian bertujuan menganalisis peningkatan hasil belajar siswa kelas IV yang berjumlah 16 siswa SD 1 Jepang tahun ajaran 2020/2021. Metode penelitian yang digunakan yakni penelitian tindakan kelas. Tahap penelitian terdiri: perencanaan, tindakan, pengamatan, refleksi. Metode pengumpulan data wawancara, observasi, tes dan dokumentasi. Instrumen pengumpulan data berupa observasi, tes dan dokumentasi. Teknik analisis data yakni teknik analisis data deskriptif kualitatif dan kuantitatif. Kondisi pra siklus menunjukkan muatan Bahasa Indonesia terdapat 9 siswa yang mencapai ketuntasan dengan nilai rata-rata kelas 70 dan muatan IPS hanya 5 siswa yang mencapai ketuntasan dengan nilai rata-rata kelas 67. Hasil Penelitian menunjukkan bahwa pada Hasil belajar aspek pengetahuan siklus I memperoleh ketuntasan klasikal 62,5% ke siklus II memperoleh 87,5% berkategori sangat baik, sedangkan aspek keterampilan siklus I memperoleh 57,14% ke siklus II 83,52% berkategori sangat baik. Hal ini membuktikan penggunaan model pembelajaran Numbered Head Together meningkatkan hasil belajar siswa tema 4 Berbagai Pekerjaan kelas IV SD 1 Jepang.

Abstract Background Pancreatic cancer (PC) is a major cause of cancer death. In an effort to improve treatment strategies and outcomes, DNA damage repair (DDR) pathways have been introduced as a new target in PC and in other cancers, through the exploitation of synthetic lethality. Furthermore, genes involved in DDR are among the major determinants of cancer susceptibility. In addition to the well-known BRCA1 and BRCA2 genes, a plethora of other targets in the same pathways are now emerging. Methods We analyzed samples from 60 patients, affected by PC and already tested for BRCA, using a panel with 24 other cancer susceptibility genes. Results We detected 8 pathogenic or likely pathogenic mutations (13.3% of samples analyzed), 4 of which were found in non-BRCA genes (2 in ATM, 1 each in PALB2 and RAD50). Furthermore, 4 pathogenic or likely pathogenic mutations were found in patients without a personal or familial history of cancer. Conclusions Our results suggest that genetic testing with a comprehensive gene panel should be perfomed in all patients with PC, in order to allow screening for PC and other gene-related cancers in all at risk family members and to assess patients’ eligibility for emerging therapeutic options.

Penelitian ini bertujuan untuk menganalisis bagaimana prestasi belajar anak pada pembelajaran daring saat pandemi covid-19. Jenis penelitian yang digunakan yakni penelitian kualitatif dengan pendekatan deskriptif. Teknik pengumpulan data dalam penelitian ini menggunakan teknik wawancara mendalan dan dokumentasi yang bersumber pada data yang valid. Hasil penelitian adalah pandemi covid-19 membawa dampak besar pada hasil prestasi belajar anak. Dalam belajar pada pembelajaran daring siswa mengalami lebih banyak kesulitan dalam belajar. Prestasi belajar anak sulit dipantau secara langsung oleh guru. Penerapan cara belajar yang efektif dan efisien pada pembelajaran daring akan memengaruhi prestasi belajar yang baik. Terdapat faktor-faktor lain yakni faktor eksternal yakni keluarga sangat berpengaruh pada prestasi belajar anak.

Penelitian ini bertujuan untuk mendeskripsikan peningkatan aktivitas belajar siswa melalui keterampilan guru mengunakan media kertas surat misterius dengan menggunakan model pembelajaran Two Stay Two Stray pada tema 7 Indahnya Keragaman Di Negeriku di SD 1 Purwosari dan subjek dari penelitian ini adalah guru dan siswa Kelas IV. Jenis Penelitian yang dilaksanakan adalah penelitian tindakan kelas. Penelitian terdiri dari dua siklus, setiap siklus terdapat dua pertemuan. Teknik pengumpulan data yang digunakan meliputi observasi, wawancara, dan dokumentasi. Hasil penelitian ini meunjukkan bahwa nilai ketuntasan klasikal mengalami peningkatan yaitu dari siklus I ke siklus II yaitu dengan nilai rata-rata klasikal 73,05dengan kriteria cukup di siklus I menjadi 75,01 di siklus II dengan kriteria cukup. Keterampilan mengajar guru pada siklus I yaitu 69,5 dengan persentase 69,5% termasuk dalam kreteria baik. Skor rata-rata tersebut meningkat pada siklus II yaitu 84 dengan persentase 84% dan termasuk dalam kriteria sangat baik. Pelaksanaan siklus II telah berhasil kerena keseluruhan indikator keberhasilan dalam penelitian ini telah tercapai. Dengan demikian penerapan model Two Stay Two Stray berbantuan surat misterius di SD 1 Purwosari dapat meningkatkan aktivitas belajar siswa.

In our study, we investigated the chemical composition and cytotoxic activity of essential oils isolated from Dalmatian sage (Salvia officinalis L.) collected along the Adriatic coast of Croatia. Scanning electron microscopy (SEM) was used to examine the morphology of the stem and leaf surfaces. Essential oil excretory glands were detected on both the leaves and stem surfaces. The essential oils were isolated by hydrodistillation, and their chemical composition was determined by gas chromatography and mass spectrometry (GC-MS). Sage essential oils were mixtures of terpene compounds, among which the most common were: α- and β-thujone, camphor, and 1,8-cineol. Cytotoxic activity was tested using MTS assay on multiple cell lines: normal and immortalized fibroblasts (HF77FA and HDF-Tert), immortalized lung line (BEAS-2B), and breast adenocarcinoma (MDA-MB-231). The growth of treated cells was determined relative to control conditions without treatment. The immortalized lung line was the least resistant to the activity of the essential oils, whereas immortalized fibroblasts were the most resistant. Statistical analysis has connected the cytotoxic effect and chemical composition of the studied essential oils. To the best of our knowledge, this work is the first testing of the cytotoxic activity of S. officinalis EO’s on the BEAS-2B, HF77FA, and HDF-Tert cell lines. The presented data on essential oil chemical composition and cytotoxic effect on 4 types of human cells supports pharmacotherapeutic potential this plant is known to have.

This study reports the development of a set of 20 highly polymorphic genomic SSR markers which can be used for both cultivar identification and genetic diversity studies in several Origanum species, including some of the most popular ones like Greek oregano (Origanum vulgare L. ssp. hirtum), common oregano (O. vulgare L. ssp. vulgare), and sweet marjoram (O. majorana L.). Analysis of the polymorphic information content (PIC) showed an average PIC value of 0.75 with a minimum of 0.41 and a maximum of 0.89, where 17 of the markers showed PIC values above 0.73. Comparative analysis of the genetic diversity of eight natural populations of Greek oregano in Bulgaria showed that six of the genomic SSR markers revealed significantly higher portions of genetic diversity in the populations, compared to 12 EST SSR markers used in our previous study. We also compared the performance of the same six genomic SSR markers with the results for eight SRAP primer combinations, which showed that SRAP markers captured more precisely the genetic structure in natural populations. The developed highly polymorphic genomic SSR markers can be successfully applied to evaluation of the genetic diversity in the genus Origanum, based on the expected and observed heterozygosity in the populations as well as for easy identification of breeding lines and cultivars based on unique SSR fingerprints.

COMMUNITIES WITH RESPONSE AND RESPONSE TO COVID-19: COMMUNITY SERVICE IN CIKARANG VILLAGE, KADU HEJO VILLAGE, PULOSARI DISTRICT, PANDEGLANG. This community service activity provided services and assistance to children in rural areas during the Covid-19 Pandemic which hit the whole world and Indonesia was also affected, from the economic sector to education. For education itself, the government has agreed to study at home or online. By using various strategies so that the nation's successors can still learn even though not face to face. Lecturers and students of Unma Banten guidance and counseling had the opportunity to go to the field by prioritizing health protocols and providing disaster counseling services at Cikarang Village, Kadu Hejo Village, Pulosari District, Pandeglang.

Birt–Hogg–Dubé syndrome (BHDS) is a rare autosomal dominant inherited disorder caused by a mutation in folliculin (FLCN) gene transmitted via germline autosomal dominant pattern. Patients with this syndrome have an increased susceptibility to renal cell carcinoma, lung cysts, spontaneous pneumothorax, and benign skin hamartomas, and its diagnosis is not easy and consequently underestimated. Several mutations have been identified in FLCN gene, among which the majority of alterations are frameshift (insertion/deletion), nonsense, or splice-site mutations that generally produce unfunctional truncated FLCN proteins. Our aim is to present a case of a BHDS family whose proband is a 56-year-old patient who has been experiencing multiple disorders, has an FLCN genetic mutation, and has also been identified to have a pathogenic variant in BRCA2 gene. Our further purpose is to emphasize the importance of the next-generation sequencing (NGS) approach to identify potential multiple germline mutations in complex and rare oncologic disorders, allowing strict and more targeted cancer screening programs.

This study aims to examine the relationship of earnings and operating cash flow as an independent variable on the value relevance of accounting information proxied by stock returns by using book value as a moderating variable. The utilitation of stock returns as an independent variable is choosed as previous research on value relevance tends to use stock prices as an independent variable. The sample of this study is all population of companies listed on the Jakarta Islamic Index (JII) in the 2016-2018 period June-November (issued from June 1st) using saturation sampling. The data used in this study is compound from annual reports in the Indonesia Stock Exchange (IDX) and stock prices from Yahoo Finance. Further, data were tested using multiple linear regression analysis. The results showed that earnings and cash flow have an effect on value relevance proxied by stock returns. However, book value neither strengthens nor weakens earnings and cash flow towards stock returns as a moderating variable. Keywords : Earnings, Operation Cash Flow, Stock Return, Value Relevance, Jakarta Islamic Index

Pendahuluan: Saat ini obat topikal antijerawat telah banyak beredar dalam bentuk gel dan krim, tetapi masih sedikit antijerawat topikal yang megandung herbal, sebagai bahan aktif atau agen berpotensi dapat mencegah dan mengobati jerawat seperti pegagan (Centella asiatica (L.) Urb) dengan sifat anti bakterinya. Tujuan: Mengembangkan formulasi sediaan gel pegagan yang stabil. Metode: Pengujian Formulasi pegagan sesuai persyaratan evaluasi dengan basis gel konsentrasi 7%, 8%, 9%, selanjutnya dilakukan evaluasi meliputi pengujian organoleptik, pH, dan viskositas. Formula ditambah ekstrak herba pegagan dengan konsentrasi 2,5% dan 5%. Uji evaluasi formula yang dilakukan meliputi pengamatan homogenitas, uji derajat keasaman, kekentalan dan daya sebar sediaan. Hasil: Rerata pH sediaan didapatkan 6,66. Formula 1 dan Formula 2 terdapat sedikit perbedaan viskositas. Formula 1 dan Formula 2 menunjukkan homogenitas dan daya sebar yang sudah sesuai persyaratan. Kesimpulan: Selama 14 hari, pengujian Formula 2 dengan konsentrasi ekstrak 5% lebih stabil dibandingkan Formula 1 dengan konsentrasi ekstrak 2,5%.

The genetic and flower volatile diversity of 59 plants from two natural populations of Hyssopus officinalis L. situated 73 km away from each other in typical growing regions for this species in Bulgaria were analysed. Analysis with 10 sequence related amplified polymorphism (SRAP) primer combinations scored a total of 1045 peaks of which 88.7% were polymorphic. Principal Coordinate Analysis (PCoA) and unweighted pair group method with arithmetic mean (UPGMA) clustering revealed clear grouping of samples based on their population origin. However, analysis of the genetic differentiation revealed that the two populations (Godech and Izvor) are genetically similar as shown by the low Fst and Gst values as well as by the low Nei’s genetic distance and high gene flow (Nm). Gas chromatography–mass spectrometry (GC-MS) analysis of flower extracts from the same individual plants that were used in the genetic diversity analysis identified 32 compounds. Principal Component Analysis (PCA) based on compound abundances revealed two major clusters of samples which did not correspond to their population origin. In depth analysis of the compound abundances showed large variation between the two identified clusters including complete presence/absence of major compounds and the existence of two distinct chemotypes corresponding to the identified clusters. Our results indicate that future efforts towards development of genetic resource collections as well as transition towards field cultivation of this species in Bulgaria should take into account the presence of the two identified chemotypes in natural populations and the factors (both genetic and epigenetic) which determine their existence.

Background: previous worldwide reports indicated a substantial short-term reduction in various respiratory infections during the early phase of the SARS-CoV-2 pandemic. Aims: exploring the long-term impact of the COVID-19 pandemic on respiratory pathogens. Methods: retrospective analysis of bacterial and viral positivity rate in respiratory samples, between 1 January 2017–30 June 2022 in a tertiary hospital in Jerusalem, Israel. Results: A decline in overall respiratory tests and positivity rate was observed in the first months of the pandemic. Respiratory isolations of Hemophilus influenza and Streptococcus pneumoniae were insignificantly affected and returned to their monthly average by November 2020, despite a parallel surge in COVID-19 activity, while Mycoplasma pneumoniae was almost eliminated from the respiratory pathogens scene. Each viral pathogen acted differently, with adenovirus affected only for few months. Human-metapneumovirus and respiratory-syncytial-virus had reduced activity for approximately a year, and influenza A virus resurged in November 2021 with the elimination of Influenza-B. Conclusions: After an immediate decline in non-SARS-CoV-2 respiratory infections, each pathogen has a different pattern during a 2-year follow-up. These patterns might be influenced by intrinsic factors of each pathogen and different risk reduction behaviors of the population. Since some of these measures will remain in the following years, we cannot predict the timing of return to pre-COVID-19 normalcy.

The indigenous yeasts associated with the spontaneous fermentation of phenolic-rich rose oil distillation wastewater (RODW) generated after the industrial distillation of rose oil were studied. The ITS-rDNA sequence analysis of the samples collected from RODW fermented at semi-sterile conditions, a waste deposition lagoon and endophytic yeasts isolated from industrially cultivated Rosa damascena suggests that the spontaneous RODW fermentation is caused by yeasts from the genus Cyberlindnera found also as endophytes in the rose flowers. Phylogenetic analysis based on the nucleotide sequences of the translation elongation factor (TEF1α) and 18S- and 26S- rRNA genes further confirmed the taxonomic affiliation of the RODW yeast isolates with the genus Cyberlindnera. The RODW fermentation capacity of a selected set of indigenous yeast isolates was studied and compared with those of common yeast strains. The indigenous yeast isolates demonstrated a superior growth rate, resulting in a nearly double reduction in the phenolic content in the fermented RODW. The indigenous yeasts’ fermentation changed the RODW phenolics’ composition. The levels of some particular phenolic glycosides decreased through the depletion and fermentation of their sugar moiety. Hence, the relative abundance of the corresponding aglycons and other phenolic compounds increased. The capacity for the biotransformation of RODW phenolics by indigenous yeasts is discussed.

У овом раду испитују се глаголи у српском језику чијe се примарно значење промене положаја у простору (на вертикалној оси) у оквиру перифрастичних предиката мења у значење интензитета, те они добијају функцију интензификатора значења именица које обележавају процес и које су семантички центри датих конструкција (нпр. Вредност је скочила; Утонуо је у мисли). Спроведена је структурна анализа перифраза, те је уочено пет структурних модела у којима се именице јављају на различитим синтаксичким позицијама и могу се сврстати у више семантичких група. Дат је осврт и на когнитивне механизме на основу којих долази до промене значења глагола, са закључком да се концепт интензитета, који је апстрактан, везује за перцептивно докучиве појмове квантитета и дубине, те да се промена положаја навише повезује са високим интензитетом, а промена наниже са ниским.

BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p < 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients.

Background and Objectives: The vaccine against human papilloma virus (HPV) infection is recommended, according to the Serbian National Immunization Program, for children and adolescents aged 9–19 years. Three doses are given keeping in mind the recommendation that the second dose should be administered at least one month after the first dose, and the third at least three months after the second dose. No children who participated in this first study received the third dose because they did not meet these criteria. The study explored parents’ knowledge about HPV infection and their awareness of the HPV vaccine. Materials and Methods: A cross-sectional questionnaire-based study was carried out in the city of Nis, in southeastern Serbia. According to the 2011 population census, the sample of children aged 9 to 19 was 850, and during the observed period, 631 children received the vaccine. A total of 615 fully completed questionnaires filled out by parents were included in the study. The study was carried out from 6 June 2022 to 7 October 2022. Multivariable logistic regression analysis was used. The odds ratio (OR) and 95% confidence intervals (CI) were calculated. The statistical significance was p < 0.05. Results: A total of 615 children were included in the study (499 were vaccinated with the first dose and 116 with the second). Out of 499 children vaccinated with the first dose, 398 (79.6%) were girls, which is significantly higher than the rate for boys (101). The independent variable sex was statistically significant at the level of p = 0.84, OR = 2.664 (95% CI from 0.879 to 7.954). Boys are 164% less likely to be vaccinated with the HPV vaccine than girls. We determined that the independent variable place of residence was significant at the level of p = 0.041, (OR = 3.809, 95% CI from 1.702 to 8.525). Based on these findings, we determined that parents who came from rural areas were 82% less likely to know about HPV infection and HPV vaccination. Children under 15 years of age were significantly more vaccinated than those ≥15 years (OR = 3.698, 95% CI from 1.354 to 12.598). The independent variable parental education was significant at the level of OR = 0.494, 95% CI from 0.301 to 0.791. Parents who had medical education showed significantly higher awareness about the infection caused by HPV and about the HPV vaccine (p = 0.004) than parents with no medical education. The possibility that a parent would decide to vaccinate a child significantly increased upon a pediatrician’s recommendation, p = 0.000 with OR = 0.250 (95% CI from 0.127 to 0.707). Health insurance coverage of HPV vaccination for children aged 9–19 years significantly increased the probability of a positive parental decision to vaccinate a child, p = 0.001 with OR = 3.034 (95% CI from 1.063 to 8.662). Conclusion: We identified several significant factors that were important for HPV vaccination such as: children under 15 years, female sex, urban place of residence, medical education of parents, pediatrician’s recommendation of the HPV vaccination, and HPV vaccination free of charge. Health education and the promotion of HPV vaccination as well as healthy sexual behavior are important factors in the preservation and improvement of the health of the whole population.

Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)-a parasitic worm transmitted to human by blackflies. NS seems to be an 'Autoimmune Epilepsy' in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a -794 CATT5-8 microsatellite repeat and a -173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS. Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy.

Antiviral defenses can sense viral RNAs and mediate their destruction. This presents a challenge for host cells since they must destroy viral RNAs while sparing the host mRNAs that encode antiviral effectors. Here, we show that highly upregulated interferon-stimulated genes (ISGs), which encode antiviral proteins, have distinctive nucleotide compositions. We propose that self-targeting by antiviral effectors has selected for ISG transcripts that occupy a less self-targeted sequence space. Following interferon (IFN) stimulation, the CpG-targeting antiviral effector zinc-finger antiviral protein (ZAP) reduces the mRNA abundance of multiple host transcripts, providing a mechanistic explanation for the repression of many (but not all) interferon-repressed genes (IRGs). Notably, IRGs tend to be relatively CpG rich. In contrast, highly upregulated ISGs tend to be strongly CpG suppressed. Thus, ZAP is an example of an effector that has not only selected compositional biases in viral genomes but also appears to have notably shaped the composition of host transcripts in the vertebrate interferome.

Viruses cause widely transmitted diseases resulting in pandemic conditions. Currently, the world is being hit by the Covid-19 pandemic caused by the SAR-CoV-2 infection. Countries in the world are competing to develop antivirals to overcome this problem. Diterpene compounds derived from natural ingredients (plants, corals, algae, fungi, sponges) and synthesized products have potential as antivirals. This article summarizes the different types of diterpenes such as daphnane, tiglilane, kaurane, abietane, pimarane, labdane, dollabelane, jatrophane, dolastane, prenylated guaiane, tonantzitlolone, casbane, have antivirals activity such as targeting HIV, Coxsackie virus, herpes virus, hepatitis virus, influenza virus, Chikungunya virus, Zika virus, dengue virus, and SARS-CoV. Some compounds such as andrographolide and its derivatives show promising activity in inhibiting the influenza virus. Additionally, compounds such as pineolidic acid, forskolin, sugiol, and many other diterpene compounds showed anti-SAR-CoV activity. The diterpene compound class's high antivirals potential does not rule out the possibility that these compounds can also act as anti-SAR-CoV-2 drugs in the future.

Helichrysum italicum (Roth) G. Don (Asteraceae), also known as immortelle, usually grows in the Mediterranean area. The composition of the essential oil (EO) of immortelle is a mixture of various aromatic substances, mainly monoterpenes and sesquiterpenes. Distillation is the most widely used method for extraction of EO immortelle, although the yield is very low (

Background and Objectives: The relationship between osteoarthritis (OA) and osteoporosis (OP) has been analysed for over four decades. However, this relationship has remained controversial. Numerous observational and longitudinal studies have shown an inverse association between the two diseases and a protective effect of one against the other. On the other hand, some studies show that patients with OA have impaired bone strength and are more prone to fractures. The study’s main objective was to determine the bone mineral density (BMD) of the spine and hip (femoral neck) of postmenopausal women of different ages, with radiologically determined OA of the hip and knee, as well as to determine the correlation between BMD values and age in the experimental group. Materials and Methods: The retrospective cohort study included 7018 patients with osteoarthritis of peripheral joints and the spine, examined by a rheumatologist in an outpatient rheumatology clinic at the Institute for Treatment and Rehabilitation, Niška Banja from July 2019 to March 2021. A nested anamnestic study was conducted within the cohort study of patients, and it included two groups: an experimental group composed of 60 postmenopausal women, and a control group composed of the same number of women. Out of 120 patients, 24 did not meet the criteria for the continuation of the study (due to technical errors—radiographic and/or densitometry artefacts). Fifty-six postmenopausal women (aged 45–77 years) with hip and knee radiological OA were examined as an experimental group. The participants were divided into two subgroups according to age (45–60 years and over 61 years). The control group included 40 healthy postmenopausal women of the same age range, without radiological OA, with normal BMD of the hip and spine. All patients with OA met the American College of Radiology (ACR) criteria. OA of the hip and knee was determined radiologically according to Kellgren and Lawrence (K&L) classification, and patients were included in the study if a K&L grade of at least ≥ 2 was present. Hip and spine BMD was measured by dual-energy X-ray absorptiometry (DXA). Results: Compared to the control group, we found statistically significantly lower BMD and T-scores of the spine in older postmenopausal women: BMD (g/cm2), p = 0.014; T-score, p = 0.007, as well as of the hip: BMD (g/cm2), p = 0.024; T-score p < 0.001. The values of BMD and T-score of the spine and hip are lower in more severe forms of OA (X-ray stage 3 and 4, according to K&L), p < 0.001. We found negative correlation between BMD and T-score and age only for the hip: BMD (g/cm2), ρ = 0.378, p = 0.005; T-score ρ = −0.349, p = 0.010. Conclusions: Older postmenopausal women with radiographic hip and knee OA had significantly lower BMD of the hip and spine as compared to the control group without OA, pointing to the need for the prevention and treatment of OA, as well as early diagnosis, monitoring, and treatment of low bone mineral density.

Due to the role of cancer stem cells (CSCs) in tumor resistance and glycosphingolipid (GSL) involvement in tumor pathogenesis, we investigated the effect of a newly synthesized compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide 1 on the percentage of CSCs and the expression of six GSLs on CSCs and non-CSCs on breast cancer cell lines (MDA-MB-231 and MCF-7). We also investigated the effect of 1 on the metabolic profile of these cell lines. The MTT assay was used for cytotoxicity determination. Apoptosis and expression of GSLs were assessed by flow cytometry. A GC–MS-coupled system was used for the separation and identification of metabolites. Compound 1 was cytotoxic for both cell lines, and the majority of cells died by treatment-induced apoptosis. The percentage of CSCs was significantly lower in the MDA-MB-231 cell line. Treatment with 1 caused a decrease of CSC IV6Neu5Ac-nLc4Cer+ MDA-MB-231 cells. In the MCF-7 cell line, the percentage of GalNAc-GM1b+ CSCs was increased, while the expression of Gg3Cer was decreased in both CSC and non-CSC. Twenty-one metabolites were identified by metabolic profiling. The major impact of the treatment was in glycolysis/gluconeogenesis, pyruvate and inositol metabolism. Compound 1 exhibited higher potency in MBA-MB-231 cells, and it deserves further examination.

We studied the genetic and flower volatile diversity in natural populations of Origanum vulgare subsp. hirtum (Link) Ietsw. in Bulgaria using simple sequence repeat (SSR) and sequence-related amplified polymorphism (SRAP) markers and gas chromatography/mass spectrometry (GC/MS) analysis of flower volatiles from individual plants. Two regions, including the Kresna Gorge and Eastern Rhodopes, typical for the species comprising eight populations and 239 individual plants were included in this study. An analysis with 11 SSR markers and eight SRAP primer combinations showed that SRAP markers were substantially more informative than the SSR markers and were further used for genetic diversity analysis. The results showed low-range to mid-range genetic differentiation between the populations with pairwise fixation index (Fst) values ranging between 0.0047 and 0.11. A total of 10 genetic clusters were identified. An analysis of the flower volatile diversity identified a total of 63 compounds with the vast majority of plants belonging to the carvacrol chemotype and just a single plant to the thymol chemotype. Large deviations were observed for individual compounds within each region as well as within the populations. Hierarchical clustering showed a clear sample grouping based on the two different regions. In addition, an in-depth analysis identified six major and 23 minor metabolite clusters. The overall data set and cluster analysis were further used for the development and testing of a simple and straightforward strategy for the selection of individual plants for the development of a core collection representing the sampled natural populations for this species in Bulgaria. The proposed strategy involves precise genetic clustering of the tested plants followed by the selection of a minimal set from each genetic cluster representing the different metabolite clusters. The selected core set was further compared with a core set extracted by the PowerCore software. A comparison of the genetic and metabolic affiliation of the members of both sets showed that the reported approach selected representatives from each genetic cluster and minor metabolic cluster, whereas some metabolic clusters were unrepresented in the PowerCore set. The feasibility and efficiency of applying the pointed strategy for the development of a core collection representing both the genetic and metabolite diversity of natural populations in aromatic and medicinal plants toward subsequent steps of selection and breeding are discussed.

We studied the petal number trait in a population obtained after self-pollination of R. x damascena f. trigintipetala following analysis of molecular markers which have previously been mapped near the major dominant locus Blfo/d6 determining this trait in other rose species including R. multiflora and R. hybrida. The results showed that the same genetic mechanism, which determines the petal number trait in R. multiflora and R. hybrida also controls the trait in R. x damascena f. trigintipetala and is related to the dominant effect of a single copy allele in the tetraploid genome of this species. We also analyzed the expression of several flower homeotic genes including R. x damascena APETALA1/FUL-like (paleo AP1 type), R. x damascena euAPETALA 3 (euAP3 line) and R. x damascena AGAMOUS in early stage flower buds corresponding to plants with double and simple flowers. The obtained results showed that only R. x damascena AGAMOUS was differentially expressed between the samples of double and simple flowers, its relative expression being upregulated 3.5-fold in simple flowers. We further cloned and sequenced the four genomic clones of R. x damascena AGAMOUS and studied the potential additive effect of this gene by analysing the segregation of its four alleles in the population of self-pollinated R. x damascena. Analysis of variance of the data for petal number and allele segregation did not show a statistically significant effect of any allele configuration of the AGAMOUS gene on the petal number trait in R. x damascena f. trigintipetala.