Predominant Target Research Articles

Discovery and engineering of the antibody response to a prominent skin commensal.

The ubiquitous skin colonist Staphylococcus epidermidis elicits a CD8+ T cell response pre-emptively, in the absence of an infection1. However, the scope and purpose of this anti-commensal immune program are not well defined, limiting our ability to harness it therapeutically. Here, we show that this colonist also induces a potent, durable, and specific antibody response that is conserved in humans and non-human primates. A series of S. epidermidis cell-wall mutants revealed that the cell surface protein Aap is a predominant target. By colonizing mice with a strain of S. epidermidis in which the parallel β-helix domain of Aap is replaced by tetanus toxin fragment C, we elicit a potent neutralizing antibody response that protects mice against a lethal challenge. A similar strain of S. epidermidis expressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labeled commensal elicits high antibody titers under conditions of physiologic colonization, including a robust IgA response in the nasal and pulmonary mucosa. Thus, immunity to a common skin colonist involves a coordinated T and B cell response, the latter of which can be redirected against pathogens as a novel form of topical vaccination.

HBV shows different levels of adaptation to HLA class I-associated selection pressure correlating with markers of replication

Background & AimsImmune responses by CD8 T cells are essential for control of HBV replication. Although selection of escape mutations in CD8 T cell epitopes has been previously described in HBV infection, its overall influence on HBV sequence diversity and correlation with markers of HBV replication remain unclear. MethodsWhole-genome sequencing was applied to HBV isolates from 532 patients with chronic HBV infection and high-resolution HLA class I genotyping. Using a Bayesian model (HAMdetector) for Identification of HLA-associated mutational states (HAMs) the frequency and location of residues under CD8 T cell selection pressure were determined and the levels of adaptation of individual isolates were quantified. ResultsUsing previously published thresholds for the identification of HAMs, a total of 295 residues showed evidence of CD8 T cell escape, the majority of which were located in previously unidentified epitopes. Interestingly, HAMs were highly enriched in the HBV core protein compared to all other proteins. When individual HBV isolates were compared, different levels of adaptation to HLA class I immune pressure were noted. The level of adaptation increased with patient age and correlated with markers of replication, with low levels of adaptation in HBeAg-positive infection. Furthermore, the levels of adaptation negatively correlated with HBV viral load and HBsAg levels, consistent with high levels of HLA class I-associated selection pressure in patients with low replication level. ConclusionsHBV sequence diversity is shaped by HLA class I-associated selection pressure with the HBV core protein being a predominant target of selection. Importantly, different levels of adaptation to immune pressure were observed between HBV infection stages, which need to be considered in the context of T cell-based therapies. Impact and implicationsThe immune response mediated by CD8 T cells plays a critical role in controlling HBV infection and shows promise for therapeutic strategies aimed at achieving a functional cure. This study demonstrates that mutational escape within CD8 T cell epitopes is common in HBV and represents a key factor in the failure of immune control. Notably, the HBV core protein emerges as the primary target of CD8 T cell selection pressure. Additionally, the observed correlation between HBV adaptation levels and viral replication markers indicates that CD8 T cell immunity may influence transitions between phases of chronic HBV infection.

Appearance-related cyberbullying and its association with the desire to alter physical appearance among adolescent females

Cyberbullying is associated with various mental health concerns in adolescents, including body dissatisfaction and disordered eating behaviours. However, there is a significant research gap concerning the unique effects of appearance-related cyberbullying (ARC) on adolescent mental health. This study examined the prevalence and psychological consequences of ARC among middle to late adolescent females (aged 14–19 years, Mage = 15.98, N = 336). Participants completed an online survey regarding their experiences of ARC, body image variables, and eating disorder symptomology. Findings indicate the widespread occurrence of ARC among adolescent females, with body shape and size emerging as predominant targets. Experiences of ARC-victimisation positively correlated with increased concerns about body shape, body shame, and eating disorder symptomology. Conversely, experiences of ARC-victimisation were negatively correlated with body esteem and body appreciation. Finally, appearance-related cybervictimisation was significantly associated with adolescent females’ desire to pursue appearance alterations through methods such as dieting and exercising, altering self-presentation, and undergoing cosmetic procedures due to perceived experiences of ARC. These findings highlight the urgent need for preventative measures, such as age-appropriate social media policies and health promotion programs that encourage positive online behaviour, and strategies to address the impacts of ARC to protect the mental well-being of adolescent females.

Implementation of the School as a Learning Organisation Approach in Vocational Education: The Case of Latvia

Context. Recent studies recognise that the use of the School as a Learning Organisation (SLO) approach in educational management is the key factor ensuring a general education institution’s ability to effectively implement the education policy goals and adapt to change as the use of SLO. Although vocational education has different predominant goals and different target groups, likewise general education, it is exposed to dynamic change and new challenges.Purpose. Within the framework of the study, it was researched whether and how SLO can be applied in vocational education as the use of SLO facilitates a high level of professional competence of the management and academic staff, enhances common strategic vision, responsibility and autonomy, diverse collaboration, effective resource management, and the dissemination of knowledge and good practice, which are also important in vocational education.Methods. Using qualitative data analysis, the paper analyses the experience of EU and OECD countries in the implementation of SLO in vocational education and identifies, which dimensions of the SLO model are represented in the policy and practice of vocational education in Latvia. In the focus group interviews with representatives of vocational education institutions of Latvia, the characteristics of the SLO approach in vocational education were studied, challenges were described and solutions proposed for the targeted implementation of the SLO approach in vocational education in Latvia.Results. All 7 dimensions of the SLO can be found in the education policy documents of the EU and OECD countries and Latvia, as well as in the focus group interviews, which shows that there is a gradual progress towards the transformation of vocational education institutions into learning organisations.Conclusions. For education policy makers: Since the features of SLO are only partially visible in vocational education documents in Latvia, the framework should be improved to cover all dimensions of the SLO, and norms and agreements on collective understanding should be harmonised in policy documents. For school representatives: Raise awareness of the staff of vocational education institutions of the essence of the SLO and its role in improving the quality of education and ensure that all dimensions of SLO are understood and addressed appropriately. For entrepreneurs: Help define the diverse, varied manifestations of professions in the sector in order to engage the individual potential of learners as effectively as possible. For researchers: Help find ways to resolve controversies by identifying good practice and research.

Turkey Hemorrhagic Enteritis (THE): A Short Overview.

Turkey Hemorrhagic Enteritis (THE) is an acute disease caused by a Siadenovirus that affects 4 week-aged and older turkeys, characterized by acute depression, bloody droppings, and a high mortality rate. The immunosuppressive attributes of THE can protract disease progression and create a predisposition in birds towards subsequent bacterial infectiodoralns involving Escherichia coli and Clostridium perfringens (necrotic enteritis). Turkey Hemorrhagic Enteritis Virus (THEV) predominantly affects turkeys and carries substantial economic implications for this industry. Macrophages and B lymphocytes are recognized as the predominant target cells for the virus, while the spleen is the principal site of viral replication. Infected cells have also been observed in various other tissues, including the intestines, bursa of Fabricius, cecal tonsils, thymus, liver, kidney, peripheral blood leukocytes, and lungs. The economic relevance of this disease is derived both from the high mortality rate, which can reach 60% depending on the virulence of the strain, and from subclinical disease responsible for poor performance in vaccinated animals. This review aims to provide a comprehensive overview of THE, spanning etiology, epidemiology clinical signs and gross lesions, prevention, and management.

Prognostic value of clinical and radiomic parameters in patients with liver metastases from uveal melanoma.

Approximately every second patient with uveal melanoma develops distant metastases, with the liver as the predominant target organ. While the median survival after diagnosis of distant metastases is limited to a year, yet-to-be-defined subgroups of patients experience a more favorable outcome. Therefore, prognostic biomarkers could help identify distinct risk groups to guide patient counseling, therapeutic decision-making, and stratification of study populations. To this end, we retrospectively analyzed a cohort of 101 patients with newly diagnosed hepatic metastases from uveal melanoma by using Cox-Lasso regression machine learning, adapted to a high-dimensional input parameter space. We show that substantial binary risk stratification can be performed, based on (i) clinical and laboratory parameters, (ii) measures of quantitative overall hepatic tumor burden, and (iii) radiomic parameters. Yet, combining two or all three domains failed to improve prognostic separation of patients. Additionally, we identified highly relevant clinical parameters (including lactate dehydrogenase, thrombocyte counts, aspartate transaminase, and the metastasis-free interval) at first diagnosis of metastatic disease as predictors for time-to-treatment failure and overall survival. Taken together, the risk stratification models, built by our machine-learning algorithm, identified a comparable and independent prognostic value of clinical, radiological, and radiomic parameters in uveal melanoma patients with hepatic metastases.

NFS-27. SELUMETINIB FOR SYMPTOMATIC, INOPERABLE PLEXIFORM NEUROFIBROMAS IN NEUROFIBROMATOSIS TYPE 1: A SINGLE-INSTITUTION EXPERIENCE

Abstract BACKGROUND Half of patients with Neurofibromatosis type 1 (NF1) develop plexiform neurofibromas (PNs). PNs may grow during childhood causing significant complications, including pain, functional impairment, and disfigurement. Treatment options are limited, given their tendency to regrow following surgery and their propensity to transform into malignant tumors following radiation. Selumetinib is an oral selective inhibitor of RAS-mitogen activated protein kinase (MAPK) 1 and 2, which has shown efficacy for tumor shrinkage/ stabilisation and symptom improvement. METHODS Single-institution retrospective review of patients with NF1 treated with selumetinib for symptomatic PNs between 2020 and 2023. Clinical data were abstracted from medical records. Treatment consisted of selumetinib 25 mg/m2 BID. Patient follow-up included monthly complete physical examination, evaluation of treatment adherence, blood analysis, echocardiogram, ophthalmologic assessment every 3 months, and MRI every 6 months. Response evaluation criteria in solid tumors (RECIST) was used for assessment. RESULTS Ten patients were treated with selumetinib during the period indicated. Mean age 13.9 years (range 7-21). Predominant target locations were head and neck (60%), and abdomen-pelvis (30%). The most important comorbidities were disfigurement (50%) and pain (50%). The mean follow-up time was 519 days (range 45–1460). None of the patients presented grade 3-4 toxicities; all of them had associated grade 1-2 skin toxicity. None presented cardiac or ophthalmologic alterations. All the patients with pain had sustained clinical improvement in the first 35–60 days of treatment. At one year of treatment 6/8 patients showed stable disease and 2/8 partial response on MRI. In one patient, treatment was discontinued after 270 days (lack of clear benefit).Another patient has not reached one year of therapy yet. CONCLUSIONS In this study we expose that selumetinib for symptomatic, inoperable plexiform neurofibromas in NF1 was associated with clinical and radiological response. Our study also confirms the safety and good tolerance of this drug.

CircUGGT2 downregulation by METTL14-dependent m6A modification suppresses gastric cancer progression and cisplatin resistance through interaction with miR-186–3p/MAP3K9 axis

Chemoresistance is a major therapeutic challenge in advanced gastric cancer (GC). N6-methyladenosine (m6A) RNA modification has been shown to play fundamental roles in cancer progression. However, the underlying mechanisms by which m6A modification of circRNAs contributes to GC and chemoresistance remain unknown. We found that hsa_circ_0030632 (circUGGT2) was a predominant m6A target of METTL14, and METTL14 knockdown (KD) reduced circUGGT2 m6A levels but increased its mRNA levels. The expression of circUGGT2 was markedly increased in cisplatin (DDP)-resistant GC cells. CircUGGT2 KD impaired cell growth, metastasis and DDP-resistance in vitro and in vivo, but circUGGT2 overexpression prompted these effects. Furthermore, circUGGT2 was validated to sponge miR-186–3p and upregulate MAP3K9 and could abolish METTL14-caused miR-186–3p upregulation and MAP3K9 downregulation in GC cells. circUGGT2 negatively correlated with miR-186–3p expression and harbored a poor prognosis in patients with GC. Our findings unveil that METTL14-dependent m6A modification of circUGGT2 inhibits GC progression and DDP resistance by regulating miR-186–3p/MAP3K9 axis.

The Potential Mechanisms Behind Adverse Effect of Coronavirus Disease-19 on Heart and Liver Damage: A Review.

Coronaviruses (CoVs) belong to the RNA viruses family. The viruses in this family are known to cause mild respiratory disease in humans. The origin of the novel SARS-COV2 virus that caused the coronavirus-19 disease (COVID-19) is the Wuhan city in China from where it disseminated to cause a global pandemic. Although lungs are the predominant target organ for Coronavirus Disease-19 (COVID-19), since its outbreak, the disease is known to affect heart, blood vessels, kidney, intestine, liver and brain. This review aimed to summarize the catastrophic impacts of Coronavirus disease-19 on heart and liver along with its mechanisms of pathogenesis. The information used in this review was obtained from relevant articles published on PubMed, Google Scholar, Google, WHO website, CDC and other sources. Key searching statements and phrases related to COVID-19 were used to retrieve information. Original research articles, review papers, research letters and case reports were used as a source of information. Besides causing severe lung injury, COVID-19 has also been reported to affect and cause dysfunction of many other organs. COVID-19 infection can affect people by downregulating membrane-bound active angiotensin-converting enzyme (ACE). People who have deficient ACE2 expression are more vulnerable to COVID-19 infection. The patients' pre-existing co-morbidities are major risk factors that predispose individuals to severe COVID-19. The disease severity and its broad spectrum phenotype is a result of combined direct and indirect pathogenic factors. Therefore, protocols that harmonize many therapeutic preferences should be the best alternatives to de-escalate the disease and obviate deaths caused as a result of multiple organ damage and dysfunction induced by the disease.

Age of Flexible Electronics: Emerging Trends in Soft Multifunctional Sensors.

With the commercialization of first-generation flexible mobiles and displays in the late 2010s, humanity has stepped into the age of flexible electronics. Inevitably, soft multifunctional sensors, as essential components of next-generation flexible electronics, have attracted tremendous research interest like never before. This review is dedicated to offering an overview of the latest emerging trends in soft multifunctional sensors and their accordant future research and development (R&D) directions for the coming decade. First, key characteristics and the predominant target stimuli for soft multifunctional sensors are highlighted. Second, important selection criteria for soft multifunctional sensors are introduced. Next, emerging materials/structures and trends for soft multifunctional sensors are identified. Specifically, the future R&D directions of these sensors are envisaged based on their emerging trends, namely i) decoupling of multiple stimuli, ii) data processing, iii) skin conformability, and iv) energy sources. Finally, the challenges and potential opportunities for these sensors in future are discussed, offering new insights into prospects in the fast-emerging technology.

Chromatin activity identifies differential gene regulation across human ancestries

BackgroundCurrent evidence suggests that cis-regulatory elements controlling gene expression may be the predominant target of natural selection in humans and other species. Detecting selection acting on these elements is critical to understanding evolution but remains challenging because we do not know which mutations will affect gene regulation.ResultsTo address this, we devise an approach to search for lineage-specific selection on three critical steps in transcriptional regulation: chromatin activity, transcription factor binding, and chromosomal looping. Applying this approach to lymphoblastoid cells from 831 individuals of either European or African descent, we find strong signals of differential chromatin activity linked to gene expression differences between ancestries in numerous contexts, but no evidence of functional differences in chromosomal looping. Moreover, we show that enhancers rather than promoters display the strongest signs of selection associated with sites of differential transcription factor binding.ConclusionsOverall, our study indicates that some cis-regulatory adaptation may be more easily detected at the level of chromatin than DNA sequence. This work provides a vast resource of genomic interaction data from diverse human populations and establishes a novel selection test that will benefit future study of regulatory evolution in humans and other species.

Parabens and their metabolite in a marine benthic-dominated food web from the Beibu gulf, South China Sea: Occurrence, trophic transfer and health risk assessment

Parabens are of particular concern due to their ubiquity in aquatic environments and endocrine-disrupting effects. However, information on their bioaccumulation and trophic magnification is limited. In the present study, we performed a comprehensive survey to investigate the occurrence, bioaccumulation and trophic magnification of parabens and their metabolite 4-hydroxybenzoic acid (4-HB) in a marine food web from the Beibu Gulf, South China Sea. Results showed that methylparaben (MeP) and 4-HB were the predominant target pollutants in marine organisms, with their concentrations being in the range of 0.18–13.77 and 13.48–222.24 ng/g wet weight, respectively. The bioaccumulation factors (BAFs) for target analytes were all lower than 5000, suggesting negligible bioaccumulation. However, the biota-sediment accumulation factors (BSAFs) for MeP and 4-HB were 4.51 and 3.21, respectively, which indicates significant bioaccumulation from the sediment. Furthermore, the estimated trophic magnification factor (TMF) was 2.88 for MeP, suggesting its biomagnification along the food web. In contrast, a lower TMF of 0.45 was found for 4-HB, suggesting trophic dilution along the food web. The hazard quotients (HQs) for parabens were far less than 1 in all organisms, suggesting low risks for humans through consuming marine organisms from the Beibu Gulf. This study provides substantial data on the fate and trophic transfer of parabens in a subtropical marine ecosystem.

The C-Terminal Region of HTRA1 Is the Predominant Target for Autoimmunity in HTRA1-Associated Membranous Nephropathy (MN)

The C-Terminal Region of HTRA1 Is the Predominant Target for Autoimmunity in HTRA1-Associated Membranous Nephropathy (MN)

Simulation and forecasting CTLs response effectualness against global dynamics of SARS-CoV-2/HIV coinfection

Quantifying the dynamical traits and harshness of SARS-CoV-2/HIV coinfection, a modified deterministic seven compartmental mathematical model is framed at cellular level encapsulating the interrelationships between epithelial cells (predominant target cells of COVID-19 infection), CD4+ T cells (target cells of HIV/AIDS infection), SARS-CoV-2 virions, HIV virions and HIV-specific CTL response. As a way to comprehend the kinetics of SARS-CoV-2/HIV coinfection and to provide prediction of model outcomes, the positivity, boundedness and existence conditions of the biologically feasible equilibrium points have been studied. The criteria of local stability and global stability of the coinfection system around the non-negative equilibrium points have been investigated and the analytical results are enhanced numerically. To measure the influence of the model parameters in SARS-CoV-2/HIV transmission dynamics, sensitivity analysis has been performed. Semi-relative sensitivity analysis demonstrates the maximum deviation of the concentration of infected epithelial cells due to changes in the model parameters and states that six parameters are most sensitive. The numerical simulation stipulates that the COVID-19 infection is likely to be died out from a HIV patient body by increasing the apoptosis of infected epithelial cells and that is possible through the proliferation of the CD4+ T cells count of an individual living with HIV via antiretroviral therapy (ART). Additionally, elevated concentration of CD4+ T cells in people living with HIV assists in heightening the CTLs response to combat COVID-19 and other opportunistic infections.

QingXiaoWuWei decoction alleviates methicillin-resistant Staphylococcus aureus-induced pneumonia in mice by regulating metabolic remodeling and macrophage gene expression network via the microbiota-short-chain fatty acids axis.

QingXiaoWuWei decoction (QXWWD) exerts a prominent therapeutic effect on the methicillin-resistant Staphylococcus aureus (MRSA)-induced pneumonia model in mice; however, its pharmacological mechanisms remain unclear. This study aimed to investigate the underlying pharmacological mechanisms of QXWWD in MRSA-induced pneumonia. In the present study, 62 compounds were identified using high-resolution mass spectrometry. Network analysis, leveraging mass spectrometry, pinpointed the infection-linked, immunity-associated, and inflammation-related pathways as predominant targets. QXWWD significantly alleviated MRSA-induced pneumonia in mice and decreased the levels of pro-inflammatory cytokines and chemokines. 16S ribosomal RNA (16S rRNA) sequencing revealed that QXWWD regulated gut microbiota composition in mice with MRSA-induced pneumonia, which correlated with the enrichment of certain short-chain fatty acids (SCFAs)-producing strains. Further analysis with targeted metabolomics confirmed that the acetic, propionic, and butyric acid levels in the mice's serum were elevated significantly after QXWWD treatment. The fecal microbiota transplantation experiment suggested that gut microbiota from QXWWD-treated mice and SCFAs treatment may alleviate MRSA-induced pneumonia. Additionally, the untargeted metabolomic analysis further demonstrated that metabolic remodeling is significantly regulated by the QXWWD, particularly by the enhancement of the citrate cycle. In the case of QXWWD treatment, global transcriptome profiling revealed that genes, such as NLRP12 and CYP1A1, associated with macrophage antibacterial and immune activity, were downregulated. The results revealed that QXWWD regulated metabolic remodeling and macrophage gene expression network via the microbiota-SCFAs axis and thus alleviated MRSA-induced pneumonia in mice.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA) colonizes the upper respiratory airways and is resistant to antibiotics. MRSA is a frequently acquired infection in hospital and community settings, including cases of MRSA-induced pneumonia. Multidrug-resistant Staphylococcus aureus and the limited efficacy of antibiotics necessitate alternative strategies for preventing or treating the infection. QingXiaoWuWei decoction (QXWWD) protects against both gut microbiota dysbiosis and MRSA-induced pneumonia. Furthermore, the QXWWD-regulated metabolic remodeling and macrophage gene expression network contribute to its protective effects through the microbiota-short-chain fatty acid axis. The results of this study suggest that QXWWD and its pharmacodynamic compounds might have the potential to prevent and treat pulmonary infections, especially those caused by multidrug-resistant organisms. Our study provides a theoretical basis for the future treatment of pulmonary infectious diseases by manipulating gut microbiota and their metabolites via traditional Chinese medicine.

The actions of methotrexate on endothelial cells are dependent on the shear stress-induced regulation of one carbon metabolism.

The disease-modifying anti-rheumatic drug methotrexate (MTX) is recognized to reduce cardiovascular risk in patients with systemic inflammatory diseases. However, the molecular basis for these cardioprotective effects remains incompletely understood. This study evaluated the actions of low-dose MTX on the vascular endothelium. Human endothelial cells (EC) were studied under in vitro conditions relevant to inflammatory arthritis. These included culture in a pro-inflammatory microenvironment and exposure to fluid shear stress (FSS) using a parallel plate model. Respectively treated cells were analyzed by RNA sequencing and quantitative real-time PCR for gene expression, by immunoblotting for protein expression, by phosphokinase activity arrays, by flow cytometry for cell cycle analyses and by mass spectrometry to assess folate metabolite levels. In static conditions, MTX was efficiently taken up by EC and caused cell cycle arrest concurrent with modulation of cell signaling pathways. These responses were reversed by folinic acid (FA), suggesting that OCM is a predominant target of MTX. Under FSS, MTX did not affect cell proliferation or pro-inflammatory gene expression. Exposure to FSS downregulated endothelial one carbon metabolism (OCM) as evidenced by decreased expression of key OCM genes and metabolites. We found that FSS significantly downregulated OCM and thereby rendered EC less susceptible to the effects of MTX treatment. The impact of shear stress on OCM suggested that MTX does not directly modulate endothelial function. The cardioprotective actions of MTX likely reflect direct actions on inflammatory cells and indirect benefit on the vascular endothelium.

Looking at the periphery—new hypothesis to look for new targets for Alzheimer’s disease therapy

Currently, the predominant targets for the treatment of Alzheimer’s disease (AD) are the main components of the two pathological structures: senile plaques (composed of amyloid beta peptide aggregates) or neurofibrillary tangles (constructed of tau protein polymers). However, the existence of adequate disease modifiers based on such targets is discussed. In this special issue, it has been suggested to search for new possible targets for AD therapy. This contribution tries to analyze non-neuronal tissues (periphery) to identify potential factors (target) involved in the development of AD.

An Epidemiological Analysis of Terrorist Attacks in the Nordic and Baltic Countries from 1970 through 2020.

Russia's annexation of Crimea in 2014, and the recent Russo-Ukrainian war that started in 2022, were triggers that radically changed the perception of security in the Nordic and Baltic countries. The on-going Russian hybrid war has resulted in a renewed global interest in the safety and security of many countries (eg, the Nordic-Baltic Eight). The prospective North Atlantic Treaty Organization (NATO) membership of Finland and Sweden may drastically change the regional military and political landscape.The objective of this study was to identify and characterize all documented terrorist attacks in this region as reported to the Global Terrorism Database (GTD) from 1970 through 2020. The GTD was searched using the internal database functions for all terrorism incidents in the Nordic-Baltic states: Denmark, Estonia, Finland, Iceland, Latvia, Lithuania, Norway, and Sweden.Temporal factors, location, target type, attack and weapon type, perpetrator type, number of casualties, and property value loss were collated. Results were exported into an Excel spreadsheet for analysis. There were 298 terrorism-related incidents from 1970 through 2020. Most attacks occurred in Sweden, followed by Norway and Finland. No entries were recorded for the Baltic states prior to their independency in 1991. The 298 incidents resulted in a total of 113 fatalities and 277 injuries.Facility/infrastructure attacks were the most frequently identified attack type (35.0%), followed by bombings and explosions (30.9%). Armed assaults were responsible for 80 fatalities and 105 injuries, followed by bombings/explosions with 15 fatalities and 72 injuries. The predominant target types were immigrants and refugee shelters (64/298 incidents). In only 33.6% of the incidents, perpetrators were known. Right-wing assailants represented the largest group, accounting for 27 incidents. From 1970 through 2020, there were 298 terrorist attacks in the Nordic-Baltic Eight. Sweden accounted for 50% of incidents.The profile of terrorist attacks was very diverse, as were the perpetrators and targets. Every country had its own incident characteristics. The surge of right-wing extremism must be closely monitored.

Cancer-biomarkers associated with sex hormone receptors and recent therapeutic advancements: a comprehensive review

Hormones and its regulation plays vital role in causing breast, prostate, ovarian and endometrial cancers collectively known as hormone-sensitive cancers. This review discusses the various functions of the sex hormones and the biological pathways involved in causing hormone-associated cancer under differential regulation. We have also attempted to explore the biomarkers associated with the cancers and the current therapeutic availability to treat such cancers. Among various sex hormones such as estrogen, progesterone and androgen, estrogen the female sex hormone and its receptor had a major contribution in causing cancer and hence are considered a predominant target in treating the associated cancers. Other hormones and receptors such a androgen, progesterone, and their respective receptors were also reported to have a significant correlation in causing cancers. Apart from these receptors certain enzymes that act as precursors or as promoters are also targeted for treatment strategies. The drugs commonly used belong to the selective drug classes such as selective estrogen receptor modulators and selective progesterone receptor modulators. In the case of androgen regulation androgen deprivation therapies are practiced. It is also suggested that the use of natural substances to treat cancer could prevent resistance and reduce side effects. Identification of significant targets and the discovery of many efficient drugs shall be possible in the future with better understanding of hormone regulation and its influence on cancer causative mechanisms.

The RNA cap methyltransferases RNMT and CMTR1 co-ordinate gene expression during neural differentiation.

Regulation of RNA cap formation has potent impacts on gene regulation, controlling which transcripts are expressed, processed and translated into protein. Recently, the RNA cap methyltransferases RNA guanine-7 methyltransferase (RNMT) and cap-specific mRNA (nucleoside-2'-O-)-methyltransferase 1 (CMTR1) have been found to be independently regulated during embryonic stem (ES) cell differentiation controlling the expression of overlapping and distinct protein families. During neural differentiation, RNMT is repressed and CMTR1 is up-regulated. RNMT promotes expression of the pluripotency-associated gene products; repression of the RNMT complex (RNMT-RAM) is required for repression of these RNAs and proteins during differentiation. The predominant RNA targets of CMTR1 encode the histones and ribosomal proteins (RPs). CMTR1 up-regulation is required to maintain the expression of histones and RPs during differentiation and to maintain DNA replication, RNA translation and cell proliferation. Thus the co-ordinate regulation of RNMT and CMTR1 is required for different aspects of ES cell differentiation. In this review, we discuss the mechanisms by which RNMT and CMTR1 are independently regulated during ES cell differentiation and explore how this influences the co-ordinated gene regulation required of emerging cell lineages.