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DNA N6-adenine methylation (6mA) has recently gained importance as an epigenetic modification in eukaryotes. Its function in lineages with high levels, such as early-diverging fungi (EDF), is of particular interest. Here, we investigated the biological significance and evolutionary implications of 6mA in EDF, which exhibit divergent evolutionary patterns in 6mA usage. The analysis of two Mucorales species displaying extreme 6mA usage reveals that species with high 6mA levels show symmetric methylation enriched in highly expressed genes. In contrast, species with low 6mA levels show mostly asymmetric 6mA. Interestingly, transcriptomic regulation throughout development and in response to environmental cues is associated with changes in the 6mA landscape. Furthermore, we identify an EDF-specific methyltransferase, likely originated from endosymbiotic bacteria, as responsible for asymmetric methylation, while an MTA-70 methylation complex performs symmetric methylation. The distinct phenotypes observed in the corresponding mutants reinforced the critical role of both types of 6mA in EDF.

The literature has yet to review the differential effects of Natural Environment Teaching (NET) and Discrete Trial Teaching (DTT) on adaptive skills. A sample of 142 children diagnosed with ASD between the ages of 16 and 35 months received either DTT, NET, or both interventions (NET+ DTT). The Bayley Scales of Infant and Toddler Development (BSID) Adaptive Subscale and the Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP) Barriers Assessment were used as baseline and posttest measures. Children who received NET and NET+DTT conditions showed significant improvements compared to the DTT condition indicating that the addition of NET leads to increased adaptive skills and decreased barrier behaviors in participants. DTT may also play a necessary foundational role for children with more significant delays. These results provide support for the use of a combination of teaching strategies in community-based early intervention and refine protocols for teaching adaptive skills to toddlers with ASD.

Abstract DNA N6-adenine methylation (6mA) has recently gained importance as an epigenetic modification in eukaryotes. Its function in lineages with high levels, such as early-diverging fungi (EDF), is of particular interest. Here, we investigated the biological significance and evolutionary implications of 6mA in EDF, which exhibit divergent evolutionary patterns in 6mA usage. The analysis of two Mucorales species displaying extreme 6mA usage reveals that species with high 6mA levels show symmetric methylation enriched in highly expressed genes. In contrast, species with low 6mA levels show mostly asymmetric 6mA. Interestingly, transcriptomic regulation throughout development and in response to environmental cues is associated with changes in the 6mA landscape. Furthermore, we identify an EDF-specific methyltransferase, likely originated from endosymbiotic bacteria, as responsible for asymmetric methylation, while an MTA-70 methylation complex performs symmetric methylation. The distinct phenotypes observed in the corresponding mutants reinforced the critical role of both types of 6mA in EDF.

(Series Information) European Papers - A Journal on Law and Integration, 2024 9(1), 179-208 | Article | (Table of Contents) I. Introduction: structuralising crisis. – II. “Crisification”: the incremental normalisation of exceptions. – III. The 2015 ”Refugee Crisis”: the suspension of governance (as a form of governance) – III.1. Relocation (and Dublin prorogation) – III.2. The Hotspot Fiasco – IV. The New Pact Reforms: generalising derogations – IV.1. Screening process: hotspots extended – IV.2. Border Procedure: hotspots normalised – V. Conclusion: reversing the rule, decreasing legality. | (Abstract) This Article problematises the role of crisis in the governance of asylum in Europe. It unveils its nature, predominance, and implications as a structural component of EU law and policy in this domain. The main point I intend to convey is that crisis, in and by itself, constitutes a system of governance producing very problematic effects. The association between (unwanted) migration and refugee flows with crisis in the European context has allowed for the exceptionalisation of rights and legal safeguards, with the pre-emption of unauthorised arrivals becoming the main concern. The danger, instability, and abnormality connected with crisis pervades law and policy, justifying mechanisms that contravene minimal rule of law standards, including due process guarantees and effective judicial protection. The incremental normalisation of exceptions has led to a position where the suspension of (rule of law-based) governance has become a form of governance. The prorogation of “normal” (rule of law-compliant) arrangements has given way to “exceptional” means of managing asylum, starting with the 2015 “refugee crisis” and the relocation-plus-hotspots scheme, which have now been streamlined as part of the New Pact on Migration and Asylum reforms. The resulting generalisation of derogations, the proliferation of legal fictions and rights negations that the envisaged amendments involve, is progressively normalising a situation of non-access to international protection in the EU, with deleterious consequences not only for asylum seekers, but for the integrity of the EU legal order and fundamental rights at large.

Gregarines are a large and diverse subgroup of Apicomplexa, a lineage of obligate animal symbionts including pathogens such as Plasmodium, the malaria parasite. Unlike Plasmodium, however, gregarines are poorly studied, despite the fact that as early-branching apicomplexans they are crucial to our understanding of the origin and evolution of all apicomplexans and their parasitic lifestyle. Exemplifying this, the earliest branch of gregarines, the archigregarines, are particularly poorly studied: around 80 species have been described from marine invertebrates, but almost all of them were assigned to a single genus, Selenidium. Most are known only from light micrographs and largely unresolved rDNA phylogenies, where they exhibit a great deal of sequence variation, and fall into four subclades. To resolve the relationships within archigregarines, we sequenced 12 single-cell transcriptomes from species representing all four known subclades, as well as one blastogregarine (which frequently branch with Selenidium). A 190-gene phylogenomic tree confirmed four maximally supported individual clades of archigregarines and blastogregarines. These clades are discrete and distantly related, and also correlate with host identity. We propose the establishment of three novel genera of archigregarines to reflect their phylogenetic diversity and host range, and nine novel species isolated from a range of marine invertebrates.

Abstract Background Relapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined. Methods The REFRACT trial is an investigator-initiated, UK National Cancer Research Institute, open-label, multi-centre, randomised phase II platform trial aimed at accelerating clinical development of novel therapies by addressing evidence gaps. The first of the three sequential novel therapy arms is epcoritamab plus lenalidomide, to be compared with investigator choice standard therapy (ICT). Patients aged 18 years or older with biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma and assessable disease by PET-CT are eligible. The primary outcome is complete metabolic response by PET-CT at 24 weeks using the Deauville 5-point scale and Lugano 2014 criteria. Secondary outcomes include overall metabolic response, progression-free survival, overall survival, duration of response, and quality of life assessed by EQ-5D-5 L and FACT-Lym. The trial employs an innovative Bayesian design with a target sample size of 284 patients: 95 in the ICT arm and 189 in the novel therapy arms. Discussion Whilst there are many promising novel drugs in early clinical development for rrFL, understanding the relative efficacy and safety of these agents, and their place in modern treatment pathways, is limited by a lack of randomised trials and dearth of published outcomes for standard regimens to act as historic controls. Therefore, the aim of REFRACT is to provide an efficient platform to evaluate novel agents against standard therapies for rrFL. The adaptive Bayesian power prior methodology design will minimise patient numbers and accelerate trial delivery. Trial registration ClinicalTrials.gov: NCT05848765; 08-May-2023. EudraCT 2022-000677-75; 10-Feb-2022.

Abstract Mucorales are basal fungi that opportunistically cause a potentially fatal infection known as mucormycosis (black fungus disease), which poses a significant threat to human health due to its high mortality rate and its recent association with SARS-CoV-2 infections. On the other hand, histone methylation is a regulatory mechanism with pleiotropic effects, including the virulence of several pathogenic fungi. However, the role of epigenetic changes at the histone level never has been studied in Mucorales. Here, we dissected the functional role of Set1, a histone methyltransferase that catalyzes the methylation of H3K4, which is associated with the activation of gene transcription and virulence. A comparative analysis of the Mucor lusitanicus genome (previously known as Mucor circinelloides f. lusitanicus) identified only one homolog of Set1 from Candida albicans and Saccharomyces cerevisiae that contains the typical SET domain. Knockout strains in the gene set1 lacked H3K4 monomethylation, dimethylation, and trimethylation enzymatic activities. These strains also showed a significant reduction in vegetative growth and sporulation. Additionally, set1 null strains were more sensitive to SDS, EMS, and UV light, indicating severe impairment in the repair process of the cell wall and DNA lesions and a correlation between Set1 and these processes. During pathogen-host interactions, strains lacking the set1 gene exhibited shortened polar growth within the phagosome and attenuated virulence both in vitro and in vivo. Our findings suggest that the histone methyltransferase Set1 coordinates several cell processes related to the pathogenesis of M. lusitanicus and may be an important target for future therapeutic strategies against mucormycosis.

Abstract Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical success has been limited by on-target, off-tumor activity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist (ɑ4-1BB-LAIR), which consists of a ɑ4-1BB antibody fused to the collagen-binding protein LAIR. While combination treatment with an antitumor antibody (TA99) shows only modest efficacy, simultaneous depletion of CD4+ T cells boosts cure rates to over 90% of mice. Mechanistically, this synergy depends on ɑCD4 eliminating tumor draining lymph node regulatory T cells, resulting in priming and activation of CD8+ T cells which then infiltrate the tumor microenvironment. The cytotoxic program of these newly primed CD8+ T cells is then supported by the combined effect of TA99 and ɑ4-1BB-LAIR. The combination of TA99 and ɑ4-1BB-LAIR with a clinically approved ɑCTLA-4 antibody known for enhancing T cell priming results in equivalent cure rates, which validates the mechanistic principle, while the addition of ɑCTLA-4 also generates robust immunological memory against secondary tumor rechallenge. Thus, our study establishes the proof of principle for a clinically translatable cancer immunotherapy.

Background and aims: The false-root knot nematode (Nacobbus spp.) comprises polyphagous species, with pepper (Capsicum annuum) being one of the most affected crops. Due to the lack of resistant pepper genotypes, we compared the responses of different commercial cultivars to identify possible plant defence mechanisms against N. celatus. M&M: Nematodes from Río Cuarto (Córdoba Province) and Lisandro Olmos (Buenos Aires Province) were inoculated on pepper cultivars: California Wonder (control), Fyuco INTA, Yatasto, and Fenomeno RZ. Plants were grown under a greenhouse and galls were analysed by histopathological techniques. Results: The roots of the commercial cultivars showed the typical morpho-anatomical alterations induced by N. celatus: gall formation, hyperplasia reactions, development of syncytia in the central cylinder and disorganisation of vascular tissues. Syncytial cells in contact with females of nematodes from Lisandro Olmos showed a defence reaction by Fyuco INTA, whereas feeding sites in Fenomeno RZ did not denote high metabolic activity in nematodes of both origins. Conclusions: The different responses observed between populations and/or hosts demonstrate the importance of considering nematodes from different geographical origins when testing plant material for tolerance and/or resistance to N. celatus. Studies of this nature are necessary since they facilitate a more in-depth understanding of the parasite-plant interaction.

This paper introduces the design and analysis of novel planar mobile robot operated by a single actuator. Distinct from conventional multi-actuator designs, this robot achieves both walking and turning motions through a single actuator mechanism, thereby simplifying construction and control. The design focuses on mechanical and electronic minimalism and efficiency. We formulate the governing dynamic equations using Euler-Lagrange formalism by which we optimize the robot’s design. The study concludes with a series of experiments that demonstrate the robot’s translation and rotation.

Abstract Background Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM. Methods ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events. Discussion Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development. Trial registration ISRCTN: 11460478. ClinicalTrials.Gov: NCT05629702.

Abstract Little is known about changes in the personal living conditions of long-term blood cancer survivors in Germany. To gather information about social relationships, work life, overall well-being, and religion, we performed a questionnaire-based retrospective study on 1551 survivors who had been on follow-up for ≥ 3 years (median, 9 years). Most survivors reported that marital status and relationships with relatives and friends remained constant before and after blood cancer. Vocational activities were temporarily impaired for 47.5%, with a median time of 11 months to return to work. More than a third of the patients (35.6%) discontinued work permanently, with disability and retirement pension rates of 7.9% and 38.1%, respectively, at the time of the survey. Financial problems due to reduced income were reported by 26.2%, in particular after relapse or allogeneic transplantation. Patient reports addressing their quality of life showed large variations. It was best in acute leukemia survivors without a history of allogeneic transplantation and worst in patients with myeloproliferative disorders. Religion tended to become more important after blood cancer. In conclusion, vocational impairment and financial problems are frequent among German blood cancer survivors. Efforts should be made at an early stage to reestablish the patients’ ability to work.

Background: The COVID-19 pandemic presented families with novel challenges. Mothers were at particular risk for parental burnout, however, there is limited research on self-care behaviors to ameliorate it explicitly for mothers of young children (aged 3 and younger). Moreover, there has been little in-depth analysis on barriers to self-care and how mothers realistically implement it in their lives. Methods: In this article, we explore influences on and barriers to self-care in mothers of young children during the COVID-19 pandemic. Using a content analysis approach, we used verbal testimony from mothers to create a coding framework and applied that framework to the sample (N?=?717). Results: Qualitative analyses revealed that beauty and personal care were the most utilized self-care acts. Two major barriers were lack of childcare and limited time. Social support was the most frequently reported asset to engaging in self-care. Participants noted that the pandemic significantly restricted their access to activities and social support. Conclusions: These findings emphasize the need to encourage mothers to prioritize self-care and incorporate their support systems to facilitate engagement. These results can inform programming to increase self-care behaviors in mothers, particularly during times of high environmental stressors. Future research should examine how resources can be allocated toward barriers of self-care to reduce burnout and improve quality of life.

In instructional settings, evolution and natural selection are challenging concepts to teach, due to the fact that these topics are difficult to observe in the laboratory or lecture hall. In the past few years, Avida-ED has emerged as an innovative tool for teaching evolutionary principles. It allows students to directly observe effects of evolution by changing different variables, such as environmental conditions and genetic sequences. In our study, we used pretest and posttest questionnaires to investigate the use of Avida-ED in undergraduate coursework. We showed that students demonstrated similar improvement in evolutionary understanding irrespective of major, undergraduate level, sex, or final end-of-course grade. These results reinforce the idea that Avida-ED can facilitate learning of evolution in all student populations.

Background: Persons living with disabilities have difficulty finding work, are discriminated against, and have high rates of unemployment. They face many barriers, including stereotyped perceptions that prevent employers from hiring people with disabilities. Objective: To promote equality in the employment market and to lower barriers, we at Gal College in cooperation with the School of Social Work at Tel-Aviv University developed an innovative multidimensional integrative program. Methods: The program offers a beneficial learning experience that integrates professional studies with a personal rehabilitation process as the students themselves cope and live with their disability. The program graduates then become rehabilitators who serve as employment placement workers and rehabilitation facilitators for others coping with disability. All the students completed at least 12 years of school, were between the ages of 25 and 55, and were out of work for a long period of time. Findings: The quantitative results reveal a high placement rate for program graduates. Over the years, this rate has increased from 79% to 100%, testifying to the program's success.