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Many biomolecular condensates are thought to form through phase separation driven by weak and multivalent, non-stoichiometric interactions between intrinsically disordered protein regions (IDRs). IDRs are abundant in the transcription-related proteome. In vitro, different transcription-related IDRs coalesce into the same droplets, providing support for this IDR-centric paradigm of protein enrichment in transcription condensates in the cell nucleus. But our experiments show that IDRs are not sufficient to account for the degree of enrichment observed for full-length proteins in endogenous transcription condensates. Instead, we find a pattern in which IDRs facilitate engagement of structured interaction domains with a binding substrate. Instead, we find a pattern in which IDRs facilitate engagement of structured interaction domains with a binding substrate. Our results indicate that the role of IDRs in transcription condensates requires further investigation with tools that assess their mode of action in situ. Understanding the role of different protein domains and their interplay will also be important for interpreting biotechnological assays that utilize parts of condensate forming proteins.

The distributed architecture of the SKA Regional Centre Network (SRCNet) aims to provide scientific communities worldwide with efficient computational and storage resources to exploit the massive data volumes produced by the SKA Observatory (SKAO). Given the amount of SKAO data, traditional data management paradigms - where data is transferred to computational resources- are no longer feasible. Instead, computational workflows must increasingly be relocated closer to data storage locations, emphasizing efficient data access strategies and avoiding unnecessary duplication or redundancy. In this context, we present PrepareData, a modular and extensible data delivery service developed within SRCNet prototyping activities. Our proposal for this service addresses the critical challenge of redundant data transfers and duplication at both node and user levels by enabling seamless delivery of requested datasets from local Rucio Storage Elements (RSEs) directly into users' working environments. PrepareData operates as a local service within each SRCNet node and it is integrated into a broader ecosystem of federated services. Specifically, we designed and evaluated two distinct yet complementary implementations to avoid unnecessary data duplication and to enable a dynamic data bridge between the RSEs and the user storage areas, through: (1) a filesystem-based solution leveraging CephFS, which uses shared filesystem mount points and bind mounts to ensure consistent and immediate data availability of the data across computational nodes, and (2) a Kubernetes model using Persistent Volumes and Persistent Volume Claims, dynamically injecting data into a user's areas. To tackle this work we detail the architectural design and development, the technical implementation, the integration of both solutions with science enabling tools, such as JupyterHub, CARTA or virtually any application, and finally we provide a performance evaluation. This contribution provides a scalable and sustainable blueprint for data delivery in federated scientific infrastructures, supporting the broader goals of green computing and efficient resource utilisation. Modern scientific projects such as the Square Kilometre Array Observatory (SKAO) produce extremely large amounts of data — far more than traditional research systems have handled before. Scientists around the world need efficient ways to access and work with these vast datasets without unnecessary delays or wasteful copying of information. In the SKA Regional Centre Network (SRCNet), data are stored in distributed storage systems. However, these storage systems are not directly visible to the software tools scientists use for analysis, such as interactive notebooks, visualisation platforms, or specialised processing services. To make the data usable, it must be moved or linked into the scientists’ working environments. Our research focuses on a service called PrepareData, designed to manage this delivery process in a way that is both fast and resource-efficient. We describe and test different technical methods for exposing data to users, including techniques that avoid repeatedly copying large files. We ran experiments to measure how fast and scalable each method is under realistic conditions. The results show that by linking data instead of copying it, PrepareData can reduce delays and lower the burden on storage systems. This leads to better performance for scientists and less wasted computing and storage resources. These improvements are especially important for major international science projects, where efficient data delivery can accelerate research and reduce environmental impact.

Mental health challenges among Zambian youths are an increasing public health concern. Recent studies estimate that ~20% of the Zambian population is affected by mental health disorders, with adolescents showing a sharp rise in reported cases, from 0.7% in 2021 to 1.54% in 2023 (2 914 to 6 825 cases). Despite this growing burden, only 0.1% of government health expenditure is allocated to mental health services, and there is currently no youth-specific policy framework in place. With young people aged 15 - 35 years comprising 36.7% of Zambia's total population, the lack of investment and targeted interventions underscores the urgency of addressing barriers and strengthening facilitators to improve youth access to mental healthcare. To explore the barriers and facilitators that influence youths' access to mental health services in Zambia, with a focus on understanding the underlying factors that impact service utilisation. A systematic literature review was conducted, drawing on studies published between 2005 and 2025 from databases including Google Scholar, PubMed and ResearchGate. A total of 20 articles were identified and reviewed, with inclusion based on relevance to youth mental health service accessibility in Zambia. The review did not involve any primary participants; instead, the sample consisted of peer- reviewed studies, national reports and institutional documents. Data were analysed manually using a qualitative thematic approach, where key patterns, recurring themes and emerging categories of barriers and facilitators were identified and synthesised. This approach allowed for an in-depth understanding of the cultural, social and systemic factors that influence youths' access to mental health services. The findings highlight several barriers to accessing mental health services, including stigma, cultural beliefs, inadequate infrastructure and resources, low mental health awareness and gendered norms. The majority of the reviewed literature focused on urban and peri-urban settings, with fewer studies addressing rural contexts. In urban and peri-urban settings, common themes included stigma, limited infrastructure concentrated in tertiary hospitals and gendered expectations that discouraged male youths from seeking care. In rural contexts, the analysis revealed geographical inaccessibility, severe shortages of trained personnel and reliance on traditional or informal sources of support. Across both settings, low awareness of mental health conditions consistently emerged as a barrier. Conversely, facilitators such as school-based mental health programmes, community outreach initiatives, peer support groups and mobile-based interventions were identified as effective strategies to enhance accessibility for youths. Access to mental health services for Zambian youths is a multifaceted web of social, cultural and systemic factors. Addressing these challenges requires a comprehensive approach. The article concludes with recommendations aimed at improving youth-friendly mental health service delivery and access.

The last step in the biosynthesis of the lipoyl cofactor (LipCo) is the addition of two sulfur atoms at C6 and C8 of an n -octanoyl chain attached in an amide linkage to a target lysyl residue of a lipoyl carrier protein. The enzyme that catalyzes this reaction, lipoyl synthase (LipA in bacteria, and LIAS in humans), is a member of the radical S -adenosylmethionine (SAM) superfamily. As such, it requires a [4Fe-4S] cluster cofactor to cleave SAM reductively to generate two 5'-deoxyadenosyl 5'-radicals (5'-dA•) that abstract the C6 and C8 hydrogen atoms (H•) of the substrate in two distinct steps. LipAs also contain a second [4Fe-4S] cluster, termed the auxiliary cluster, degraded during turnover as the source of the attached sulfur atoms. The auxiliary cluster is ligated by three cysteines in a CX 4 CX 5 C motif and one serine residue (Ser308 in Escherichia coli ) in a highly conserved R 306 SS 308 Y motif in the C-terminal region of the protein. Here, we show that Arg306 and Ser308 are absolutely required for LipCo formation. Substitution of Arg306 with Lys results in a protein that is essentially inactive due to poor substrate binding and positioning in the active site. Multiple different substitutions of Ser308 were engineered. Most notable were the S308C and S308A variants, which gave greatly diminished LipCo formation. However, the S308C variant resulted in greater production of the 6-mercaptooctanoyl peptide, an intermediate in the reaction, and the formation of a desaturated product, determined to be a 6-octenoyl group attached to the peptide substrate. Furthermore, the 3Fe cluster formed during cannibalization of the auxiliary cluster during C6 sulfur substitution in the wild-type reaction is not observed with the S308C variant. Instead, the auxiliary cluster remains tetranuclear and forms a monothiolated cross-linked species with a high-spin, S = 7/2, configuration that decays to the 6-octenoyl-containing product. Other amino acids in the RSSY motif were not essential for catalysis.

This article offers an original theoretical basis for the claim that public engagement and bioethics are natural allies. It draws on Walker's expressive-collaborative model, which conceptualises morality as a social reality in which differently situated individuals continuously negotiate moral understandings and shared responsibilities to sustain social equilibrium. By highlighting the collective, dialogic, and interpretative nature of moral reasoning-and the epistemic partiality of all actors, including experts-it underscores the necessity of intersubjective processes for achieving legitimate and inclusive governance in bioethics. Deliberative forms of engagement materialise this approach by fostering moral knowledge co-production among individuals with unequally distributed authority over moral claims, thereby helping mitigate epistemic power imbalances between laypeople and experts. Realising this democratic ideal, however, requires rethinking engagement practices that are often expert-driven and work in silos (i.e., engaging citizens and experts separately). This limits the potential for mutual learning and the reconfiguration of moral knowledge to reflect the societal values, needs, and concerns. Instead, engagement practices should stress the interdependence and complementarity of laypeople and experts in solving complex ethical issues.

Despite scientific evidence on the environmental causes of obesity, policies that target these causes frequently face public opposition. This study investigates the mental model that the public hold about obesity, including perceptions of the causes, consequences and responsibility for obesity, alongside support for different preventive policies. N = 2400 members of the public undertook a cross-sectional online survey across 3 English-speaking countries with high obesity rates: Ireland, the UK and the US. We benchmarked public perceptions against N = 51 experts. We found differences between countries and larger differences between the public and expert samples. The public assigned considerable blame and responsibility to individuals, while the expert sample focused more on societal and environmental causes. Although the public and expert samples concurred on the seriousness of the problem, the latter endorsed more radical policies, such as taxes and restrictions. Public health communications often focus on highlighting obesity as a public health problem, but our findings suggest that this message has been received. Instead, more work may be needed to challenge public beliefs about the causes of, and responsibility for, the obesity epidemic.

Identifying DNA replication origins in human and other metazoan genomes has been challenging, as highlighted by the fact that various methods for mapping them have produced conflicting results. A popular method, short nascent strand sequencing (SNS-seq), enriches newly replicated short single-stranded DNA by size selection and λ -exonuclease ( λ -exo) digestion of parental DNA. Surprisingly, SNS-seq has never been validated in Saccharomyces cerevisiae where origins have been well characterized genome-wide. We improved the SNS-seq protocol through biochemical optimization and benchmarked its origin-mapping sensitivity and precision with traditional SNS-seq in asynchronous populations of S. cerevisiae . The improved SNS-seq protocol significantly enhanced the enrichment of origin-derived DNA. Strikingly, the traditional SNS-seq failed to detect known origins and instead enriched non-origin DNA, likely arising from RNA:DNA hybrids. These findings have important implications for the interpretation of previously published datasets that rely on λ -exo for origin mapping. Overall, our biochemical and genomic analyses help unravel the mystery of the inconsistencies between SNS-seq and other techniques used to map DNA replication origins genome-wide.

Spinal cord injury (SCI) disrupts long-distance communication between the brain and spinal circuits, resulting in persistent motor, sensory and autonomic dysfunction 1 . These deficits arise from the limited regenerative capacity of adult central nervous system (CNS) neurons and the presence of a growth-inhibitory extracellular environment. Among pathways that control voluntary movement, failure of corticospinal tract (CST) regeneration is a major contributor to impaired motor function. Strategies to promote regeneration have focused on enhancing the intrinsic growth capacity of injured neurons, such as through activation of the mTOR pathway via phosphatase and tensin homolog (PTEN) suppression, as well as reducing extrinsic inhibition through enzymatic digestion of chondroitin sulfate proteoglycans (CSPGs) using chondroitinase ABC (chABC). Because these mechanisms act through distinct but complementary processes, we investigated their combination as a strategy to improve regeneration. Adeno-associated viral (AAV) vectors are widely used to enhance intrinsic growth pathways and represent a clinically relevant platform for gene delivery. In contrast, CSPG digestion has primarily been achieved using lentiviral or focal delivery approaches. We therefore examined whether reducing extrinsic inhibition could be implemented using AAV2-mediated chABC delivery, alone and in combination with AAV2-retro-mediated PTEN knockdown, following cervical SCI. AAV2-mediated delivery of chABC produced robust and persistent CSPG digestion that extended beyond the injection site, and this spatial extent was influenced by viral dose and expression magnitude. Despite effective CSPG degradation, AAV2-chABC treatment did not improve functional outcomes relative to controls and did not enhance the effects of intrinsic growth activation via PTEN knockdown. Instead, AAV2-chABC treatment, alone or in combination with AAV2-retro-mediated PTEN knockdown, was associated with impaired motor performance in behavioral assays. These findings indicate that the extent and persistence of CSPG degradation critically shape functional outcomes after SCI and that simultaneous enhancement of intrinsic growth capacity and extracellular permissiveness does not necessarily translate into improved functional recovery. Together, these results underscore the importance of carefully controlling transgene expression levels and duration in AAV-based gene therapies, where suboptimal delivery parameters may offset the benefits of otherwise promising targets.

Catalyst turnover number is traditionally measured at the macroscopic scale, yielding a single numerical value under specific reaction conditions. This bulk-averaged approach assumes uniform catalyst longevity, masking intrinsic heterogeneity within a sample and limiting meaningful comparisons across different systems. Here, we present a novel method to simultaneously quantify the number of active sites and total catalytic charge of individual platinum nanoparticles during electrochemical hydrogen evolution at high current densities (>0.4 A/cm2). This enables direct calculation of single-particle turnover numbers, one at a time, which reveals orders of magnitude of variation among monodisperse particles. We further show that the observed turnover number heterogeneity cannot be primarily attributed to stochastic particle-size variation within the monodisperse population, but instead is governed by applied potential and active-site connectivity. This work redefines our understanding of catalytic turnover number, establishing a framework for assessing catalyst longevity distribution at the single-particle level. Understanding the origins of turnover number heterogeneity and the underlying molecular nuances within electrocatalysts can inform strategies to enhance durability and optimize catalytic performance.

Eating disorders are often perceived to mainly affect young women, however previous research shows that they can both appear and persist in older populations. Research on eating disorders in older people is scarce, and there are no treatment guidelines or specialized diagnostic criteria, meaning that disordered eating in older adults is often misattributed to dementia, somatic illness, or the ageing process itself. This increases the risk of incorrect diagnosis and treatment, and hinders person-centred care. In order to start bridging this knowledge gap, the present study aimed to describe nursing home staff's experiences and reflections on disordered eating among the residents. The study adopted a qualitative approach and a descriptive design. A total of 26 participants (registered nurses, licensed practical nurses and care assistants) were recruited from three nursing homes in mid-Sweden. Four focus group interviews were conducted, using a fictional patient case - a vignette - to help discussion. The interviews were audio recorded, transcribed, and analysed using qualitative content analysis inspired by Graneheim and Lundman. Three themes were identified during the analysis. The theme It's not disordered eating behavior, it's dementia or ageing - or is it? referred to staff's initial attribution of all problematic eating behaviors to dementia or other age-related illnesses. The theme Lack of knowledge, lack of time, lack of resources - We don't know, and no one else does, either contained reflections on the lack of education and resources that was experienced in all professions. The theme Navigating conflicts of interest related to problematic eating behaviors - a rocky path included perceptions of conflicts and ethical dilemmas related to food and eating. Staff in nursing homes do not have sufficient training and resources to identify and diagnose residents with disordered eating behaviors, which is a barrier to safe and person-centred care. Not much is known about eating disorders (EDs) in older people, even though EDs affect all age groups. In this study, we carried out four focus group interviews with staff at three nursing homes in Sweden, and asked them to discuss and reflect on their experiences of disordered eating behaviors among the older people they work with. In the results, we found that the staff described disordered eating among the older people, but they often did not realize that the behaviors may be because of an ED. Instead, the staff thought that they might be caused by dementia, or by other illnesses related to the ageing process. The results also showed that nursing home staff lacked education and resources to deal with EDs among the residents, and that they didn’t know where to turn for help. They also described conflicts and ethical dilemmas around food and eating. It is important to improve nursing staff’s knowledge about EDs in older people, and to make sure there is access to suitable resources and specialized care.

Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening opportunistic infection. Recent studies have demonstrated a poor prognosis and higher mortality rate in non-human immunodeficiency virus (HIV) patients, with associated risk factors including cytomegalovirus (CMV) co-infection. We aimed to investigate the outcomes of concomitant PJP and CMV infection in non-HIV mechanically ventilated critically ill patients. We retrospectively enrolled adult patients admitted to an intensive care unit (ICU) and diagnosed with PJP infection from January 2017 to December 2022. Data were retrieved from the Chang Gung Research Database, including clinical manifestations, comorbidities and mortality. A total of 132 adult patients without HIV infection received mechanical ventilation in the ICU, underwent bronchoalveolar lavage and diagnosed with PJP were enrolled, of whom 26 patients had concomitant CMV infection and 106 did not. The PJP and concomitant CMV infection group had a significantly lower PaO2/FiO2 ratio (73.5 vs. 95.6, p = 0.04) and higher procalcitonin level (2.2 ng/ml vs. 0.4 ng/ml, p = 0.004). While CMV co-infection was associated with higher ICU mortality in the univariate analysis (33.3% vs. 11.1%, p = 0.002), multivariate analysis revealed that systemic CMV co-infection was not an independent predictor of mortality. Instead, the extended model demonstrated that mortality was significantly associated with acute respiratory distress syndrome (ARDS) (HR 4.281, 95% CI:1.178-15.565, p = 0.027) and the duration of PJP treatment (HR: 0.892, 95% CI: 0.803-0.990, p = 0.006). Concomitant CMV infection was about one-fifth in the non-HIV critically ill patients with PJP infection but does not independently increase mortality risk. Clinical management should prioritize early, sustained anti-pneumocystis therapy and lung-protective strategies for ARDS.

In medical ultrasound imaging, breaking the diffraction limit to achieve super-resolution imaging has long been a research focus. Acoustical structured illumination (ASI) technology projects a pre-defined multi-focus acoustic field to shift high-frequency information into the system's passband, demonstrating the potential for resolution enhancement. However, the reconstruction quality of ASI heavily relies on the precise prior knowledge of the illumination field. In practical clinical applications, especially in heterogeneous tissues, the acoustic velocity inhomogeneity of human tissues can lead to severe wavefront distortion and phase aberrations, disrupting the intended illumination pattern and causing traditional ASI reconstruction to fail with serious image artifacts. To address these challenges of ASI in heterogeneous media, this study proposes a multi-focus blind acoustical structured illumination (B-ASI) imaging method. This approach no longer depends on the precise prior acoustic field information. Instead, it utilizes the statistical characteristics of the illumination patterns and combines them with an iterative optimization framework to blindly compute super-resolved images under conditions of unknown field distortion. Simulation and phantom experiments show that under heterogeneous medium conditions, mismatch between the decoding acoustic field and the actual acoustic field leads to decoding errors in ASI. In contrast to the failure of traditional ASI methods, B-ASI effectively leverages the structural characteristics still present in the actual acoustic field to circumvent decoding failures caused by aberrations, thereby successfully resolving closely spaced point targets. This study provides a practical and effective solution for high-resolution ultrasonic structured acoustic illumination imaging in complex imaging media environments.

Oral isotretinoin is an indispensable treatment for patients with resistant and severe acne vulgaris, both in South Africa (SA) and globally. While routine laboratory monitoring is often deemed unnecessary for young, healthy patients, it remains unclear whether this applies in the SA context. To assess the need for routine blood monitoring for acne vulgaris patients on isotretinoin treatment at Tygerberg Hospital, SA. Specifically, we wanted primarily to determine the prevalence of patients with acne vulgaris whose oral isotretinoin treatment was altered owing to blood result abnormalities, and secondarily, to determine the prevalence of adverse events and liver function and lipid profile abnormalities associated with isotretinoin. This was a retrospective cohort study of hospital records from patients with acne vulgaris treated with oral isotretinoin at the dermatology clinic at Tygerberg Hospital between 1 January 2020 and 31 December 2023. There were 89 eligible records extracted from the Tygerberg Hospital Enterprise Content Management system. Baseline and 6-week follow-up laboratory data, including liver function tests and lipid profile, were extracted retrospectively from the National Health Laboratory Service. The sample comprised 89 patient hospital records, 62% male and 38% female. Of the total, 53% were aged between 12 and 20 years. Blood result abnormalities led to alterations in treatment regimens for 2/89 (2.2%) patients: one patient required treatment termination, while another continued on low-dose isotretinoin instead of the planned dose increase. Two patients (2.2%) developed increased aspartate aminotransferase levels and five (5.6%) developed new alanine aminotransferase increases above the upper limit of the normal range. Elevated triglyceride levels occurred in two patients (2.2%), and elevated cholesterol levels in nine (10.1%). Adverse events resulting in the premature termination of treatment with isotretinoin included one case of severe chest pain, one patient with pseudotumour cerebri and one patient who developed exuberant granulation tissue. This single-centre retrospective review highlights the scarcity of blood result abnormalities due to isotretinoin in patients with acne vulgaris. There were only two patients (2.2%) who had their management altered owing to blood result abnormalities, and both had chronic conditions. This may suggest that routine monitoring is indicated in patients with comorbidities, but not in otherwise healthy young patients with acne. However, larger prospective studies are needed in SA before such conclusions can be drawn.

Periods of elevated ambient temperature challenge the body's ability to maintain internal homeostasis, and heat stress poses particular risks during pregnancy. Epidemiological studies associate gestational heat exposure with higher rates of congenital anomalies such as hypospadias, yet the direct link between gestational heat exposure and reproductive anomalies remains unknown. In this study, we examined the effects of intermittent heat exposure on reproductive development in male mouse offspring. Pregnant dams either remained at constant temperature of 22°C (control) or were exposed to 38°C for 2 hours daily (experimental) from embryonic day (E)10 to E18, modeling intermittent heat exposure during mid-to-late gestation. Embryos were collected at E18 for analysis. While heat exposure did not affect pregnancy outcomes, including placental development, litter size, sex ratio, or fetal growth, male embryos exhibited significantly reduced anogenital distance and increased hypospadias scores, which are both markers of disrupted androgen signaling. Despite these phenotypic changes, expression of genes involved in androgen synthesis in the fetal testis, as well as gene expression in external genitalia, remained unchanged. Instead, transcriptomic analysis revealed significant alterations in testicular pathways related to RNA splicing and mRNA processing. Together, these findings reveal that maternal heat stress disrupts reproductive development of male offspring, with altered gene regulatory processes being a potential driver.

Individual microbes often respond differently to the same environment, yet the magnitude of such niche variation inherent to individuals remains unresolved and is anticipated to differ substantially from community-level average responses. We conducted metagenomic binning on monthly time-series soil samples from three sites across seasonal cycles. By considering 440,571 genes as dimensions of the fundamental individualised niche (FIN), we traced FIN trajectories of archaea and bacteria during warming, cooling, and turning periods. We found that neither mean temperature nor temperature difference had a significant effect on FIN breadth or overlap. Instead, we discovered a temporally constant, stepwise gradient of niche differentiation across taxonomic categories. At the interdomain level (Archaea vs. Bacteria), niche overlap is approximately 25%, rising to ~40% at the interphylum level and ~60% at the interorder level. This discontinuous gradient likely marks the limit boundaries of niche variation, is closely linked to functional synergy within FINs, and provides a preliminary comparable ecological carrying capacity for each niche step, particularly regarding the interdomain balance.

α-Synuclein (αSyn) is an intrinsically disordered protein that preferentially binds anionic membranes with lipid packing defects. Cholesterol is an abundant membrane component that regulates packing and organization within membranes, yet its effect on αSyn binding remains unclear as prior studies report both cholesterol-mediated enhancement and suppression. Here, we investigated whether these conflicting effects reflect differences in the intrinsic packing state of the phospholipid bilayer. Using a quantitative fluorescence microscopy-based binding assay, we measured αSyn binding preferences among reconstituted phosphatidylcholine/phosphatidylserine membranes with varied cholesterol content, lipid tail chemistry, and vesicle curvature. We found that cholesterol's effect depended on the underlying packing regime of the membrane. In defect-rich membranes, cholesterol reduced αSyn binding, consistent with cholesterol tightening lipid packing and reducing αSyn-accessible defects. In membranes with intermediate defect content, cholesterol enhanced binding, whereas tightly packed membranes remained largely insensitive to cholesterol except when high cholesterol content was combined with high membrane curvature. Curvature further shaped these responses, with high curvature compressing cholesterol-dependent differences between membrane compositions. These results show that cholesterol does not universally promote or inhibit αSyn binding. Instead, cholesterol regulates αSyn-membrane interactions through a packing-regime-dependent mechanism shaped by both lipid tail chemistry and membrane curvature. This framework helps reconcile opposing reports in the literature and highlights membrane physical state as a key determinant of how cholesterol modulates αSyn binding. αSyn is a membrane-binding protein associated with Parkinson's disease, but the role of cholesterol in regulating its membrane interactions has remained unclear. Some studies report that cholesterol enhances αSyn association with membranes, whereas others show that cholesterol suppresses it. This work helps explain why both outcomes can occur. We show that cholesterol's effect depends on the membrane's underlying packing state: cholesterol can reduce, enhance, or have little effect on αSyn binding depending on the membrane environment. These findings shift the question from whether cholesterol is generally pro- or anti-binding to how cholesterol reshapes the membrane physical states that control αSyn association.

While there are many choices among gene transfer vectors for basic or applied research, non-replicating adenoviruses are among the most studied. The virus is well suited for in vivo gene therapy since the vector can be produced with relatively high titers, is an efficient platform for in vivo modification of a variety of target cells and is relatively safe considering that the viral genome remains episomal. The production of adenoviral vectors is scalable and, once virus particles have been recovered, does not depend on the transfection of plasmids, a costly and laborious process to perform on large scale and with pharmaceutical quality. These vectors can be extensively modified to provide targeting at the level of transduction and transgene expression. The use of a non-replicating vector implies that it will not express viral proteins but instead can be modified to carry coding or non-coding sequences, including those that may be prejudicial to the life cycle of replicating viruses. Admittedly, immunogenicity of adenoviral vectors is an issue that requires careful consideration but may be leveraged to act as an adjuvant for vaccines or to overcome the immunosuppressive tumor microenvironment. Modifications also allow adenoviral vectors to act as important allies for achieving long-term expression. If viral replication is desired, non-replicating vectors can be paired with conditionally replicating adenovirus, thus providing the best of both approaches. To date, three cancer gene therapy products, Gendicine, Adstiladrin, and Papzimeos, that are based on non-replicating adenovirus have been approved for commercialization. As we will explore here, non-replicating adenoviral vectors continue to be developed for cancer gene therapy.

Acute leukemias of ambiguous lineage (ALALs) are rare acute leukemias with poor prognosis, encompassing acute undifferentiated leukemia (AUL) and mixed-phenotype acute leukemia (MPAL). The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HEM) recommends excluding ALAL cases with myelodysplasia-associated mutations and/or cytogenetic abnormalities from classification as AUL or MPAL, instead categorizing them as acute myeloid leukemia with myelodysplasia (AML-MR; hereafter referred to as AML-MR/ALAL), a distinct entity with limited genetic and clinical characterization to date. In this study, the genetic and clinical characteristics of AML-MR/ALAL were investigated in comparison with those of ALAL and AML-MR. RUNX1 (7/11; 63.6%), WT1 (3/11; 27.3%), DNMT3A (2/11; 18.2%), TET2 (2/11; 18.2%), BCORL1 (2/11; 18.2%), and TP53 (2/11; 18.2%) were identified as the most frequently mutated genes in AML-MR/ALAL. Moreover, AML-MR/ALAL shared genetic features with AML-MR and was distinct from ALAL. Although no significant difference in overall survival was observed between AML-MR/ALAL and ALAL, AML-MR/ALAL patients showed a trend toward worse prognosis. In summary, these findings suggest that AML-MR/ALAL may be more appropriately classified as AML-MR; however, validation in larger cohorts is required.

Traditional online reinforcement learning (RL) systems operate by actively engaging with their environments to acquire data, with the goal of formulating an optimal policy that maximizes a predefined cumulative reward. However, in scenarios where cost and safety are paramount, the practicality of online RL is constrained. In response, offline RL emerges as a viable solution, leveraging previously amassed datasets to craft an effective policy without the need for ongoing interaction with the environment. An obstacle in offline RL lies in its tendency to overestimate the values of actions not adequately represented in the data, known as out-of-distribution (OOD) actions. While previous approaches have typically sought to enhance performance through increased algorithmic complexity, this article introduces a novel methodology that significantly improves the offline performance, with only minor additional memory cost. This study delves into the analysis of retaining high performance throughout the fully offline training. Since offline learning is unable to correct errors without interaction with the environment, it is highly dependent on the dataset. For example, a good policy can never be trained on a random dataset. On the other hand, even if an algorithm can give good performance temporarily, it will easily lead to OOD errors. Instead of resorting to complicated policy regularization, propose a simple center replacement approach that adjusts the offline dataset to suit the proposed algorithm, so that the OOD errors can be avoided, as well as improving the training performance. Our method introduces an adaptive regularization target that evolves with policy improvement, effectively relaxing the conservatism constraint over time without requiring online interaction.