Polyethylene glycol has immunoprotective effects on sciatic allografts, but behavioral recovery and graft tolerance require neurorrhaphy and axonal fusion.

JOURNAL/nrgr/04.03/01300535-202504000-00033/figure1/v/2024-07-06T104127Z/r/image-tiff Behavioral recovery using (viable) peripheral nerve allografts to repair ablation-type (segmental-loss) peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration. Furthermore, such peripheral nerve allografts undergo immunological rejection by the host immune system. In contrast, peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks, reduced immune responses, and many axons do not undergo Wallerian degeneration. The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study. We hypothesized that polyethylene glycol might have some immune-protective effects, but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery. We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion. Ablation-type sciatic nerve injuries in outbred Sprague-Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts, but peripheral nerve allografts were loose-sutured (loose-sutured polyethylene glycol) with an intentional gap of 1-2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons. Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts, animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively. Other morphological signs of rejection, such as collapsed Schwann cell basal lamina tubes, were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively. Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts. While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts, loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively. MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts, but MHCII expression was modestly lower compared to negative control at 21 days postoperatively. We conclude that, while polyethylene glycol per se reduces some immune responses of peripheral nerve allografts, successful polyethylene glycol-fusion repair of some axons is necessary to prevent Wallerian degeneration of those axons and immune rejection of peripheral nerve allografts, and produce recovery of sensory/motor functions and voluntary behaviors. Translation of polyethylene glycol-fusion technologies would produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation peripheral nerve injuries.

Deformability of Heterogeneous Red Blood Cells in Aging and Related Pathologies.

Aging is interrelated with changes in red blood cell parameters and functionality. In this article, we focus on red blood cells (RBCs) and provide a review of the known changes associated with the characterization of RBC deformability in aging and related pathologies. The biophysical parameters complement the commonly used biochemical parameters and may contribute to a better understanding of the aging process. The power of the deformability measurement approach is well established in clinical settings. Measuring RBCs' deformability has the advantage of relative simplicity, and it reflects the complex effects developing in erythrocytes during aging. However, aging and related pathological conditions also promote heterogeneity of RBC features and have a certain impact on the variance in erythrocyte cell properties. The possible applications of deformability as an early biophysical biomarker of pathological states are discussed, and modulating PIEZO1 as a therapeutic target is suggested. The changes in RBCs' shape can serve as a proxy for deformability evaluation, leveraging single-cell analysis with imaging flow cytometry and artificial intelligence algorithms. The characterization of biophysical parameters of RBCs is in progress in humans and will provide a better understanding of the complex dynamics of aging.

Pyrroloquinoline quinone: a potential neuroprotective compound for neurodegenerative diseases targeting metabolism.

Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues. Pyrroloquinoline quinone is present in the diet being available in foodstuffs, conferring the potential of this compound to be supplemented by dietary administration. Pyrroloquinoline quinone's nutritional role in mammalian health is supported by the extensive deficits in reproduction, growth, and immunity resulting from the dietary absence of pyrroloquinoline quinone, and as such, pyrroloquinoline quinone has been considered as a "new vitamin." Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established, the wide range of benefits for health provided has been reported in many studies. In this respect, pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts, thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life. Through the regulation of different metabolic mechanisms, pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death. Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration, although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated. Here, we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts. In addition, we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone's potential in health and disease.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination.

During the development of the nervous system, there is an overproduction of neurons and synapses. Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening. We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway, at the neuromuscular junction, in the axonal development and synapse elimination process versus the synapse consolidation. The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination, in relation to other molecular pathways that we and others have found to regulate this process. In particular, we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors, coupled to downstream serine-threonine protein kinases A and C (PKA and PKC) and voltage-gated calcium channels, at different nerve endings in developmental competition. The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site, influence each other, and require careful studies to individualize the mechanisms of specific endings. We describe an activity-dependent balance (related to the extent of transmitter release) between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals. The downstream displacement of the PKA/PKC activity ratio to lower values, both in competing nerve terminals and at postsynaptic sites, plays a relevant role in controlling the elimination of supernumerary synapses. Finally, calcium entry through L- and P/Q- subtypes of voltage-gated calcium channels (both channels are present, together with the N-type channel in developing nerve terminals) contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination (the weakest in acetylcholine release and those that have already become silent). The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development. Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

Perspectives on label-free microscopy of heterogeneous and dynamic biological systems.

Significance: Advancements in label-free microscopy could provide real-time, non-invasive imaging with unique sources of contrast and automated standardized analysis to characterize heterogeneous and dynamic biological processes. These tools would overcome challenges with widely used methods that are destructive (e.g., histology, flow cytometry) or lack cellular resolution (e.g., plate-based assays, whole animal bioluminescence imaging). Aim: This perspective aims to (1) justify the need for label-free microscopy to track heterogeneous cellular functions over time and space within unperturbed systems and (2) recommend improvements regarding instrumentation, image analysis, and image interpretation to address these needs. Approach: Three key research areas (cancer research, autoimmune disease, and tissue and cell engineering) are considered to support the need for label-free microscopy to characterize heterogeneity and dynamics within biological systems. Based on the strengths (e.g., multiple sources of molecular contrast, non-invasive monitoring) and weaknesses (e.g., imaging depth, image interpretation) of several label-free microscopy modalities, improvements for future imaging systems are recommended. Conclusion: Improvements in instrumentation including strategies that increase resolution and imaging speed, standardization and centralization of image analysis tools, and robust data validation and interpretation will expand the applications of label-free microscopy to study heterogeneous and dynamic biological systems.

Impact of Collared Peccaries Dycotiles tajacu (Artiodactyla: Tayassuidae) on understory vegetation in the tropical rainforest of the Nogal-La Selva Biological Corridor, Costa Rica / Impacto del pecarí de collar, Dycotiles tajacu (Artiodactyla: Tayassuidae) en la vegetación del sotobosque del bosque tropical húmedo del Corredor Biológico Local Nogal-La Selva, Costa Rica

Abstract Introduction: Evidence suggests that herbivores, such as peccaries, shape vegetation structure and diversity through predation, trampling, dispersal, and rooting behavior. Objective: To evaluate the impact of peccaries (Dycotiles tajacu) on the understory vegetation of the tropical rainforest in the Nogal-La Selva Local Biological Corridor, Costa Rica, comparing a site with the absence of peccaries to another with the presence of these animals. Methodology: From June to November 2021, 20 experimental exclusions and 20 free access plots, each measuring 2 m2 were used to quantify herbivory, the number of leaf blades, damaged leaves, healthy leaves, sapling height, and fallen biomass at both sites. Results: A higher sapling density was found in the Nogal Reserve, but a lower sapling diversity, while in La Selva there was a higher sapling diversity, but a lower density of seedlings. Herbivory and sapling height in La Selva exceeded those in Nogal. The exclusion of peccaries reduced seedling damage but did not affect the dynamics of fallen biomass. Conclusion: For the design, implementation, and evaluation of the effectiveness of biological corridors, it is crucial to consider plant-animal interactions to enhance the flow of ecological processes through functional and structural connectivity, analyzed from interactions such as those presented in this paper.

Resumen Introducción: Existe evidencia que herbívoros, como los saínos, dan forma a la estructura y diversidad de la vegetación a través del comportamiento de depredación, pisoteo, dispersión y enraizamiento. Objetivo: Evaluar el impacto de los saínos (Dycotiles tajacu) en la vegetación del sotobosque del bosque tropical húmedo en el Corredor Biológico Local Nogal-La Selva, Costa Rica, en un sitio con ausencia y en otro con presencia de saínos. Métodos: De junio a noviembre de 2021 se utilizaron 20 exclusiones experimentales y 20 parcelas de acceso libre de 2 m2, se cuantifico la herbivoría, número de láminas foliares, hojas dañadas, hojas sanas, altura de brinzales y biomasa caída en ambos sitios. Resultados: Se encontró una mayor densidad de brinzales en Reserva Nogal pero una menor diversidad, contrario en La Selva donde se encontró una mayor diversidad de brinzales, pero una menor densidad de plántulas. La herbivoría y la altura de brinzales en La Selva fue mayor que en Nogal. La exclusión de los saínos disminuyó el daño a las plántulas, pero no afectó la dinámica de la biomasa caída. Conclusión: Es necesario contemplar para el diseño, implementación y evaluación de la efectividad de corredores biológicos, las interacciones planta-animal, para potencializar el flujo de procesos ecológicos mediante la conectividad funcional y estructural, analizada a partir de interacciones como las presentadas en este trabajo.

Estimated glomerular filtration rate in clinical practice: Consensus positioning of the Brazilian Society of Nephrology (SBN) and Brazilian Society of Clinical Pathology and Laboratory Medicine (SBPC/ML) / Estimativa da taxa de filtração glomerular na prática clínica: posicionamento consensual da Sociedade Brasileira de Nefrologia (SBN) e Sociedade Brasileira de Patologia Clínica e Medicina Laboratorial (SBPC/ML)

ABSTRACT Chronic kidney disease (CKD) represents one of today's main public health problems. Serum creatinine measurement and estimation of the glomerular filtration rate (GFR) are the main tools for evaluating renal function. There are several equations to estimate GFR, and CKD-EPI equation (Chronic Kidney Disease - Epidemiology) is the most recommended one. There are still some controversies regarding serum creatinine measurement and GFR estimation, since several factors can interfere in this process. An important recent change was the removal of the correction for race from the equations for estimating GFR, which overestimated kidney function, and consequently delayed the implementation of treatments such as dialysis and kidney transplantation. In this consensus document from the Brazilian Societies of Nephrology and Clinical Pathology and Laboratory Medicine, the main concepts related to the assessment of renal function are reviewed, as well as possible existing controversies and recommendations for estimating GFR in clinical practice.

RESUMO A doença renal crônica (DRC) representa um dos principais problemas de saúde pública da atualidade. A dosagem da creatinina sérica e a estimativa da taxa de filtração glomerular (TFG) são as principais ferramentas para avaliação da função renal. Para a estimativa da TFG, existem diversas equações, sendo a mais recomendada a CKD-EPI (Chronic Kidney Disease - Epidemiology). Existem ainda algumas controvérsias com relação à dosagem da creatinina sérica e da estimativa da TFG, uma vez que vários fatores podem interferir nesse processo. Uma importante mudança recente foi a retirada da correção por raça das equações para estimativa da TFG, que superestimavam a função renal, e consequentemente retardavam a implementação de tratamentos como diálise e transplante renal. Neste documento de consenso da Sociedade Brasileira de Nefrologia e Sociedade Brasileira de Patologia Clínica e Medicina Laboratorial são revisados os principais conceitos relacionados à avaliação da função renal, possíveis controvérsias existentes e recomendações para a estimativa da TFG na prática clínica.

Mindfulness trait and the potential mediating role of emotional regulation strategies in bipolar disorder / Mindfulness rasgo y el potencial papel mediador de las estrategias de regulación emocional en el trastorno bipolar

En este estudio transversal se investiga la asociación entre los principales síntomas del Trastorno bipolar (TB) y las dificultades asociadas a las estrategias de regulación emocional (ERE) adaptativas y desadaptativas. Además, este estudio examina los efectos mediadores de las ERE con el mindfulness rasgo y el TB. Método. Veinticuatro adultos con TB completaron la Escala de Conciencia de Atención Plena (MAAS), el Inventario de Depresión de Beck (BDI-II), la Escala de Autoevaluación de Manía de Altman (ARSM), el Inventario de Ansiedad Rasgo (STAI-R), y el Cuestionario de Regulación Emocional Cognitiva (CERQ). Resultados. El análisis de regresión múltiple mostró cómo la depresión se relacionaba significativa y positivamente con la autoculpabilización, mientras que la ansiedad rasgo estaba positivamente asociada con la autoculpabilización y el catastrofismo. En segundo lugar, el análisis de mediación mostró un efecto de mediación significativo para la autoculpabilidad en la relación entre mindfulness y depresión (a*b = -.15; ICB 95% [-.36, -.03]) y entre mindfulness y ansiedad rasgo (a*b = -.09; ICB 95% [-.27, -.01]). Conclusiones. Nuestros resultados informan del papel de la auto-culpabilidad y el catastrofismo en el TB y de cómo éstas podrían mediar significativamente entre el mindfulness rasgo y el TB. Estos resultados sugieren que una práctica de meditación enfocada en el catastrofismo y la autoculpabilidad puede ser especialmente útil para reducir los síntomas en los pacientes bipolares.(AU)

This cross-sectional study investigates the association between the main symptoms of Bipolar disorder (BD) and emotional regulation dif-ficulties in adaptive and maladaptive emotional regulation strategies (ERS). In addition, this study examines the possible mediating effects of ERS with dispositional mindfulnessand bipolar symptoms. Method.Twenty-four adults diagnosed with BD completed the Mindful Attention Awareness Scale (MAAS), the Beck Depression Inventory (BDI-II), the Altman Mania Self-Assessment Scale (ARSM), the Trait Anxiety Inventory (STAI-R), and the Cognitive Emotional Regulation Questionnaire (CERQ). Results. First, mul-tiple regression analysis showed how depression was significantly positively related to self-blame, whereas trait anxietywas positively associated with self-blame and catastrophizing. Second, the results of the mediation analy-sis have shown a significant mediation effect for the self-blamein the rela-tionship between mindfulnessand depression (a*b = -.15; BCI 95% [-.36, -.03]) and between mindfulnessand trait anxiety (a*b = -.09; BCI 95% [-.27, -.01]). Conclusions. Our results report the role of self-blame and catastrophiz-ing in BD and how these might significantly mediate between dispositional mindfulness and symptoms of depression and anxiety. These results suggest that a meditation practice focused on reducing catastrophizing and self-blame may be especially helpful for symptoms of depression and anxiety in bipolar patients.(AU)

Na6MCl8 rock-salt compounds with M = Mg, Ca, Ba, Zn, Sr as components for solid-state sodium ion batteries.

We investigate a new series of rock-salt type structures, Na6MCl8 with M = Mg, Ca, Ba, Zn and Sr using advanced atomistic simulations. Calculated results show a direct relationship between the size of the M2+ cation and lattice parameters as well as the defect formation energy variation. The NaCl Schottky defect type is highly favourable, and the Na6BaCl8 structure possesses the lowest values of defect formation energies. These structures are predicted to be mechanically stable and ductile, implying their compatibility with possible use as electrodes/electrolytes. The Na6MCl8 structures exhibit semiconductor characteristics with an energy gap ranging between 4.1-4.6 eV, which differs from the previous value of Na6MgCl8. A 3D migration pathway is identified in each rock-salt structure. Despite the small variation of the Na diffusivity and conductivity at 250 K within the structures considered, the Na6BaCl8 is characterized by the highest conductivity at 250 K, while the Na6MgCl8 structure has the highest conductivity and diffusivity values. The outstanding properties predicted for a Na ion battery suggest future development of synthetic strategies for their actual preparation.

Recent developments in the synthesis and applications of terpyridine-based metal complexes: a systematic review.

Terpyridine-based metal complexes have emerged as versatile and indispensable building blocks in the realm of modern chemistry, offering a plethora of applications spanning from materials science to catalysis and beyond. This comprehensive review article delves into the multifaceted world of terpyridine complexes, presenting an overview of their synthesis, structural diversity, and coordination chemistry principles. Focusing on their diverse functionalities, we explore their pivotal roles in catalysis, supramolecular chemistry, luminescent materials, and nanoscience. Furthermore, we highlight the burgeoning applications of terpyridine complexes in sustainable energy technologies, biomimetic systems, and medicinal chemistry, underscoring their remarkable adaptability to address pressing challenges in these fields. By elucidating the pivotal role of terpyridine complexes as versatile building blocks, this review provides valuable insights into their current state-of-the-art applications and future potential, thus inspiring continued innovation and exploration in this exciting area of research.

Highly sensitive AIEE active fluorescent probe for detection of deferasirox: extensive experimental and theoretical studies.

High concentrations of deferasirox (DFX) in living organisms cause hepatic, gastric and renal malfunctions. Therefore, it is significant to establish an accurate and efficient approach for the detection of deferasirox (DFX) to protect public health. Herein, we synthesized a thiourea-based diphenylacetamide probe MPT for the effective sensing of deferasirox through the fluorescence quenching phenomenon. The designed probe MPT shows a fluorescence quenching response toward deferasirox (DFX) through photo-induced electron transfer (PET). Furthermore, DFT studies were performed to support the experimental results. 1H-NMR titration experiment was used to explore the interaction type between probe MPT and DFX. The existence of non-covalent interactions was verified with spectroscopic studies that were assisted by NCI studies, QTAIM and SAPT0 analysis. Dynamic light scattering (DLS) analysis and scanning electron microscopy (SEM) were used to investigate the complexation of probe MPT with DFX. Moreover, the on-site solution phase and solid-state detection of DFX by probe MPT are executed. Additionally, the practical applications of probe MPT to sense DFX were also revealed in human plasma as well as in artificial urine samples.

Solar photocatalysts: non-metal (C, N, and S)-doped ZnO synthesized through an industrially sustainable in situ approach for environmental remediation applications.

One of the biggest issues the world is currently experiencing is the scarcity of pure water due to the contamination of pure water by human activities. Highly efficient, semiconducting photocatalytic materials have great potential as future catalytic materials for facilitating the clean-up process of contaminated water. Among the many semiconductor photocatalysts, non-metal-doped zinc oxide (ZnO) nanoparticles have attracted special attention in the scientific field for environmental remediation applications. The present paper reports an easy and viable synthesis of C-, N-, and S-based ZnO semiconductor photocatalysts through a simple heating method. The structural changes in the obtained samples were studied using XRD, TG/DTA, and FT-IR analyses, and morphological examinations were performed using TEM and SEM. The quantification of non-metal dopants was carried out using CNS and XPS analyses. The surface areas of the samples were analyzed using the BET method and the band energies of the samples were measured using UV-vis-diffuse reflectance Kubelka-Munk plots. Photoactivity studies were performed and revealed that the utilized in situ method resulted in the development of high-performance sulphur - (81.4%, k = 1.951 × 10-2 min-1), nitrogen - (78.5%, k = 2.271 × 10-2 min-1), and carbon - (67.2%, k = 1.392 × 10-2 min-1) doped ZnO photocatalysts. As revealed through XPS and UV analyses, a possible electron-transfer mechanism is suggested, wherein electronic transition occurred from different sub-bands when non-metal elements were introduced into the ZnO lattice. The study paves the way for the bulk-scale fabrication of doped nanoparticles through a simple heating method, whereby the unique combination of the present method with bandgap engineering will ultimately produce advanced non-metal-based ZnO photocatalysts that could find useful applications in sustainable industrial sectors.

Exploration of the VEGFR-2 inhibition activity of phthalazine derivatives: design, synthesis, cytotoxicity, ADMET, molecular docking and dynamic simulation.

Novel phthalazine derivatives were designed, synthesized and evaluated against Hep G2 and MCF-7 as VEGFR-2 inhibitors. In particular, compounds 2g and 4a were found to be the most potent derivatives among all the tested compounds against MCF-7 and Hep G2 cancer cell lines with IC50 values of 0.15 and 0.12 and 0.18 and 0.09 µM respectively. Moreover, compounds 3a, 3c, 5a and 5b displayed excellent anticancer activities against MCF-7 and Hep G2 cancer cell lines. The highly active derivatives 2g, 3a, 3c, 4a, 5a and 5b were evaluated for their inhibitory activities against VEGFR-2. The tested compounds displayed high to low inhibitory activities with IC50 values ranging from 0.148 to 0.892 µM. Among them, compounds 2g and 4a were found to be the most potent derivatives that inhibited VEGFR-2 with IC50 values of 0.148 and 0.196 µM respectively. Compounds 3a, 3c, 5a and 5b exhibited good activity with IC50 values of 0.375, 0.892, 0.548 and 0.331 µM respectively. Sorafenib was used as a reference drug in this study. Molecular modeling studies were carried out for all compounds against the VEGFR-2 active site. The data obtained from biological testing highly correlated with those obtained from molecular modeling studies. Moreover, MD simulation results indicated the stability of ligand-target interaction. Furthermore, our derivatives 2g and 4a showed a good in silico calculated ADMET profile.

Implementation of ultra-hypofractionated radiotherapy schedules for breast cancer during the COVID-19 pandemic in the Netherlands.

Background and purpose: The COVID-19 pandemic resulted in an accelerated recommendation to use five-fraction radiotherapy schedules, according to the FAST- and FAST-Forward trial. In this study, trends in the use of different radiotherapy schedules in the Netherlands were studied, as well as the likelihood of receiving five fractions. Materials and methods: Data from the NABON Breast Cancer Audit-Radiotherapy and Netherlands Cancer Registry was used. Women receiving radiotherapy for their primary invasive breast cancer or DCIS between 01-01-2020 and 31-12-2021 were included. Logistic regression was used to investigate the association between patient-, tumour-, treatment-, and radiotherapy institution-related characteristics and the likelihood of receiving five fractions in tumours meeting the FAST and FAST-Forward criteria. Results: Detailed information about radiotherapy treatment was available for 9,392 tumours. Shortly after the start of the COVID-19 pandemic, i.e. April 2020, 19% of the tumours being treated with radiotherapy received five fractions of 5.2 or 5.7 Gray (Gy). While only 3% of the tumours received five fractions in March 2020. The usage of five fractions increased to 26% in December 2021. Partial breast irradiation, compared to whole breast irradiation, was significantly associated with the administration of five fractions, as well as radiotherapy delivered in an academic radiotherapy institution compared to an independent institution. Conclusion: The start of the COVID-19 pandemic was associated with the early use of ultra-hypofractionated radiotherapy schedules. After publication of the trials, and mainly after the recommendation by the national radiotherapy society, the implementation further increased. These schedules were not yet used in all patients meeting the eligibility criteria for the FAST- or FAST-Forward trial.

Ubiquitination contributes to the regulation of GDP-mannose pyrophosphorylase B activity.

GDP-mannose pyrophosphorylase B (GMPPB) loss-of-function is associated with muscular dystrophy and variable additional neurological symptoms. GMPPB facilitates the catalytic conversion of mannose-1-phosphate and GTP to GDP-mannose, which serves as a mannose donor for glycosylation. The activity of GMPPB is regulated by its non-catalytic paralogue GMPPA, which can bind GDP-mannose and interact with GMPPB, thereby acting as an allosteric feedback inhibitor of GMPPB. Using pulldown, immunoprecipitation, turnover experiments as well as immunolabeling and enzyme activity assays, we provide first direct evidence that GMPPB activity is regulated by ubiquitination. We further show that the E3 ubiquitin ligase TRIM67 interacts with GMPPB and that knockdown of TRM67 reduces ubiquitination of GMPPB, thus reflecting a candidate E3 ligase for the ubiquitination of GMPPB. While the inhibition of GMPPB ubiquitination decreases its enzymatic activity, its ubiquitination neither affects its interaction with GMPPA nor its turnover. Taken together, we show that the ubiquitination of GMPPB represents another level of regulation of GDP-mannose supply.

Youth attention, perceptions, and appeal in response to e-cigarette advertising features: A focus group study.

Background: E-cigarette marketing exposure may influence vaping-related outcomes among youth, but less is known on which specific advertising features impact youth attention, perceptions, and appeal. This study qualitatively examines responses to different e-cigarette advertising features among e-cigarette-naïve youth. Methods: We conducted four online focus groups in 2021 with a national U.S. sample of 13-17 year olds (n = 25) who had never used e-cigarettes. Participants viewed and discussed their reactions to different e-cigarette advertisements varying in the inclusion of ad features, including color, models in imagery, text claims targeting smokers, and the nicotine warning label. Results: Participants were attracted to ads with bright colors, particularly when contrasted against a dark background. Ads featuring models attracted attention and reduced perceptions that the product is harmful. Comments indicated mixed reactions to smoker-targeted text claims. On one hand, participants perceived ads with text that specified "for smokers" as targeting older adults. On the other hand, text referring to "switching" from cigarettes to e-cigarettes led to some perceptions that the product is healthy, and certain text that implicitly referred to smoking (e.g., "no odor") had the potential to appeal to youth who wanted to use e-cigarettes discreetly. The level of attention paid to warnings depended on warning size and the color contrast between the warning and the rest of the ad. Conclusions: Findings suggest specific e-cigarette ad features play an important role in attracting youth attention and influencing perceptions. More research is needed on the potential public health benefits versus unintended consequences of smoker-targeted text claims.

Growing evidence of pharmacotherapy effectiveness in managing attention-deficit/hyperactivity disorder in young children with or without autism spectrum disorder: a minireview.

Many children with autism spectrum disorder (ASD) also have attention-deficit/hyperactivity disorder (ADHD). ADHD in children is associated with increased risk of negative outcomes, and early intervention is critical. Current guidelines recommend psychosocial interventions such as behavioral training as the first line of therapy in managing ADHD symptoms in children with or without ASD. Where symptoms are refractory to these interventions, medications such as stimulants, α2-adrenergic agonist inhibitors, selective norepinephrine reuptake inhibitors, and second-generation antipsychotics are recommended. However, these pharmacotherapies do not have regulatory approval for use in children of preschool age, and evidence on their safety and efficacy in this population has historically been very limited. Since publication of the current guidelines in 2020, several new randomized controlled trials and real-world studies have been published that have investigated the efficacy and tolerability of these medications in preschool children with ADHD, with or without comorbid ASD. Here, we provide a review of the key findings of these studies, which suggest that there is growing evidence to support the use of pharmacological interventions in the management of ADHD in preschool children with comorbid ASD.

Perceptions of mental disorder causes, treatments, and prevention among the general population in Saudi Arabia.

This study investigates the community's perception of mental health in Saudi Arabia, emphasizing its influence on attitudes toward the causes, treatment, and prevention of mental health issues. This understanding is vital for creating evidence-based mental health interventions. A cross-sectional national mental health screening was conducted in 2023, utilizing proportional quota sampling for age, gender, and regional representation among 4547 Saudi participants aged 18-90, randomly selected from national databases. Data were gathered using the ZDataCloud system. The study covered all 13 administrative regions of Saudi Arabia: Riyadh, Makkah, Madinah, Qassim, Eastern Province, Asir, Tabuk, Hail, Northern Borders, Jazan, Najran, Baha, and Al-Jouf. The majority (86.5%) had no personal history of mental health diagnosis or treatment. Key findings identified psychological trauma (78.36%) and substance abuse (72.88%) as primary perceived causes of mental disorders. Preferred treatments included non-pharmacological psychotherapies (74.97%) and pharmacological methods (71.08%). Prevention strategies focused on raising awareness of mental illness (80.4%) and enhancing positive relationships (70.6%). A multivariate logistic regression analysis revealed significant associations between demographic variables and perceptions of mental disorder causes, treatments, and prevention strategies. Females were more likely than males to perceive psychological trauma, drug and alcohol abuse, and domestic violence and sexual harassment as causes of mental disorders. Regarding treatments, females and those with personal or close connections to mental health issues were more likely to endorse non-pharmacological psychotherapy and Roquia in the Qur'an. For prevention strategies, females, those with a mental health diagnosis, and those living with someone diagnosed with a mental disorder were more likely to endorse increasing awareness, positive social relationships, and physical activity. The study suggests integrating religious and social beliefs into mental health programs to enhance community engagement and effectiveness.