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Anticancer drugs targeting topoisomerase II for antifungal treatment

Abstract Fungal topoisomerase II (TopoII) has been identified as essential for viability. Thus, our research aimed to investigate the potential of fungal TopoII as a novel target for antifungal chemotherapy. We conducted studies on eleventh antitumor compounds targeting human topoisomerase II, either approved by the U.S. Food and Drug Administration (FDA) or currently under clinical trials to evaluate their potential for use in other therapeutic applications. While most of the compounds we analyzed are potent inhibitors of yeast TopoII, only a few exhibited antifungal activity. Idarubicin emerged as the most potent compound effectively inhibiting the growth of five reference fungal strains as well as clinical Candida glabrata fluconazole-resistant cells. Antifungal activity of this compound corresponded with its very high yeast TopoII inhibitory effectiveness. Additionally, idarubicin ability to be effectively accumulated into fungal cells is crucial for yeast TopoII targeting. Idarubicin, epirubicin, and bisantrene appeared to be even more effective inhibitors of yeast enzyme than its human counterpart. In fungal cells idarubicin exhibited a multifaceted mechanisms of action, including nuclear DNA fragmentation, disruption of mitochondrial network architecture and mitochondrial DNA aggregation as well as oxidative stress induction. Our results indicate that fungal topoisomerase II targeting is worth considering in antifungal treatment and the reported drugs may serve as a starting point for the reinnovation of a new molecule.

A unified neural representation model for spatial and conceptual computations

The hippocampus and entorhinal cortex encode spaces by spatially local and hexagonal grid activity patterns (place cells and grid cells), respectively. In addition, the same brain regions also implicate neural representations for nonspatial, semantic concepts (concept cells). These observations suggest that neurocomputational mechanisms for spatial knowledge and semantic concepts are related in the brain. However, the exact relationship remains to be understood. Here, we show a mathematical correspondence between a value function for goal-directed spatial navigation and an information measure for word embedding models in natural language processing. Based on this relationship, we integrate spatial and semantic computations into a neural representation model called “disentangled successor information” (DSI). DSI generates biologically plausible neural representations: spatial representations like place cells and grid cells, and concept-specific word representations which resemble concept cells. Furthermore, with DSI representations, we can perform inferences of spatial contexts and words by a common computational framework based on simple arithmetic operations. This computation can be biologically interpreted by partial modulations of cell assemblies of nongrid cells and concept cells. Our model offers a theoretical connection of spatial and semantic computations and suggests possible computational roles of hippocampal and entorhinal neural representations.

Correction: Perceptions of primary health care professionals from Brazil about the food and nutrition monitoring system

Publisher Correction: Novel application of sinh cosh optimizer for robust controller design in hybrid photovoltaic-thermal power systems

Structural mechanisms underlying the modulation of CXCR4 by diverse small-molecule antagonists

CXCR4 (CXC chemokine receptor type 4), a member of the G protein–coupled receptor superfamily, plays a role in cell migration and functions as a coreceptor for HIV entry. Molecular therapeutics targeting CXCR4 have been under intensive investigation. To date, only two small-molecule antagonist drugs targeting CXCR4, plerixafor (AMD3100) and mavorixafor (AMD070), have been approved. Here, we present the high-resolution structures of CXCR4 complexed with AMD3100 and AMD070, as well as a small-molecule antagonist HF51116 that has very different chemical structure and binding mechanism from AMD3100 and AMD070. The interactions between these antagonists and the receptor are analyzed in details, and the mechanisms of antagonism are elucidated. Both the major and minor subpockets on CXCR4 are found to be involved in binding of these small-molecule antagonists. The distinct conformations of Trp94 2.60 observed in these structures highlight the plasticity of the binding pocket on CXCR4, offering valuable insights into the exploration and refinement of therapeutic strategies targeting this chemokine receptor.

The mechanisms of manual therapy: A living review of systematic, narrative, and scoping reviews

Introduction Treatment mechanisms are the underlying process or pathway through which a treatment influences the body. This includes molecular, cellular and physiological processes or pathways contributing to treatment effect. Manual therapy (MT) evokes complex mechanistic responses across body systems, interacting with the individual patient and context to promote a treatment response. Challenges arise as mechanistic studies are spread across multiple professions, settings and populations. The purpose of this review is to summarize treatment mechanisms that have been reported to occur with MT application. Methods Four electronic databases were searched (Medline, CINAHL, Cochrane Library, and PEDro) for reviews investigating mechanistic responses which occur during/post application of MT. This review was registered a priori with PROSPERO (CRD42023444839). Methodological quality (AMSTAR-2) and risk of bias (ROBIS) were assessed for systematic and scoping reviews. Data were synthesized by mechanistic domain. Results Sixty-two reviews were included. Systematic reviews (n = 35), narrative reviews (n = 24), and scoping reviews (n = 4) of asymptomatic (n = 37), symptomatic (n = 43), non-specified human subjects (n = 7) and animals (n = 7) were included. Reviews of moderate quality supported neurovascular, neurological, and neurotransmitter/neuropeptide changes. Reviews of low quality supported neuroimmunce, neuromuscular, and neuroendocrine changes. Reviews of critically low quality support biomechanical changes. Conclusions Findings support critically low to moderate quality evidence of complex multisystem mechanistic responses occurring with the application of MT. Results support peripheral, segmental spinal, and supraspinal mechanisms occurring with the application of MT, which can be measured directly or indirectly. The clinical value of these findings has not been well established. While MT has proven to be an effective intervention to treat conditions such as pain, the current body of literature leaves uncertainty as to ‘why’ MT interventions work, and future research should look to better define which mechanisms (or combinations of mechanisms) are mediators of clinical response.

Therapeutic path of Brazilians with spinal cord injury until rehabilitation

A mechanistic basis for genetic assimilation in natural fly populations

Genetic assimilation is a process by which a trait originally driven by the environment becomes independent of the initial cue and is expressed constitutively in a population. More than seven decades have passed since Waddington’s pioneering demonstration of the acquisition of morphological traits through genetic assimilation, but the underlying mechanism remains unknown. Here, we address this gap by performing combined genomic analyses of Waddington’s genetic assimilation experiments using the ectopic veins (EV) phenocopy in Drosophila as a model. Our study reveals the assimilation of EV in both outbred and inbred fly natural populations, despite their limited genetic diversity. We identified key changes in the expression of developmental genes and pinpointed selected alleles involved in EV assimilation. The assimilation of EV is mainly driven by the selection of regulatory alleles already present in the ancestral populations, including the downregulation of the receptor tyrosine kinase gene Cad96Ca by the insertion of a transposable element in its 3′ untranslated region. The genetic variation at this locus in the inbred population is maintained by a large chromosomal inversion. In outbred populations, the evolution of EV results from a polygenic response shaped by the selective environment. Our results support a model in which selection for multiple preexisting alleles in the ancestral population, rather than stress-induced genetic or epigenetic variation, drives the evolution of EV in natural fly populations.

Utility of a patient similarity-based digital tool for risk communication to patients with type 2 diabetes mellitus: perspectives from primary care physicians in ambulatory care

Background Inaccurate risk perceptions of diabetes complications are responsible for the inertia among patients to engage in protective health behaviours. One potential approach to changing risk perceptions is to use social comparison of their diabetes to other people of similar clinicodemographic profiles. Objectives This study examined the perspectives of primary care physicians (PCPs) in ambulatory care on the utility of a patient similarity-based digital tool for risk communication to patients with type 2 diabetes mellitus (T2DM). Methods A qualitative study design using direct observation and in-depth interviews was conducted on 11 PCP participants. Participants had at least 6 months of clinical experience in ambulatory primary care. Participants went through three hypothetical case scenarios using the digital tool under direct observation and shared their perspectives on its utility during an in-depth interview. Data were coded and analysed using thematic analysis. Results PCPs perceived the digital tool to be useful in educating patients with newly diagnosed or uncontrolled T2DM and to motivate them to achieve better glycated haemoglobin (HBA1c) levels. Patients who do not practise social comparison would refrain from HBA1c comparison and prefer to know the absolute state of their diabetes. PCPs were also concerned about patients’ potential for false reassurance or negative reactions instead of correctly understanding the risk message intended for them. Conclusion The patient similarity-based digital tool requires further work to support PCPs in risk communication to patients with T2DM. Usage should be targeted at patient subgroups with newly diagnosed or uncontrolled T2DM and who practise social comparison. Strategies to maximise benefit include identifying patients who practise social comparison and training PCPs to be adept at framing and communicating risk information in a person-centric manner to mitigate the possibility of false reassurance or negative reactions from their patients.

Effects of ramp width variation on the hydraulic conditions of spillway that affect downstream migrating fish

Learning reshapes the hippocampal representation hierarchy

A key feature of biological and artificial neural networks is the progressive refinement of their neural representations with experience. In neuroscience, this fact has inspired several recent studies in sensory and motor systems. However, less is known about how higher associational cortical areas, such as the hippocampus, modify representations throughout the learning of complex tasks. Here, we focus on associative learning, a process that requires forming a connection between the representations of different variables for appropriate behavioral response. We trained rats in a space-context associative task and monitored hippocampal neural activity throughout the entire learning period, over several days. This allowed us to assess changes in the representations of context, movement direction, and position, as well as their relationship to behavior. We identified a hierarchical representational structure in the encoding of these three task variables that was preserved throughout learning. Nevertheless, we also observed changes at the lower levels of the hierarchy where context was encoded. These changes were local in neural activity space and restricted to physical positions where context identification was necessary for correct decision-making, supporting better context decoding and contextual code compression. Our results demonstrate that the hippocampal code not only accommodates hierarchical relationships between different variables but also enables efficient learning through minimal changes in neural activity space. Beyond the hippocampus, our work reveals a representation learning mechanism that might be implemented in other biological and artificial networks performing similar tasks.

Retraction: Impact of donors’ financial fairness perception on donation intention in nonprofit organizations after COVID-19 outbreak

Transfer learning for securing electric vehicle charging infrastructure from cyber-physical attacks

Astrocytes in the mouse brain respond bilaterally to unilateral retinal neurodegeneration

Glaucomatous optic neuropathy, or glaucoma, is the world’s primary cause of irreversible blindness. Glaucoma is comorbid with other neurodegenerative diseases, but how it might impact the environment of the full central nervous system to increase neurodegenerative vulnerability is unknown. Two neurodegenerative events occur early in the optic nerve, the structural link between the retina and brain: loss of anterograde transport in retinal ganglion cell (RGC) axons and early alterations in astrocyte structure and function. Here, we used whole-mount tissue clearing of full mouse brains to image RGC anterograde transport function and astrocyte responses across retinorecipient regions early in a unilateral microbead occlusion model of glaucoma. Using light sheet imaging, we found that RGC projections terminating specifically in the accessory optic tract are the first to lose transport function. Although degeneration was induced in one retina, astrocytes in both brain hemispheres responded to transport loss in a retinotopic pattern that mirrored the degenerating RGCs. A subpopulation of these astrocytes in contact with large descending blood vessels were immunopositive for LCN2, a marker associated with astrocyte reactivity. Together, these data suggest that even early stages of unilateral glaucoma have broad impacts on the health of astrocytes across both hemispheres of the brain, implying a glial mechanism behind neurodegenerative comorbidity in glaucoma.

Neural correlates of the uncanny valley effect for robots and hyper-realistic masks

Viewing artificial objects and images that are designed to appear human can elicit a sense of unease, referred to as the ‘uncanny valley’ effect. Here we investigate neural correlates of the uncanny valley, using still images of androids (robots designed to look human), and humans wearing hyper-realistic silicone masks, as well as still images of real humans, in two experiments. In both experiments, human-like stimuli were harder to distinguish from real human faces than stimuli that were clearly not designed to mimic humans but contain facial features (mechanical robots and Halloween masks). Stimulus evoked potentials (electromagnetic brain responses) did not show convincing differences between faces and either androids or realistic masks when using traditional univariate statistical tests. However, a more sensitive multivariate analysis identified two regions of above-chance decoding, indicating neural differences in the response between human faces and androids/realistic masks. The first time window was around 100–200 ms post stimulus onset, and most likely corresponds to low-level image differences between conditions. The second time window was around 600 ms post stimulus onset, and may reflect top-down processing, and may correspond to the subjective sense of unease characteristic of the uncanny valley effect. Objective neural components might be used in future to rapidly train generative artificial intelligence systems to produce more realistic images that are perceived as natural by human observers.

Electrocardiogram analysis for cardiac arrhythmia classification and prediction through self attention based auto encoder

The SUbventral-Gland Regulator (SUGR-1) of nematode virulence

Pathogens must precisely tailor their gene expression to cause infection. However, a signaling cascade from host signal to effector production has remained elusive for metazoan pathogens. Here, we show that plants contain molecular signals, termed effectostimulins, that activate the first identified regulator of plant-parasitic nematode effectors. SUGR-1 directly binds effector promoters, and is central to a transcriptional network that activates 58 effector genes. Importantly, we demonstrate that downregulation of sugr-1 inhibits parasitism, underlining SUGR-1 signaling as a valuable target for crop protection and food security. This, in the wider context of nematodes as parasites of humans and other animals, has scope for potentially broader impact: Disrupting effector production could, in principle, be applied to any pathogen that secrets effectors.

Evaluation of community pharmacists’ knowledge and attitude about Hajj and Umrah-related health conditions in the western region, Saudi Arabia: A cross-sectional study

Background During the Hajj and Umrah seasons in Saudi Arabia, pilgrims tend to experience a higher frequency of various health conditions. Respiratory infections, gastrointestinal infections, and food poisoning are among the most prevalent ailments. To address these health concerns, community pharmacists (CPs) have developed standardized treatment protocols. Pharmacists’ skills in medication dispensing, health consultations, and preventive care enhance pilgrims’ well-being in challenging pilgrimage settings. Aims The objective of this study was to investigate the knowledge and attitude of CPs towards health conditions related to Hajj and Umrah in the Western Region of Saudi Arabia where the Hajj and Umrah are taking place. Methods Between March and April 2023, an online cross-sectional study using Google form was carried out among CPs who work in the western region of Saudi Arabia. The study made use of a self-administered questionnaire consisting of four sections that aimed to obtain information about the CPs’ knowledge and attitudes towards health conditions related to Hajj and Umrah. Data analysis was conducted using the Statistical Package for the Social Sciences version 26 (SPSS). Result A total of 496 CPs completed and returned the questionnaire, by giving a response rate of 99.2% (n = 500). Among them, 55.1% were aware of the necessary vaccines for Hajj and Umrah. Approximately 46.6% of CPs provided health-related advice to pilgrims. The most common health conditions experienced by pilgrims were diarrhea (59.5%), followed by flu and cough (58%), gastrointestinal diseases (39.4%), food poisoning (33.6%), viral fever, and heat stroke (24.4%). Regarding attitudes towards vaccination, 55.3% of CPs agreed that vaccination is safe for pilgrims aged 65 years and above, and 65.7% agreed that vaccination can help reduce medical costs during Hajj and Umrah seasons. Additionally, 61.1% of CPs recommended updating immunization against vaccine-preventable diseases for all travelers to ensure a safe Hajj and Umrah. The overall mean knowledge of CPs regarding vaccination during Hajj and Umrah was 4.739(2.49) (median = 5; Range = 0-9). However, 56.7% of CPs demonstrated good knowledge, while 43.3% reported poor knowledge regarding vaccination during Hajj and Umrah. Conclusion The community pharmacists (CPs) in the Mecca region were found to have good knowledge, with more than half of them having positive attitudes about vaccination for Hajj and Umrah-related health conditions. It is crucial to enhance the knowledge and attitudes of CPs to provide better care and participate in reliable and supportive healthcare and counseling sessions for managing various health infections.

Cavity nesting birds show behavioural plasticity to simulated territorial intrusions in response to natural resource pulses

Abstract We investigated the impact of two natural pulses (food and nesting resources) on intra- and inter-specific territorial behaviour of species that co-occur year-round in multi-species groups. We simulated conspecific and heterospecific territorial intrusions in two cavity-nesting species using 974 model presentations with territorial song playbacks during and after a dual resource pulse of insect (bark beetle) prey and nest cavities across 5 years in British Columbia, Canada. As beetle abundance increased, both species increased aggression toward conspecific intruders. At peak beetle abundance the (typically) subordinate generalist insectivore, mountain chickadee (Poecile gambeli), attacked model intruders more frequently than did the dominant bark insectivore, red-breasted nuthatch (Sitta canadensis), and responded more aggressively to nuthatch intruders than to conspecifics. The reversal in the inter-specific dominance hierarchy suggests that behavioural mechanisms governing community structure may change during resource pulses. Overall, we suggest that social interactions between chickadees and nuthatches are dynamic with high complexity and flexibility to major ecological changes. Future work that examines the fitness consequences of temporal variation in community dynamics and resiliency could help to reveal evolutionary mechanisms by which these species co-exist.

Neanderthal adaptive introgression shaped <i>LCT</i> enhancer region diversity without linking to lactase persistence in East Asian populations

Positive selection at the 2q21.3 enhancer region for lactase gene ( LCT ) expression in Europeans and Africans has long been attributed to selection for lactase persistence (LP), the capacity of adults to digest lactose in milk, presumably because of the benefits associated with milk consumption. While considered a classic example of gene–culture coevolution, recently doubts have been raised about the link between selection at 2q21.3 and LP. Analysis of additional populations could shed further light; here, we demonstrate that a haplotype spanning ~467 kb at the 2q21.3 locus has risen to high frequency in East Asians (~25%) but is absent from Africans and Europeans. This haplotype likely derived from Neanderthals and has been under positive selection in East Asians. The East Asian–specific haplotype is associated with alterations in LCT expression and promoter methylation in certain cell types, similar to what is observed with LP-associated haplotypes in Europeans. Moreover, its frequency is comparable to that of LP in East Asians, suggesting a potential association with LP in East Asians. However, it is highly unlikely that selection in East Asians was related to milk-drinking habits. We find that this haplotype impacts the expression of UBXN4 , DARS1, and DARS1-AS1 in immune cells and is associated with neutrophil and white blood cell counts. Hence, the selection might be linked to certain aspects of immune function. This implies that selection on 2q21.3 has thus either occurred for different reasons in different populations or the selection observed in other populations is also not due to LP.