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With the rapid advances in technology and life science, biological security is now at a defining moment. The mandate of the 2022 Biological and Toxin Weapons Convention 9th Review Conference emphasised the urgent need for new tools to strengthen the Convention. In this paper, we review the development and efforts of the International Nuclear Security Education Network (INSEN) to provide examples of best practice for implementation of the newly founded International Biological Security Education Network (IBSEN). Learning from the lessons of the INSEN, the sustainability of the network through continuous engagement of its members is essential for the further development of global biosecurity education.

Abstract Background Auditory reaction time (ART) and visual reaction time (VRT) are critical for patients with stroke, especially during balance training. According to the research, most patients with stroke are fatigued at sub-maximal levels during their stroke rehabilitation. Sub-maximal physical fatigue may affect ART and VRT and impede stroke rehabilitation. Hence, it is important to study the effect of submaximal physical fatigue on ART and VRT. A pilot study on healthy adults paves the way for further research on stroke rehabilitation. The purpose of this research is to find out if submaximal physical fatigue affects ART and VRT in healthy adults. In addition, this study also determines if ART and VRT recover to baseline after 15 min of rest post-fatigue session. Furthermore, the goal is to determine whether sub-maximal physical fatigue has a greater effect on ART or VRT. Methods A repeated measures within-subject design was used in the study. Eighteen healthy participants (median age 24 years) completed two sessions of a sub-maximal fatigue protocol on a cycle ergometer until they reached a rating of perceived exertion (RPE) of 15 on a scale of 6–20. Two different fatigue sessions were conducted (one to study the effects of fatigue on ART and the other for VRT). ART or VRT was measured on computer software before (PRE), immediately after (POST-0), and 15 min after (POST-15) the sub-maximal physical fatigue protocol. Results The value of median ART increased significantly from PRE to POST-0 (P = 0.002) and it decreased significantly at POST-15 (P = 0.010). Similarly, the value of mean VRT increased from PRE to POST-0 (P = 0.001) before decreasing significantly at POST-15 (P = 0.001). There was no significant difference between the effects of submaximal fatigue on ART and VRT (P = 0.156). Conclusion Due to submaximal physical fatigue, ART and VRT were slower, but they returned to baseline after 15 min of rest. Submaximal physical fatigue had an equal impact on ART and VRT. As balance training requires quicker ART and VRT for optimal outcomes, it may be better if the physiotherapists consider a 15-min rest period between the exercise and balance training in patients with stroke.

Abstract Background Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5 −/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5 −/y rats. Methods To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5 −/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 −/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. Conclusions Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. Limitations This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

In this paper we highlight how the apparent double coverage of toxins and bioregulators by both the Biological and Toxin Weapons Convention (BTWC) and the Chemical Weapons Convention (CWC) in fact masks a regulatory gap that has left such potentially dangerous agents neglected by both the control regimes during a period of rapid advances in relevant chemical, life and associated sciences and technologies. We first review what toxins, bioregulators and other mid-spectrum agents are and why they are of such concern and then examine how they are regulated under the BTWC and CWC. This paper then examines an illustrative range of contemporary chemical and life science research and associated activities of concern drawn from case study research on China, India, Iran, Russia, Syria and the United States, and assesses how the CWC and BTWC States Parties have inadequately addressed these threats. We then examine how both the CWC and BTWC Review Conferences failed to address these long-term challenges, and we end by providing a series of recommendations for how both regimes can be strengthened in this area.

Abstract Cancer’s complexity is in part due to the presence of intratumor heterogeneity and the dynamic nature of cancer cell plasticity, which create substantial obstacles in effective cancer management. Variability within a tumor arises from the existence of diverse populations of cancer cells, impacting the progression, spread, and resistance to treatments. At the core of this variability is the concept of cellular plasticity - the intrinsic ability of cancer cells to alter their molecular and cellular identity in reaction to environmental and genetic changes. This adaptability is a cornerstone of cancer’s persistence and progression, making it a formidable target for treatments. Emerging studies have emphasized the critical role of such plasticity in fostering tumor diversity, which in turn influences the course of the disease and the effectiveness of therapeutic strategies. The transformative nature of cancer involves a network of signal transduction pathways, notably those that drive the epithelial-to-mesenchymal transition and metabolic remodeling, shaping the evolutionary path of cancer cells. Despite advancements, our understanding of the precise molecular machinations and signaling networks driving these changes is still evolving, underscoring the necessity for further research. This editorial presents a series entitled “Signaling Cancer Cell Plasticity and Intratumor Heterogeneity” in Cell Communication and Signaling, dedicated to unraveling these complex processes and proposing new avenues for therapeutic intervention.

Rodent studies have shown that alternative splicing in neurons plays important roles in development and maturity, and is regulatable by signals such as electrical activity. However, rodent-human similarities are less well explored. We compared basal and activity-dependent exon splicing in cortical-patterned human ESC-derived neurons with that in cortical mouse ESC-derived neurons, primary mouse cortical neurons at two developmental stages, and mouse hippocampal neurons, focussing on conserved orthologous exons. Both basal exon inclusion levels and activity-dependent changes in splicing showed human-mouse correlation. Conserved activity regulated exons are enriched in RBFOX, SAM68, NOVA and PTBP targets, and centered on cytoskeletal organization, mRNA processing, and synaptic signaling genes. However, human-mouse correlations were weaker than inter-mouse comparisons of neurons from different brain regions, developmental stages and origin (ESC vs. primary), suggestive of some inter-species divergence. The set of genes where activity-dependent splicing was observed only in human neurons were dominated by those involved in lipid biosynthesis, signaling and trafficking. Study of human exon splicing in mouse Tc1 neurons carrying human chromosome-21 showed that neuronal basal exon inclusion was influenced by cis-acting sequences, although may not be sufficient to confer activity-responsiveness in an allospecific environment. Overall, these comparisons suggest that neuronal alternative splicing should be confirmed in a human-relevant system even when exon structure is evolutionarily conserved.

Abstract Mantle cell lymphoma (MCL) is an incurable B-cell malignancy characterized by a high clinical variability. Therefore, there is a critical need to define parameters that identify high-risk patients for aggressive disease and therapy resistance. B-cell receptor (BCR) signaling is crucial for MCL initiation and progression and is a target for therapeutic intervention. We interrogated BCR signaling proteins (SYK, LCK, BTK, PLCγ2, p38, AKT, NF-κB p65, and STAT5) in 30 primary MCL samples using phospho-specific flow cytometry. Anti-IgM modulation induced heterogeneous BCR signaling responses among samples allowing the identification of two clusters with differential responses. The cluster with higher response was associated with shorter progression free survival (PFS) and overall survival (OS). Moreover, higher constitutive AKT activity was predictive of inferior response to the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib. Time-to-event analyses showed that MCL international prognostic index (MIPI) high-risk category and higher STAT5 response were predictors of shorter PFS and OS whilst MIPI high-risk category and high SYK response predicted shorter OS. In conclusion, we identified BCR signaling properties associated with poor clinical outcome and resistance to ibrutinib, thus highlighting the prognostic and predictive significance of BCR activity and advancing our understanding of signaling heterogeneity underlying clinical behavior of MCL.

Objective The metatarsophalangeal joints (MTPJs) are the most common location for synovitis in people with rheumatoid arthritis (RA), yet their association with plantar foot pressures has received very little attention. This study aimed to determine whether plantar pressures differed based on sonographic evidence of MTPJ synovitis in people with RA. Method Ultrasound was used to assess synovitis (grey scale synovial hypertrophy and power Doppler signal) in MTPJs 1 to 5 using the combined EULAR/Outcome Measures in Rheumatology scoring system. Peak pressure (PP) and pressure time integrals (PTIs) were assessed during barefoot walking for seven plantar foot regions (heel, midfoot, first metatarsal, second metatarsal, third to fifth metatarsals, hallux, lesser toes). Mixed‐effects linear regression was used to determine the difference in PP and PTI between MTPJs with none/minimal synovitis and MTPJs with moderate/severe synovitis. Results Thirty‐five participants with RA were included. Mean age was 66.3 years and mean disease duration was 22.2 years. Participants with sonographic evidence of moderate/severe synovitis at the first MTPJ had reduced PTI at the hallux compared with those with none/minimal synovitis at this joint (P = 0.039). Participants with moderate/severe synovitis at the second MTPJ and fourth MTPJ had reduced PP and reduced PTI at lesser toes compared with those with none/minimal synovitis in these joints (all P ≤ 0.048). No significant differences were observed for synovitis in other joints. Conclusion These findings may be suggestive of an inverse relationship between plantar pressure and soft tissue pathology, which is consistent with an offloading strategy and reduced use of the toes during propulsion.

Abstract Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies. Graphical Abstract

Microglia play crucial roles in immune responses and contribute to fundamental biological processes within the central nervous system (CNS). In neurodegenerative diseases, microglia undergo functional changes and can have both protective and pathogenic roles. Microglia in the retina, as an extension of the CNS, have also been shown to be affected in many neurological diseases. While our understanding of how microglia contribute to pathological conditions is incomplete, non-invasive in vivo imaging of brain and retinal microglia in living subjects could provide valuable insights into their role in the neurodegenerative diseases and open new avenues for diagnostic biomarkers. This mini-review provides an overview of the current brain and retinal imaging tools for studying microglia in vivo. We focus on microglia targets, the advantages and limitations of in vivo microglia imaging approaches, and applications for evaluating the pathogenesis of neurological conditions, such as Alzheimer’s disease and multiple sclerosis.