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3D printed sex-specific medicines: Excipient-mediated modulation boosts systemic drug exposure by more than three-fold in male rats
No full textExcipients, historically regarded as inert, are now being recognised for their ability to actively modulate biological targets, including intestinal efflux transporters such as P-glycoprotein (P-gp). We have previously shown that polyethylene glycol (PEG) excipients can selectively enhance the oral bioavailability of P-gp substrate drugs, particularly in males. This study examined how 3D printed formulations containing PEG 2000 influence the pharmacokinetics of silodosin, a P-gp substrate drug used for the treatment of benign prostatic hyperplasia in ageing men, using male and female Wistar rats. Initial concentration screening studies with aqueous solutions revealed that a 1 % w/v PEG 2000 concentration (corresponding to 5 mg) maximally increased silodosin systemic exposure by 36 % compared to the control in males, with no significant effect in females, confirming sex-specific pharmacokinetic modulation. To exploit this unique phenomenon, 5 mg of PEG 2000 was incorporated as a functional excipient into silodosin-loaded printlets (3D printed tablets) fabricated via direct powder extrusion. The printlets achieved complete drug release within 70 min, exhibiting highly similar dissolution profiles between test and control formulations (f2 = 88.6). In vivo pharmacokinetic studies revealed that printlets containing PEG 2000 resulted in a 213 % increase in plasma exposure in males relative to the control, while no significant enhancement was observed in females. By integrating biological variables such as sex into formulation design and leveraging the promising potential of 3D printing, this study demonstrates for the first time how excipient functionality can be harnessed to develop sex-specific oral therapies and advance personalised oral drug delivery. These findings pave the way for the future clinical translation of sex- and excipient-driven therapeutic approaches
Research on public trust and police legitimacy: where next, and why?
No full textPublic trust in policing and the legitimacy police command are critical issues for law enforcement agencies, policymakers, and researchers worldwide. Trust and legitimacy matter for police and policed: the former depend on public cooperation for effective functioning, while the latter rely on police for safety and problem resolution. In this article I briefly review existing research on the antecedents and consequents of trust and legitimacy before going on to consider gaps in the current evidence base. These include conceptual clarity and consistent measurement of key constructs, the need to consider antecedents of trust and legitimacy beyond procedural justice, a relative death of longitudinal studies, and a similar lack of studies exploring trust and legitimacy in the digital era. There is also a need for methodological innovation, greater engagement with community perspectives, and development of implementation strategies to translate research into practice
The Governance Triangle: Economic interactions in civil society, the state, and the market
No full textInteractions in civil society – in firms, families, neighborhoods, identity groups, and other face-toface settings – have in common that relationships are personal and enduring, and as a result,
identity and other-regarding preferences are important motivations (for better or worse). Here we
add civil society to markets and states as a third form of governance of the economy, creating the
governance triangle. We provide evidence that themes related to civil society have assumed
substantially greater importance in economic research since the 1970s. We use a standard
principal-agent model of employment in private firms to reveal three characteristics of interactions
in civil society: the role of face-to-face interactions, social norms, and the private exercise of
power. We show that market failures and other coordination problems can sometimes be more
successfully addressed by civil society than by state or market governance. Civil society may have
comparative institutional advantage where information available to state and market actors is
limited, restricting the reach of complete contracts and enforceable government regulations,
conditional on conflicts of interest being modest. When based on us-versus-them forms of identity,
however, civil society governance may promote preferences antithetical to a liberal and democratic
society
Field effects in penile squamous cell carcinoma: Insights from Wnt-related protein expression
No full textBACKGROUND: Penile squamous cell carcinoma (PeSCC) is thought to arise through two principal pathogenic pathways, via lichen sclerosus and high-risk human papillomavirus. Molecular alterations in morphologically normal peri tumoral environment are known as ‘field effect’ and are recognised in other epithelial cancers. Whether similar field effects exist around PeSCC is unknown. As Wnt signaling is a key driver of carcinogenesis, including in PeSCC, perturbations in this pathway may represent an early event in penile tumour evolution. OBJECTIVES: To determine whether a peritumoral molecular field exists around PeSCC by
assessing expression and spatial colocalisation of key Wnt-related proteins in canceradjacent versus normal penile skin. METHODS: A specialist genitourinary histopathologist reviewed haematoxylin and eosin–stained sections and identified tumour-involved regions, demarcating them from adjacent epithelium that appeared morphologically normal. In this study, immunofluorescencestained formalin fixed paraffin embedded tissue arrays were probed for Wnt4, cyclin D1, MMP7 and c-MYC proteins. The expression intensity and spatial colocalisation metrics were quantified. Comparisons between normal and cancer-adjacent tissues from 41 patients were conducted for the epidermis and dermis. RESULTS: Cancer-adjacent tissue showed significant downregulation of Wnt4 in both epidermis and dermis (p < 0.001), and marked upregulation of c-MYC (epidermis: Cohen’s d = 2.05; dermis: d = 1.37). MMP7 and Cyclin D1 expression was not significantly changed. Colocalisation analysis revealed significantly increased Global Intersection Coefficients for five combinations within the epidermis (Wnt4/cyclin D1, Wnt4/MMP7, Wnt4/c-MYC, cyclin D1/c-MYC, MMP7/c-MYC), and for two within the dermis (Wnt4/MMP7, Wnt4/c-MYC), indicating enhanced signalling convergence in canceradjacent tissues. CONCLUSIONS: This study provides the first evidence of molecular changes in peritumour tissue to
demonstrate field effect in PeSCC, characterised by downregulation of Wnt4,
upregulation of c-MYC, and altered spatial colocalisation of Wnt-related proteins in cancer-adjacent skin. These findings suggest that peritumoral tissues exhibit early molecular alterations that extend beyond the morphologically defined tumour margin. Recognising these changes may have implications for understanding tumour microenvironment conditioning and for the future development of biomarkers relevant to margin assessment in penile carcinogenesis
Genotype-phenotype characteristics and disease progression of FAN1-related karyomegalic tubulointerstitial nephropathy
No full textINTRODUCTION: Biallelic variants in Fanconi Anemia-associated Nuclease 1 (FAN1) cause karyomegalic tubulointerstitial nephropathy (KIN), a condition poorly characterized in terms of kidney survival, patient survival, and clinical characteristics. Therefore, we undertook a cross-sectional collaborative study to better characterize KIN-FAN1. METHODS: To gather data, we distributed a REDCap survey on clinical characteristics and genetic variants of KIN-FAN1 to colleagues and case report authors. RESULTS: Based on the survey, we identified 86 families affected (122 individuals) from 22 countries. There were 56 families (83 individuals) with a genetic diagnosis of KIN-FAN1, including 38 distinct FAN1 variants, and 30 families (39 individuals) with KIN with no predisposing risk factors and without molecular FAN1 testing. The median age at presentation was 38.5 years (interquartile range: 29-43), 62% male. Of the cohort, 46% had asymptomatic elevation of liver function tests, 39% had pulmonary complications, and 6% developed cancer. The median age of kidney failure was 45 years (95% confidence interval (CI): 38-56). Of the cohort, 27.1% died at a median age of 55 years (95% CI: 43-75). Pulmonary complications was/were the cause of death in 15.4% of patients on dialysis and 23.1% of kidney transplant recipients. Compared to other variants, patients with the p.W707X-FAN1 variant were at a significantly higher risk of pulmonary complications (adjusted odds ratio: 8.26 (95% CI: 1.7-40.1); and had a significantly shorter lifespan (hazard ratio: 3.24 (95% CI: 1.13-9.28). No genetic covariates were statistically associated with the progression to kidney failure. CONCLUSION: Patients with KIN-FAN1 develop kidney failure at a median age of 45 years. Survival is compromised with many dying of pulmonary disease
Male Depression: The Centre for Male Psychology's Position Statement on Identifying, Understanding, and Treating Men's Experiences of Depression
No full textDepression in men is under-recognised, under-diagnosed, and often manifests differently in men than in women. Men are less likely than women to seek help, more likely to externalise symptoms (e.g., aggression), and self-medicate (e.g., alcohol abuse).
The Centre for Male Psychology is committed to advancing evidence, improving clinical practice, and influencing public discourse on men’s mental health (Centre for Male Psychology, 2021). In this position statement we recommend a male-centred approach to understanding male depression. We hope that this document will bring about a change in how we research, treat, and talk about men’s depression
Dissecting novel object exploration in a fully automated homecage-based novel object recognition test
No full textThe novel object recognition (NOR) test is widely used to assess memory in rodents, offering strong ethological validity, cross-species relevance, and specificity for hippocampal-parahippocampal function. However, standard implementations are often confounded by uncontrolled factors. Here, we present a fully automated, homecage-based NOR test for evaluating long-term object memory in mice. Our empirically informed computational model demonstrates the robustness of this approach despite uncertainties in defining exploratory behavior. Mice reliably preferred novel over familiar objects after both 24-h and 7-day delays, with recognition emerging already at a distance. Results were replicated across two facilities. Notably, recognition after 24 h depended on prior interactions with the replaced object, but not after 7 days. We also show that external factors can bias exploration, which can be mitigated using relative discrimination measures. This automated paradigm enhances standardization, reproducibility, and our understanding of the factors influencing object exploratory behaviors and object memory
Resisting Manipulative Bots in Meme Coin Copy Trading: A Multi-Agent Approach with Chain-of-Thought Reasoning
No full textA mid‐Proterozoic coupled Sr and Li isotope excursion and its potential connection to enhanced weathering and ocean oxygenation at 1.57 Ga
No full textChemical weathering is a critical Earth system process that regulates climate, ocean chemistry and the long-term carbon cycle. However, the intensity and variability of chemical weathering remain insufficiently constrained for the mid-Proterozoic (∼1.8‒0.8 Ga), greatly limiting our understanding of the environmental context to early eukaryotic evolution. Here, we report the first coupled positive seawater 87Sr/86Sr (∼0.0007) and δ7Li (∼5‰) isotope excursions of the Mesoproterozoic Era (1.6‒1.0 Ga), which we argue signifies a substantial weathering event at ∼1.57 Ga, characterised by increased silicate weathering rates and decreased weathering congruency. Drawing on independent geological evidence, we posit that enhanced volcanic CO2 degassing, possibly alongside accretional orogenesis, increased denudation rates and invigorated the hydrological cycle, amplifying silicate weathering and secondary clay formation. This weathering pulse broadly coincided with coeval ocean oxygenation and carbon cycle disruption, implicating it in the appearance of the earliest known decimetre-scale, multicellular eukaryotic fossils