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Realistic physics-based 3D earthquake simulation for source-to-structure wave propagation consists of a powerful numerical tool for seismic response prediction of critical structures submitted to high safety standards. Structural response considering soil–structure interaction (SSI) is usually estimated by Finite Element Method (FEM) approach, as it is considered as the most flexible numerical approach for nonlinear structural dynamics. However, current engineering practice considers seismic input motion as vertically incident plane waves, despite the fact that this assumption excludes wave passage effects for large infrastructures and surface waves appearing from possible local basin effects. In this framework, a realistic input excitation needs to be defined as an input excitation of the FEM model, accounting for (i) a realistic dynamic excitation, (ii) wave propagation path in the regional scale, and (iii) local site-effects. The Domain Reduction Method (DRM), which allows for the imposition of a 3D complex incident wave field as an input to the SSI model, is adapted and examined here in a Spectral Element Method (SEM) – FEM weak coupling approach. The weak coupling is verified at first for a canonical case-study and for an increasing complexity of the dynamic excitation: (i) double-couple point-source and (ii) extended fault. An optimization approach, based on the decimation of SEM output signal, is then examined in order to decrease the computational burden by maintaining the same accuracy of the final solution. The SEM-FEM weak coupling is then used to study the SSI problem, where the impact of the reduced domain size on structural response is examined at first. The current study shows that a reduced domain of dimension greater than 4 × λ s , where λ s is the maximum wavelength, is sufficient for a proper representation of structural response. For a fixed size model, structural and soil responses are then examined for a hypothetical case-study. [ABSTRACT FROM AUTHOR]

In this paper, physics-based numerical simulation (PBS) is employed to render a broad-band (0–10 Hz) realization of the near-field seismic response of the experimental nuclear site of Cadarache, located nearby the active Middle Durance Fault (southeastern France). The sensitivity of the earthquake numerical model to geological features is investigated by comparison with geophysical measurements and past aftershock and by highlighting the amplification induced by the soft sediments below Cadarache. The blind prediction of an M W6 target earthquake is approached by synthesizing four different finite-fault scenarios. The outcome is compared to the standard ground motion prediction equations (GMPEs), unveiling a possible GMPE overestimation of the pseudospectral acceleration ordinates at short natural periods, supporting the actual need to integrate synthetic and empirical predictions when direct observations are not available. [ABSTRACT FROM AUTHOR]

Infrequent stimulus deviations from repetitive sequences elicit mismatch negativity (MMN) even passively, making MMN practical for clinical applications. Auditory MMN is typically elicited by a change in one (or more) physical stimulus parameters (eg, pitch, duration). This lower-order simple MMN (sMMN) is impaired in long-term schizophrenia. However, sMMN contains activity from release from stimulus adaptation, clouding its face validity as purely deviance-related. More importantly, it is unreliably reduced in samples of first-episode psychosis, limiting its utility as a biomarker. Complex pattern-deviant MMN (cMMN) tasks, which elicit early and late responses, are based on higher-order abstractions and better isolate deviance detection. Their abstract nature may increase the sensitivity to processing deficits in early psychosis. However, both the early and late cMMNs are small, limiting separation between healthy and psychotic samples. In 29 healthy individuals, we tested a new dual-rule cMMN paradigm to assess additivity of deviance. Sounds alternated lateralization between left and right, and low and high pitches, creating a left-low, right-high alternating pattern. Deviants were a repeated left-low, violating lateralization and pitch patterns. Early and late cMMNs on the dual-rule task were significantly larger than those on the one-rule extra tone cMMN task ( P  < .05). Further, the dual-rule early cMMN was not significantly smaller than pitch or duration sMMNs ( P  > .48, .28, respectively). These results demonstrate additivity for cMMN pattern-violating rules. This increase in cMMN amplitude should increase group difference effect size, making it a prime candidate for a biomarker of disease presence at first psychotic episode, and perhaps even prior to the emergence of psychosis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The N1 auditory evoked potential amplitude depends heavily on the inter-stimulus interval (ISI). Typically, shorter ISIs result in reduced N1 amplitudes, suggesting a decreased neural response with high stimulus presentation rates. However, an exception known as N1 facilitation occurs with very brief ISIs (∼150-500 ms), where the N1 amplitude increases. This study aimed to further characterize N1 facilitation using an experimental paradigm with a continuous distribution of ISIs (0.25 to 8 s) to identify the specific ISI where N1 facilitation occurs. We also examined the role of ISI history in N1 facilitation and explored correlations between N1 facilitation, overall N1 amplitude and ISI-sensitivity, and results of cognitive tasks. Twenty-nine participants passively listened to a random sequence of auditory clicks at varying intensities (65, 75, or 85 dB) and ISI ranges (0.25-0.5 s, 0.5-1 s, 1-2 s, 2-4 s, 4-8 s) while EEG was recorded. Up to 1800 sweeps were collected in the critical ISI range (0.25 to 0.5 s) where N1 facilitation is expected. Results support N1 facilitation occurring at ISIs under 400 ms (p = 0.03), where N1 amplitudes returned to values seen at longer ISIs (∼1.7 s). Notably, this effect was observed when the ISI two clicks before was shorter than 1.5 s (p = 0.001), but not otherwise (p = 0.37). These findings clarify the temporal dynamics of N1 facilitation and challenge the notion of a rigid, context-independent latent inhibition process explaining this phenomenon., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We study the structure and dynamics of the interface separating a passive fluid from a microtubule-based active fluid. Turbulent-like active flows power giant interfacial fluctuations, which exhibit pronounced asymmetry between regions of positive and negative curvature. Experiments, numerical simulations, and theoretical arguments reveal how the interface breaks up the spatial symmetry of the fundamental bend instability to generate local vortical flows that lead to asymmetric interface fluctuations. The magnitude of interface deformations increases with activity: In the high activity limit, the interface self-folds invaginating passive droplets and generating a foam-like phase, where active fluid is perforated with passive droplets. These results demonstrate how active stresses control the structure, dynamics, and break-up of soft, deformable, and reconfigurable liquid-liquid interfaces., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Executive control over low-level information processing is impaired proximal to psychosis onset with evidence of recovery over the first year of illness. However, previous studies demonstrating diminished perceptual modulation via attention are complicated by simultaneously impaired perceptual responses. The present study examined the early auditory gamma-band response (EAGBR), a marker of early cortical processing that appears preserved in first-episode psychosis (FEP), and its modulation by attention in a longitudinal FEP sample., Methods: Magnetoencephalography was recorded from 25 FEP and 32 healthy controls (HC) during active and passive listening conditions in an auditory oddball task at baseline and follow-up (4-12 months) sessions. EAGBR inter-trial phase coherence (ITPC) and evoked power were measured from responses to standard tones. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS)., Results: There was no group difference in EAGBR power or ITPC. While EAGBR ITPC increased with attention in HC, this modulation was impaired among FEP. Diminished EAGBR modulation in FEP persisted at longitudinal follow-up. However, among FEP, recovery of EAGBR modulation was associated with reduced PANSS negative scores., Conclusion: FEP exhibit impaired executive control over the flow of information at the earliest stages of sensory processing within auditory cortex. In contrast to previous work, this deficit was observed despite an intact measure of sensory processing, mitigating potential confounds. Recovery of sensory gain modulation over time was associated with reductions in negative symptoms, highlighting a source of potential resiliency against some of the most debilitating and treatment refractory symptoms in early psychosis.

Anomalous Mismatch Negativity (MMN) in psychosis could be a consequence of disturbed neural oscillatory activity at sensory/perceptual stages of stimulus processing. This study investigated effective connectivity within and between the auditory regions during auditory odd-ball deviance tasks. The analyses were performed on two magnetoencephalography (MEG) datasets: one on duration MMN in a cohort with various diagnoses within the psychosis spectrum and neurotypical controls, and one on duration and pitch MMN in first-episode psychosis patients and matched neurotypical controls. We applied spectral Granger causality to MEG source-reconstructed signals to compute effective connectivity within and between the left and right auditory regions. Both experiments showed that duration-deviance detection was associated with early increases of effective connectivity in the beta band followed by increases in the alpha and theta bands, with the connectivity strength linked to the laterality of the MMN amplitude. Compared to controls, people with psychosis had overall smaller effective connectivity, particularly from left to right auditory regions, in the pathway where bilateral information converges toward lateralized processing, often rightward. Blunted MMN in psychosis might reflect a deficit in inter-hemispheric communication between auditory regions, highlighting a "dysconnection" already at preattentive stages of stimulus processing as a model system of widespread pathophysiology., Competing Interests: Declaration of competing interest AB has received lecture fees from Otsuka, Janssen, and Lundbeck, as well as consultant fees from Biogen. GP has received lecture fees from Lundbeck. All other authors report no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To evaluate the diagnostic accuracy of [ 68 Ga]Ga-PSMA-11 PET/CT (PET-PSMA) in local and loco-regional nodal staging compared with histopathological results in intermediate- and high-risk prostate cancer patients treated with radical prostatectomy (RP) and pelvic lymph node dissection (PLND)., Materials Y Methods: A total of 122 intermediate- and high-risk prostate cancer (PCa) patients staged with PET-PSMA and treated with RP (36/122) and RP plus PLND (86/122) from December 2018 to December 2023 were included. Visual and semiquantitative analysis findings using the SUVmax of the molecular imaging were correlated with histopathological results., Results: The primary tumor was visible by PET-PSMA in 96.7% of the patients. A positive correlation was found between PSA levels and SUVmax (Spearman's r: 0.303, p < 0.001). PET-PSMA detected nodal involvement in 25/89 patients (28.08%). The sensitivity, specificity, and diagnostic accuracy of PET-PSMA for detecting nodal involvement were 75%, 82.2%, and 80.9%, respectively. Patients with PSA levels >20 ng/mL, Gleason score ≥7b, ISUP grade >2, and extracapsular extension showed significantly higher SUVmax values. No differences were observed in SUVmax between risk groups or in other histopathological variables., Conclusions: PET-PSMA is an effective tool for the initial staging of intermediate- and high-risk PCa. SUVmax values were significantly higher in patients with unfavorable clinical features., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

Active liquid crystals exert nonequilibrium stresses on their surroundings through constant consumption of energy, giving rise to dynamical steady states not present in equilibrium. The paradigmatic example of an active liquid crystal is a suspension of microtubule bundles powered by kinesin motor proteins, which exhibits self-sustained spatiotemporal chaotic flows. This system has been modelled using continuum theories that couple the microtubule orientation to active flows. Recently the focus has shifted to the interfacial properties of mixtures of active liquid crystals and passive fluids. Active/passive interfaces have been shown to support propagating capillary waves in the absence of inertia and offer a promising route for relating experimental parameters to those of the continuum theory. In this paper we report the derivation of a minimal model that captures the linear dynamics of the interface between an active liquid crystal and a passive fluid. We show that the dynamics of the interface, although powered by active flows throughout the bulk, is qualitatively captured by equations that couple non-reciprocally interface height and nematic director at the interface. This minimal model reproduces the dynamical structure factor evaluated from numerical simulations and the qualitative form of the wave dispersion relation seen in experiments.

Background: Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months., Methods: European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as ≥50% and ≥75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response., Results: Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models., Conclusions: This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: EC has received honoraria from Novartis, Chiesi, Lundbeck, MedScape; his salary has been partially funded by Río Hortega grant Acción Estratégica en Salud 2017–2020, Instituto de Salud Carlos III (CM20/00217). He is a junior editor for Cephalalgia. GE received travel grants and honoraria from Eli-Lilly, Novartis, Lusofarmaco, New Penta and Ecupharma. CNC has received honoraria for advisories, educational or commercial symposia from: Abbvie-Allergan, Kern Pharma, Chiesi, Lilly, Lundbeck, Novartis and Teva Pharmaceuticals And has participated as subinvestigator in Clinical Trials for: Abbvie-Allergan, Amgen, Biohaven, Lilly, Lundbeck, Pfizer and Teva Pharmaceuticals. JAM has received honoraria as consultant and/or speaker for Lilly, Novartis, Teva. FS-C received honoraria from Novartis, Lilly, TEVA, Abbvie. AM has received honoraria from Teva, Lilly, Roche, UCB, Bial, Chiesi, Allergan, Esai, Zambon, Kern Pharma, Pfizer, Biogen Idec, Novartis, TEVA, Merck, Janssen, Neuraxpharm, Genzyme, Sanofi, Bayer, Almirall and/or Celgene. JS received honoraria from Allergan, Lilly, Teva, Novartis. IBB received honoraria for presentations from Novartis, Lilly, Teva, Lundbeck and Abbvie. MW-P received honoraria from Pfizer, Allergan-Abbvie, TEVA, Polpharma. MW-P is member of Editorial Board: The Journal of Headache and Pain. LP received honoraria from Pfizer, Lilly, Abbvie, TEVA, Novartis. AL-R received honoraria for Abbvie, Lilly, Novartis and Teva. IL received honoraria from Novartis, Abbvie, Teva, Eisai, Tecnifar and Bial. LD received honoraria as a speaker for Allergan, Lilly, Teva and Lundbeck. MRA-E, received honoraria from ABBVIE, Lilly, and Novartis. AM has no COI to declare. The University Clinic Hamburg got an unrestricted scientific grant from Novartis (2019-2023). IPM has received honoraria from Allergan Teva, Novartis, Lundbeck and Eli Lilly for lecturing or participating in advisory boards; is principal investigator for phase IV trials sponsored by Novartis, Lundbeck and Teva. CS has received personal fees for lectures/ advisory boards: Novartis, Abbvie and TEVA. PI received honoraria from TEVA, Novartis, Lilly, Abbvie, Lundbeck, Exeltis. ALR received honoraria from TEVA. ABG-V has received speaker honoraria and/or clinical advisor from Novartis, Lilly, TEVA, Exeltis, Chiesi, Abbvie, Pfizer and Lundbeck. RR has received travel grants and/or honoraria for lectures or advisory boards from Allergan/AbbVie, Hormosan, Lilly, Lundbeck, Novartis, Pfizer and Teva. SS reports consultant, speaker or advisory board fees from Abbott, Allergan/Abbvie, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Eli Lilly, Medscape, Medtronic, Novartis, Pfizer, Starmed, Teva and Uriach. EC-G received honoraria from TEVA. DGA has received personal compensation for consulting/advising from the WHO. Non-profit board membership in the Spanish Society of Neurology, and the European Union of Medical Specialist section of Neurology. Research funding from the Regional Health Administration (Gerencia Regional de Salud SACYL) in Castilla y Leon, Spain and Carlos III institute, Madrid, Spain. Speaker/travel grants/ clinical trials from Teva, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis and Biohaven. JP has received honoraria from Abbvie, Lilly, Lundbeck, Novartis and Teva. RG-G received honoraria from Allergan/ Abbvie, Lilly, Lundbeck, Novartis, Pfizer, Tecnifar, Teva. MH-V has received honoraria for participating on advisory boards and for collaborations as consultant, scientific communications, speaker, research support as well as funding for travel and congress-attending expenses for Abbie-Allergan, Novartis, Lundbeck, Lilly, Almirall, Chiesi, Esai, Exeltis, Kern Pharma, Menarini, TEVA and Zambon. His research group has received research grants from Abbie-Allergan and has received funding for clinical trials from Lilly, Novartis, TEVA. JVR received honoraria from Novartis, Abbvie, Lilly, TEVA, Lundbeck. SS-L received honoraria from Allergan, Almirall, Amgen, Chiesi, Eisai, Exeltis, Lilly, Lündbeck, Novartis, Pfizer y Teva. MG-S has received honoraria and been involved in research, education and advisory boards with Teva, Lily, Novartis and Abbvie. CT received personal fees for participating in advisory or for speaking at scientific events from AbbVie, Allergan, Biohaven, Dompé, Eli Lilly, Lundbeck, Novartis and Teva. CT has received research funding from the European Commission, the Italian Ministry of Health and Migraine Research Foundation. JDdT has received honoraria as consultant and/or speaker for Lilly, Novartis, Teva. SDI has received honoraria for advisories, educational or commercial symposia from: Abbvie-Allergan, Fundació Universitat-Empresa, Ipsen Pharma, Kern Pharma, Lilly, Lundbeck, MSD-Organon, Novartis and Teva Pharmaceuticals And has participated as PI in Clinical Trials for: Abbvie-Allergan, Alder, Amgen, Biohaven, Ipsen Pharma, Lilly, Lundbeck, Pfizer and Teva Pharmaceuticals. CGO participated in clinical trials from Novartis, St Jude Medical, Lilly, Lundbeck; TEVA, Biohaven, Pfizer. CGO received honoraria as consultant for Novartis, Lilly, Allergan-abbvie, Lundbeck, TEVA, Pfizer. CGO received honoraria as speaker for Allergan-Abbvie, TEVA, Novartis,Lilly, Chiesi, MSD, Almirall. PB reports personal compensation for consulting, serving on a scientific advisory board, speaking, research support, collaborated for clinical trials or other activities with Abbvie, Alder, Allergan, Amgen, Angelini, Assosalute, Bayer, Biohaven, ElectroCore, Eli-Lilly, Fondazione Ricerca e Salute, GSK, Lundbeck, Lusofarmaco, 1MED, MSD, New Penta, Noema Pharma, Novartis, Pfizer, Stx-Med, Teva, Visufarma, Zambon and serves as President with Italian Association of Headache Sufferers. PP-R has received, in the last 3 years, honoraria as a consultant and speaker for: AbbVie, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer and Teva. Her research group has received research grants from AbbVie, Novartis and Teva; as well as, Instituto Salud Carlos III, EraNet Neuron, European Regional Development Fund (001-P-001682) under the framework of the FEDER Operative Programme for Catalunya 2014-2020 - RIS3CAT; has received funding for clinical trials from AbbVie, Amgen, Biohaven, Eli Lilly, Novartis, Teva. She is the Honorary Secretary of the International Headache Society. She is in the editorial board of Revista de Neurologia. She is an associate editor for Cephalalgia, Headache, Neurologia, The Journal of Headache and Pain and Frontiers of Neurology. She is a member of the Clinical Trials Guidelines Committee of the International Headache Society. She has edited the Guidelines for the Diagnosis and Treatment of Headache of the Spanish Neurological Society. She is the founder of www.midolordecabeza.org. PP-R does not own stocks from any pharmaceutical company. VJG, MMV, GV, JR-M, NFF, AJS, RO, GG, YG-O, GC, AL-B, FVJ, JR-V and VO reports no disclosures. RO reports personal fees from Eli Lilly, Novartis, Teva, and Pfizer, and non-financial support from Novartis, Teva, and Allergan/AbbVie. CT has received honoraria for lectures from TEVA, Lundbeck and for advisory boards from TEVA. He has received travel support from TEVA and Lundbeck. SS received honoraria from TEVA. AH declares no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. HB received honoraria from Novartis, Teva and Lundbeck. NPRP received honoraria from ABBVIE, Lilly and Novartis. CF received honoraria from Novartis and Abbvie. AAL received honoraria for Abbvie, Lilly, Novartis and Teva. EMS received a grant from the Portuguese Headache Society, supported by Teva. MTF has received honoraria from Allergan-AbbVie, Novartis, Chiesi and Teva. AA has received honoraria from Allergan-AbbVie, Novartis, Chiesi. PT received grants and honoria from Novartis, Teva, Eli-Lilly and Allergan. CA received travel grants from FB-Health, Lusofarmaco, Almirall, Eli-Lilly Novartis and Teva. RDI received speaker honoraria from Eli-Lilly, TEVA and Lundbeck. GS received personal fees as speaker or advisory board from Eli Lilly, Novartis, Teva, Lundbeck, Pfizer. SB has received honoraria from Teva. SC has received honoraria from Teva, Lilly, Roche, UCB, Bial, Chiesi, Allergan, Esai, Zambon, Kern Pharma, Pfizer, Biogen Idec, Novartis, TEVA, Merck, Janssen, Neuraxpharm, Genzyme, Sanofi, Bayer, Almirall and/or Celgene. EP reports personal fees from Novartis, Teva and Lilly. ALGP Research funding from the Regional Health Administration (Gerencia Regional de Salud SACYL) in Castilla y Leon, Spain. Speaker/travel grants/ clinical trials from Teva, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer and Biohaven. AS has received honoraria for advisory boards and lectures from Allergan/AbbVie, Hormosan, Lilly, Lundbeck, Novartis, Sanofi, Teva. AGM has received speaker honoraria from TEVA. SQ has received speaker honoraria from Novartis, Lilly and Exeltis. MSR has received consulting fees and honoraria for lectures/presentations from Eli Lily, Lundbeck, Novartis, Teva and Pfizer. Intellectual as Secretary of the European Headache Federation, Review Editor on the Editorial Board of Headache and Neurogenic Pain (specialty section of Frontiers in Neurology). Margarita Sanchez-del-Rio serves as a member of the Board of Directors in the European Headache Federation. ET has received personal fees for lectures/ advisory boards: Novartis, Eli Lilly, Abbvie, TEVA, Roche, Lundbeck, Pfizer, Biogen. Consultant for and owner of stocks and IP in Man & Science. Stocks and IP in Nordic Brain Tech and Keimon Medical. Non-personal research grants from EU, Norwegian Research Council, Dam foundation, KlinBeForsk. Commissioned research (non-personal): Lundbeck, Pfizer. BVP received honoraria from ABBVIE. AOD received honoraria from ABBVIE, Lilly, Teva, Novartis. MR received honoraria from Lilly, Novartis. BC received grants and honoria from Eli-Lilly, Novartis, Teva; SC received travel grants, honoraria for advisory boards, speaker panels or clinical investigation studies from Novartis, Teva, Lilly, Allergan, Abvie, Ibsa, Amgen, Angelini and Lundbeck; FF has received fees for participation on advisory boards, speaker honoraria or consulting activities from Angelini, Cristalfarma, Ecupharma, IBSA, Lundbeck, Novartis, PIAM, Teva; FdO received travel grant, honoraria as a speaker or for partecipating in advisory boards from Novartis, Teva, Neopharmed Gentili, Qbgroup srl, K link srl and Eli-Lilly; MA received grants from Novartis and Lilly; RR received honoraria for speaker panels from Teva, Lilly, Novartis, Allergan, Lundbeck; MZ received travel grants and honoraria from Novartis; MA received travel grants and honoraria from Novartis, Teva, Eli-Lilly and Lundbeck; CF received grants and honoraria from Novartis, Eli Lilly, TEVA, AIM group; AR received travel grants and honoraria from Teva and Eli-Lilly; SZ, RLP, MJRC, VGQ, HCO, SA, IKZ, DGA, IFL, BFP, SB, PRA, AC, AEU, AGG, IM, JPS, VC, AFR, YVE, MT, AS, AC, FZ and MA has no disclosures to declare., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Predicting treatment response would facilitate individualized medical treatment in first-episode psychosis (FEP). We examined relationships between auditory-evoked M100 and longitudinal change in positive symptoms in FEP. M100 was measured from source-resolved magnetoencephalography and symptoms were assessed at initial contact and six months later. M100 at baseline significantly predicted symptom change. Larger M100 at baseline predicted symptom improvement, as did shorter untreated psychosis. Shorter untreated psychosis also correlated with larger M100, and M100 mediated the effect of untreated psychosis on treatment response. Thus, M100 may provide a proximal and objective index of untreated psychosis and a viable route to individualized medicine., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: The tumor suppressor protein p53, a transcription factor playing a key role in cancer prevention, interacts with DNA as its primary means of determining cell fate in the event of DNA damage. When it becomes mutated, it opens damaged cells to the possibility of reproducing unchecked, which can lead to formation of cancerous tumors. Despite its critical role, therapies at the molecular level to restore p53 native function remain elusive, due to its complex nature. Nevertheless, considerable information has been amassed, and new means of investigating the problem have become available., Objectives: We consider structural, biophysical, and bioinformatic insights and their implications for the role of direct and indirect readout and how they contribute to binding site recognition, particularly those of low consensus. We then pivot to consider advances in computational approaches to drug discovery., Materials and Methods: We have conducted a review of recent literature pertinent to the p53 protein., Results: Considerable literature corroborates the idea that p53 is a complex allosteric protein that discriminates its binding sites not only via consensus sequence through direct H-bond contacts, but also a complex combination of factors involving the flexibility of the binding site. New computational methods have emerged capable of capturing such information, which can then be utilized as input to machine learning algorithms towards the goal of more intelligent and efficient de novo allosteric drug design., Conclusions: Recent improvements in machine learning coupled with graph theory and sector analysis hold promise for advances to more intelligently design allosteric effectors that may be able to restore native p53-DNA binding activity to mutant proteins., Clinical Relevance: The ideas brought to light by this review constitute a significant advance that can be applied to ongoing biophysical studies of drugs for p53, paving the way for the continued development of new methodologies for allosteric drugs. Our discoveries hold promise to provide molecular therapeutics which restore p53 native activity, thereby offering new insights for cancer therapies., Graphical Abstract: Structural representation of the p53 DBD (PDBID 1TUP). DNA consensus sequence is shown in gray, and the protein is shown in blue. Red beads indicate hotspot residue mutations, green beads represent DNA interacting residues, and yellow beads represent both., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Biomarkers for cancer immunotherapy are an unmet medical need. The group of Daniela Thommen at the NKI recently reported on novel methodologies based on short-term cultures of patient-derived tumor fragments whose cytokine concentrations in the supernatants and activation markers on infiltrating T cells were associated with clinical response to PD-1 blockade. We set up a similar culture technology with tumor-derived fragments using mouse tumors transplanted into syngeneic immunocompetent mice to test an agonist anti-CD137 mAb and its combinations with anti-PD-1 and/or anti-TGF-β. Increases in IFNγ concentrations in the tissue culture supernatants were detected upon in-culture activation with the anti-CD137 and anti-PD-1 mAb combinations or concanavalin A as a positive control. No other cytokine from a wide array was informative of stimulation with these mAbs. Interestingly, increases in Ki67 and other activation markers were substantiated in lymphocytes from cell suspensions gathered at the end of 72 h cultures. In mice bearing bilateral tumors in which one was excised prior to in vivo anti-CD137 + anti-PD-1 treatment to perform the fragment culture evaluation, no association was found between IFNγ production from the fragments and the in vivo therapeutic outcome in the non-resected contralateral tumors. The experimental system permitted freezing and thawing of the fragments with similar functional outcomes. Using a series of patient-derived tumor fragments from excised solid malignancies, we showed IFNγ production in a fraction of the studied cases, that was conserved in frozen/thawed fragments. The small tumor fragment culture technique seems suitable to preclinically explore immunotherapy combinations., Competing Interests: I. E.-S., I. R., C. H.-M., E. F.-P., A. A., S. S.-G., E. B., G. G., P. M.-G., E. C., J. A. M., S. C, F. D.-C., C. A. and A. T. declare no conflicts of interest. M. F. S. reports grants from Bristol Myers Squibb and Roche during the conduct of the study, as well as grants and personal fees from Roche and Bristol Myers Squibb, and personal fees from Numab outside the submitted work. I. M. reports grants and personal fees from Genmab during the conduct of the study, as well as grants and personal fees from Bristol Myers Squibb, Roche, AstraZeneca, and Pharmamar and personal fees from F-Star, Numab, Pieris, Boehringer Ingelheim, Gossamer, Alligator, Hotspot, Biolinerx, Bioncotech, Dompe, Highlight Therapeutics, Bright Peaks and Boston Therapeutics outside the submitted work., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Cyclam, known for its potent chelation properties, is explored for diverse applications through selective N -functionalization, offering versatile ligands for catalysis, medical research, and materials science. The challenges arising from N -alkylation, which could decrease the coordination properties, are addressed by introducing a robust C -functionalization method. The facile two-step synthesis proposed here involves the click chemistry-based C -functionalization of a hydroxyethyl cyclam derivative using Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC). Boc-protecting groups prevent undesired copper coordination, resulting in compounds with a wide range of functionalities. The optimized synthesis conditions enable C -functional cyclams to be obtained easily and advantageously, with high application potential in the previously cited fields. The methodology has been extended to trehalose-based Siamese twin amphiphiles, enabling efficient gene delivery applications.

Background: Gamma-band activity has been the focus of considerable research in schizophrenia. Discrepancies exist regarding the integrity of the early auditory gamma-band response (EAGBR), a stimulus-evoked oscillation, and its relationship to symptoms in early disease. Variability in task design may play a role. This study examined sensitivity of the EAGBR to stimulus intensity and its relation to symptoms and functional impairments in the first-episode schizophrenia spectrum (FESz)., Method: Magnetoencephalography was recorded from 35 FESz and 40 matched healthy controls (HC) during presentation of 3 tone intensities (75 dB, 80 dB, 85 dB). MRIs were collected to localize auditory cortex activity. Wavelet-transformed single trial epochs and trial averages were used to assess EAGBR intertrial phase coherence (ITPC) and evoked power, respectively. Symptoms were assessed using the Positive and Negative Syndrome Scale., Results: Groups did not differ in overall EAGBR power or ITPC. While HC exhibited EAGBR enhancement to increasing intensity, FESz exhibited reduced power to the 80 dB tone and, relative to HC, increased power to the 75 dB tone. Larger power and ITPC were correlated with more severe negative, thought disorganization, and resistance symptoms. Stronger ITPC was associated with impaired social functioning., Discussion: EAGBR showed no overall deficit at disease onset. Rather, FESz exhibited a differential response across tone intensity relative to HC, emphasizing the importance of stimulus characteristics in EAGBR studies. Associations between larger EAGBR and more severe symptoms suggest aberrant synchronization driving overinclusive perceptual binding that may relate to deficits in executive inhibition of initial sensory activity., Competing Interests: Declaration of competing interest None of the authors reported any biomedical financial interests or potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A novel family of precision-engineered gene vectors with well-defined structures built on trehalose and trehalose-based macrocycles (cyclotrehalans) comprising linear or cyclic polyamine heads have been synthesized through procedures that exploit click chemistry reactions. The strategy was conceived to enable systematic structural variations and, at the same time, ensuring that enantiomerically pure vectors are obtained. Notably, changes in the molecular architecture translated into topological differences at the nanoscale upon co-assembly with plasmid DNA, especially regarding the presence of regions with short- or long-range internal order as observed by TEM. In vitro and in vivo experiments further evidenced a significant impact on cell and organ transfection selectivity. Altogether, the results highlight the potential of trehalose-polyamine/pDNA nanocomplex monoformulations to achieve targeting transfection without the need for any additional cell- or organ-sorting component.