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Abstract Certain corona- and influenza viruses utilize type II transmembrane serine proteases for cell entry, making these enzymes potential drug targets for the treatment of viral respiratory infections. In this study, the cytotoxicity and inhibitory effects of seven matriptase/TMPRSS2 inhibitors (MI-21, MI-463, MI-472, MI-485, MI-1900, MI-1903, and MI-1904) on cytochrome P450 enzymes were evaluated using fluorometric assays. Additionally, their antiviral activity against influenza A virus subtypes H1N1 and H9N2 was assessed. The metabolic depletion rates of these inhibitors in human primary hepatocytes were determined over a 120-min period by LC–MS/MS, and PK parameters were calculated. The tested compounds, with the exception of MI-21, displayed potent inhibition of CYP3A4, while all compounds lacked inhibitory effects on CYP1A2, CYP2C9, CYP2C19, and CYP2D6. The differences between the CYP3A4 activity within the series were rationalized by ligand docking. Elucidation of PK parameters showed that inhibitors MI-463, MI-472, MI-485, MI-1900 and MI-1904 were more stable compounds than MI-21 and MI-1903. Anti-H1N1 properties of inhibitors MI-463 and MI-1900 and anti-H9N2 effects of MI-463 were shown at 20 and 50 µM after 24 h incubation with the inhibitors, suggesting that these inhibitors can be applied to block entry of these viruses by suppressing host matriptase/TMPRSS2-mediated cleavage.

Mental disorders are increasingly understood as involving complex alterations of self that emerge from dynamical interactions of constituent elements, including cognitive, bodily, affective, social, narrative, cultural and normative aspects and processes. An account of self that supports this view is the pattern theory of self (PTS). The PTS is a non-reductive account of the self, consistent with both embodied-enactive cognition and phenomenological psychopathology; it foregrounds the multi-dimensionality of subjects, stressing situated embodiment and intersubjective processes in the formation of the self-pattern. Indications in the literature already demonstrate the viability of the PTS for formulating an alternative methodology to better understand the lived experience of those suffering mental disorders and to guide mental health research more generally. This article develops a flexible methodological framework that front-loads the self-pattern into a minimally structured phenomenological interview. We call this framework ‘Examination of Self Patterns’ (ESP). The ESP is unconstrained by internalist or externalist assumptions about mind and is flexibly guided by person-specific interpretations rather than pre-determined diagnostic categories. We suggest this approach is advantageous for tackling the inherent complexity of mental health, the clinical protocols and the requirements of research.

Background: Moderately hypofractionated radiotherapy regimens or stereotactic body radiotherapy (SBRT) are standard of care for localised prostate cancer. However, some patients are unable or unwilling to travel daily to the radiotherapy department and do not have access to, or are not candidates for, SBRT. For many years, The Royal Marsden Hospital NHS Foundation Trust has offered a weekly ultra-hypofractionated radiotherapy regimen to the prostate (36 Gy in 6 weekly fractions) to patients unable/unwilling to travel daily. Methods: The current study is a retrospective analysis of all patients with non-metastatic localised prostate cancer receiving this treatment schedule from 2010 to 2015. Results: A total of 140 patients were included in the analysis, of whom 86 % presented with high risk disease, with 31 % having Gleason Grade Group 4 or 5 disease and 48 % T3 disease or higher. All patients received hormone treatment, and there was often a long interval between start of hormone treatment and start of radiotherapy (median of 11 months), with 34 % of all patients having progressed to non-metastatic castrate-resistant disease prior to start of radiotherapy. Median follow-up was 52 months. Median progression-free survival (PFS) and overall survival (OS) for the whole group was 70 months and 72 months, respectively. PFS and OS in patients with hormone-sensitive disease at time of radiotherapy was not reached and 75 months, respectively; and in patients with castrate-resistant disease at time of radiotherapy it was 20 months and 61 months, respectively. Conclusion: Our data shows that a weekly ultra-hypofractionated radiotherapy regimen for prostate cancer could be an option in those patients for whom daily treatment or SBRT is not an option.

We extend current models of the halo occupation distribution (HOD) to include a flexible, empirical framework for the forward modeling of the intrinsic alignment (IA) of galaxies. A primary goal of this work is to produce mock galaxy catalogs for the purpose of validating existing models and methods for the mitigation of IA in weak lensing measurements. This technique can also be used to produce new, simulation-based predictions for IA and galaxy clustering. Our model is probabilistically formulated, and rests upon the assumption that the orientations of galaxies exhibit a correlation with their host dark matter (sub)halo orientation or with their position within the halo. We examine the necessary components and phenomenology of such a model by considering the alignments between (sub)halos in a cosmological dark matter only simulation. We then validate this model for a realistic galaxy population in a set of simulations in the Illustris-TNG suite. We create an HOD mock with Illustris-like correlations using our method, constraining the associated IA model parameters, with the $\chi^2_{\rm dof}$ between our model's correlations and those of Illustris matching as closely as 1.4 and 1.1 for orientation--position and orientation--orientation correlation functions, respectively. By modeling the misalignment between galaxies and their host halo, we show that the 3-dimensional two-point position and orientation correlation functions of simulated (sub)halos and galaxies can be accurately reproduced from quasi-linear scales down to $0.1~h^{-1}{\rm Mpc}$. We also find evidence for environmental influence on IA within a halo. Our publicly-available software provides a key component enabling efficient determination of Bayesian posteriors on IA model parameters using observational measurements of galaxy-orientation correlation functions in the highly nonlinear regime.

IntroductionSepsis remains a major cause of mortality and morbidity in infants. In recent years, several gene marker strategies for the early identification of sepsis have been proposed but only a few have been independently validated for adult cohorts and applicability to infant sepsis remains unclear. Biomarkers to assess disease severity and risks of shock also represent an important unmet need.MethodsTo elucidate characteristics driving sepsis in infants, we assembled a multi-transcriptomic dataset from public microarray datasets originating from five independent studies pertaining to bacterial sepsis in infant < 6-months of age (total n=335). We utilized a COmbat co-normalization strategy to enable comparative evaluation across multiple studies while preserving the relationship between cases and controls.ResultsWe found good concordance with only two out of seven of the published adult sepsis gene signatures (accuracy > 80%), highlighting the narrow utility of adult-derived signatures for infant diagnosis. Pseudotime analysis of individual subjects’ gene expression profiles showed a continuum of molecular changes forming tight clusters concurrent with disease progression between healthy controls and septic shock cases. In depth gene expression analyses between bacteremia, septic shock, and healthy controls characterized lymphocyte activity, hemostatic processes, and heightened innate immunity during the molecular transition toward a state of shock.DiscussionOur analysis revealed the presence of multiple significant transcriptomic perturbations that occur during the progression to septic shock in infants that are characterized by late-stage induction of clotting factors, in parallel with a heightened innate immune response and a suppression of adaptive cell functionality.

Purpose: The urethra is a critical structure in prostate radiotherapy planning; however, it is impossible to visualise on CT. We developed a surrogate urethra model (SUM) for CT-only planning workflow and tested its geometric and dosimetric performance against the MRI-delineated urethra (MDU). Methods: The SUM was compared against 34 different MDUs (within the treatment PTV) in patients treated with 36.25Gy (PTV)/40Gy (CTV) in 5 fractions as part of the PACE-B trial. To assess the surrogate's geometric performance, the Dice similarity coefficient (DSC), Hausdorff distance (HD), mean distance to agreement (MDTA) and the percentage of MDU outside the surrogate (UOS) were calculated. To evaluate the dosimetric performance, a paired t-test was used to calculate the mean of differences between the MDU and SUM for the D99, D98, D50, D2 and D1. The D(n) is the dose (Gy) to n% of the urethra. Results: The median results showed low agreement on DSC (0.32; IQR 0.21–0.41), but low distance to agreement, as would be expected for a small structure (HD 8.4mm (IQR 7.1–10.1mm), MDTA 2.4mm (IQR, 2.2mm-3.2mm)). The UOS was 30% (IQR, 18–54%), indicating nearly a third of the urethra lay outside of the surrogate. However, when comparing urethral dose between the MDU and SUM, the mean of differences for D99, D98 and D95 were 0.12Gy (p=0.57), 0.09Gy (p=0.61), and 0.11Gy (p=0.46) respectively. The mean of differences between the D50, D2 and D1 were 0.08Gy (p=0.04), 0.09Gy (p=0.02) and 0.1Gy (p=0.01) respectively, indicating good dosimetric agreement between MDU and SUM. Conclusion: While there were geometric differences between the MDU and SUM, there was no clinically significant difference between urethral dose-volume parameters. This surrogate model could be validated in a larger cohort and then used to estimate the urethral dose on CT planning scans in those without an MRI planning scan or urinary catheter.

Kaposi's sarcoma herpesvirus (KSHV) is a leading cause of malignancy in AIDS and current therapies are limited. Like all herpesviruses, KSHV infection can be latent or lytic. KSHV latency-associated nuclear antigen (LANA) is essential for viral genome persistence during latent infection. LANA also maintains latency by antagonizing expression and function of the KSHV lytic switch protein, RTA. Here, we find LANA null KSHV is not capable of lytic replication, indicating a requirement for LANA. While LANA promoted both lytic and latent gene expression in cells partially permissive for lytic infection, it repressed expression in non-permissive cells. Importantly, forced RTA expression in non-permissive cells led to induction of lytic infection and LANA switched to promote, rather than repress, most lytic viral gene expression. When basal viral gene expression levels were high, LANA promoted expression, but repressed expression at low basal levels unless RTA expression was forcibly induced. LANA's effects were broad, but virus gene specific, extending to an engineered, recombinant viral GFP under control of host EF1α promoter, but not to host EF1α. Together, these results demonstrate that, in addition to its essential role in genome maintenance, LANA broadly regulates viral gene expression, and is required for high levels of lytic gene expression during lytic infection. Strategies that target LANA are expected to abolish KSHV infection.