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A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence.

BACKGROUND: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC. METHODS: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier: NCT04460352.

Proteins can self-assemble into amyloid fibrils or amorphous aggregates and thereby cause disease. Molecular chaperones can prevent both these types of protein aggregation, but to what extent the respective mechanisms are overlapping is not fully understood. The BRICHOS domain constitutes a disease-associated chaperone family, with activities against amyloid neurotoxicity, fibril formation, and amorphous protein aggregation. Here, we show that the activities of BRICHOS against amyloid-induced neurotoxicity and fibril formation, respectively, are oppositely dependent on a conserved aspartate residue, while the ability to suppress amorphous protein aggregation is unchanged by Asp to Asn mutations. The Asp is evolutionarily highly conserved in >3000 analysed BRICHOS domains but is replaced by Asn in some BRICHOS families. The conserved Asp in its ionized state promotes structural flexibility and has a pKa value between pH 6.0 and 7.0, suggesting that chaperone effects can be differently affected by physiological pH variations., QC 20230602

Introduction & Objectives: Although surveillance after radical prostatectomy routinely includes repeated Prostate Specific Antigen (PSA)-testing for many years, biochemical recurrence often occurs without further clinical progression. We therefore hypothesised that follow-up can be shortened for many patients without increasing the risk for prostate cancer death. We investigated the long-term probabilities of PSA recurrence, metastases and prostate cancer death in patients without biochemical recurrence 5 and 10 years after radical prostatectomy. Materials & Methods: Between 1989 and 1998, 14 urological centres in Scandinavia randomized patients to the Scandinavian Prostate Cancer Group study number 4 (SPCG-4) trial. Data was collected prospectively. All 306 patients from the SPCG-4 trial who underwent radical prostatectomy within 1 year from inclusion were eligible in our cohort. 4 patients were excluded due to surgery-related death (n=1) or salvage radiotherapy or hormonal treatment within 6 weeks from surgery (n=3). We stratified by Gleason score (≤3+4=7 or ≥4+3=7), pathological tumour stage (pT2 or ≥pT3), and negative or positive surgical margins. We analysed the cumulative incidences and absolute differences in metastatic disease and prostate cancer death. Results: We analysed 302 patients with complete follow-up during a median of 18 years. Median preoperative PSA was 9.8 ng/ml and median age at inclusion was 65 years. For patients without biochemical recurrence 5 years after radical prostatectomy the 20-year probability of biochemical recurrence was 25% among men with Gleason score ≤3+4=7 and 57% among men with Gleason score ≥4+3=7; the probabilities for metastases were 0.8% and 17%; and for prostate cancer death 0.8% and 12% respectively. The long-term probabilities were higher for pT≥3 vs. pT2 and for positive vs. negative surgical margins. Conclusions: Following radical prostatectomy, patients with Gleason score ≤3+4=7 without biochemical recurrenc

The observed magnifications and light curves of the quadruply imaged iPTF16geu supernova (SN) offers a unique opportunity to study a lens system with a variety of independent constraints. The four observed positions can be used to constrain the macrolens model. The magnifications and light curves at the four SN positions are more useful to constrain microlensing models. We define the macrolens model as a combination of a baryonic component that traces the observed light distribution, and a dark matter halo component. We constrained the macrolens model using the positional constraints given by the four observed images, and compared it with the best model obtained when magnification constraints were included. We found that the magnification cannot be explained by a macrolens model alone, and that contributions from substructures such as microlenses are needed to explain the observed magnifications. We considered microlens models based on the inferred stellar mass from the baryonic component of the macrolens model, and used the observed magnification and light curves to constrain the contribution from microlenses. We computed the likelihood of a variety of macro and micro lens models where we varied the dark matter halo, baryonic component, and microlens configurations. We used information about the position, magnification, and, for the first time, the light curves of the four observed SN images. We combined macrolens and microlens models in order to reproduce the observations; the four SN positions, magnifications, and lack of fluctuations in the light curves. After marginalizing over the model parameters, we found that larger stellar surface mass densities are preferred. This result suggests that the mass of the baryonic component is dominated by its stellar component. We conclude that microlensing from the baryonic component suffices to explain the observed flux ratios and light curves.

Type Ia supernovae (SNe Ia) in the nearby Hubble flow are excellent distance indicators in cosmology. The Zwicky Transient Facility (ZTF) has observed a large sample of SNe from an untargeted, rolling survey, reaching 20.8, 20.6, and 20.3 mag in g r, and i band, respectively. With an FoV of 47 deg2, ZTF discovered > 3000 SNe Ia in a little over 2.5 yr. Here, we report on the sample of 761 spectroscopically classified SNe Ia from the first year of operations (DR1). The sample has a median redshift z¯= 0.057, nearly a factor of 2 higher than the current low-z sample. Our sample has a total of 934 spectra, of which 632 were obtained with the robotic SEDm on Palomar P60. We assess the potential for precision cosmology for a total of 305 SNe with redshifts from host galaxy spectra. The sample is already comparable in size to the entire combined literature low-z anchor sample. The median first detection is 13.5 d before maximum light, about 10 d earlier than the median in the literature. Furthermore, six SNe from our sample are at DL < 80 Mpc, for which host galaxy distances can be obtained in the JAMES WEBB SPACE TELESCOPE era, such that we have calibrator and Hubble flow SNe observed with the same instrument. In the entire duration of ZTF-I, we have observed nearly 50 SNe for which we can obtain calibrator distances, key for per cent level distance scale measurements.