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SF1: Analysis of USP22 expression with known drivers of disease progression; SF2: USP22 modulates DNA repair factors expression and survival after DNA damage; SF3: Genetically engineered mouse model of tumor-associated USP22 expression; SF4: The USP22-sensitive ubiquitylome reveals altered modification of DNA repair proteins; SF5: USP22 deubiquitylates the NER protein XPC, modulating foci formation.

Emerging evidence indicates the deubiquitinase USP22 regulates transcriptional activation and modification of target substrates to promote pro-oncogenic phenotypes. Here, in vivo characterization of tumor-associated USP22 upregulation and unbiased interrogation of USP22-regulated functions in vitro demonstrated critical roles for USP22 in prostate cancer. Specifically, clinical datasets validated that USP22 expression is elevated in prostate cancer, and a novel murine model demonstrated a hyperproliferative phenotype with prostate-specific USP22 overexpression. Accordingly, upon overexpression or depletion of USP22, enrichment of cell-cycle and DNA repair pathways was observed in the USP22-sensitive transcriptome and ubiquitylome using prostate cancer models of clinical relevance. Depletion of USP22 sensitized cells to genotoxic insult, and the role of USP22 in response to genotoxic insult was further confirmed using mouse adult fibroblasts from the novel murine model of USP22 expression. As it was hypothesized that USP22 deubiquitylates target substrates to promote protumorigenic phenotypes, analysis of the USP22-sensitive ubiquitylome identified the nucleotide excision repair protein, XPC, as a critical mediator of the USP22-mediated response to genotoxic insult. Thus, XPC undergoes deubiquitylation as a result of USP22 function and promotes USP22-mediated survival to DNA damage. Combined, these findings reveal unexpected functions of USP22 as a driver of protumorigenic phenotypes and have significant implications for the role of USP22 in therapeutic outcomes.Significance:The studies herein present a novel mouse model of tumor-associated USP22 overexpression and implicate USP22 in modulation of cellular survival and DNA repair, in part through regulation of XPC.

PDF file - 176K, Supplementary Figure S1: USP22 Specifically Promotes AR Recruitment to Target Loci. Supplementary Figure 2: Depletion of USP22 can be mediated by multiple sequences.Supplementary Figure S3: AR Ubiquitylation Levels are not Altered in Response to USP22 Depletion.

PDF file - 50K, Primer sequences used in manuscript.

Increasing evidence links deregulation of the ubiquitin-specific proteases 22 (USP22) deubitiquitylase to cancer development and progression in a select group of tumor types, but its specificity and underlying mechanisms of action are not well defined. Here we show that USP22 is a critical promoter of lethal tumor phenotypes that acts by modulating nuclear receptor and oncogenic signaling. In multiple xenograft models of human cancer, modeling of tumor-associated USP22 deregulation demonstrated that USP22 controls androgen receptor accumulation and signaling, and that it enhances expression of critical target genes coregulated by androgen receptor and MYC. USP22 not only reprogrammed androgen receptor function, but was sufficient to induce the transition to therapeutic resistance. Notably, in vivo depletion experiments revealed that USP22 is critical to maintain phenotypes associated with end-stage disease. This was a significant finding given clinical evidence that USP22 is highly deregulated in tumors, which have achieved therapeutic resistance. Taken together, our findings define USP22 as a critical effector of tumor progression, which drives lethal phenotypes, rationalizing this enzyme as an appealing therapeutic target to treat advanced disease. Cancer Res; 74(1); 272–86. ©2013 AACR.

Reconstruction after parotidectomy can include fat grafting, which allows for symmetry, but grafts have demonstrated volume loss over time.To provide quantitative evidence for the rate of volume loss of fat grafts.Patients who received parotidectomy with fat graft reconstruction at a single institution from August 2016 to October 2020 were identified. Relationships between clinical factors and the logarithmic rate of fat graft volume loss were analyzed.Twelve patients received parotidectomy, fat graft reconstruction, and underwent a postoperative magnetic resonance imaging (MRI) scan. Rate of fat graft volume loss was a mean of 1.8% per month (standard deviation [SD]: 2.1% per month). Total parotid fat graft volume loss was a mean of 57.4% (SD: 67.5%). The mean follow-up time was 35.5 months (range: 9-89.8 months). Correlations between body mass index (BMI), history of smoking, and history of alcohol consumption and logarithmic rates of fat graft volume loss were increased but not significantly.Fat grafts have the potential of 60% volume loss at approximately 1 year. If there is clinical suspicion that patients will require adjuvant radiation or have clinical factors such as a smoking or alcohol-use history, volume requirements may be even greater to maintain adequate parotid volume for aesthetic purposes.

We develop best linear unbiased predictors (BLUP) of the latent values of labeled sample units selected from a finite population when there are two distinct sources of measurement error: endogenous, exogenous or both. Usual target parameters are the population mean, the latent values associated to a labeled unit or the latent value of the unit that will appear in a given position in the sample. We show how both types of measurement errors affect the within unit covariance matrices and indicate how the finite population BLUP may be obtained via standard software packages employed to fit mixed models in situations with either heteroskedastic or homoskedastic exogenous and endogenous measurement errors.

Accurate equations of state (EOS) and plasma transport properties are essential for numerical simulations of warm dense matter encountered in many high-energy-density situations. Molecular dynamics (MD) is a simulation method that generates EOS and transport data using an externally provided potential to dynamically evolve the particles without further reference to the electrons. To minimize computational cost, pair potentials needed in MD may be obtained from the neutral-pseudoatom (NPA) approach, a form of single-ion density functional theory (DFT), where many-ion effects are included via ion-ion correlation functionals. Standard $N$-ion DFT-MD provides pair potentials via the force matching technique but at much greater computational cost. Here we propose a simple analytic model for pair potentials with physically meaningful parameters based on a Yukawa form with a thermally damped Friedel tail (YFT) applicable to systems containing free electrons. The YFT model accurately fits NPA pair potentials or the non-parametric force-matched potentials from $N$-ion DFT-MD, showing excellent agreement for a wide range of conditions. The YFT form provides accurate extrapolations of the NPA or force-matched potentials for small and large particle separations within a physical model. Our method can be adopted to treat plasma mixtures, allowing for large-scale simulations of multi-species warm dense matter., 13 figures

Silicone breast augmentation remains one of the most common aesthetic surgery procedures, and 2022 marks the 60th anniversary of the first case. Recent studies suggest a link between double capsule (DC) formation and macro-textured devices.Between 2010 and 2015, 268 aesthetic patients underwent bilateral mammary prosthesis exchange for indications including PIP exchange, adverse capsular contracture and ultrasonographic evidence of rupture. All surgery, in the form of implant exchange and capsulectomy, was undertaken by the senior author using standard techniques. A retrospective review was undertaken, and data analysed with descriptive statistics and Fisher's exact and Mann-Whitney U tests.Of 268 patients identified, 40 (14.9%) showed some degree of capsular duplication and bilateral involvement was marginally more common (52.5%). Two macroscopic patterns of duplication were observed: complete and subtotal. Complete DCs correlated with a clinical triad of extreme firmness, mobility and minimal-to-no pain. Whilst a wide range of manufacturers was represented, macro-textured devices were associated with the highest DC prevalence (58.3% vs. 5.6%) (Fisher's exact test p0.00001). Patients with DC had been implanted for less than half the time, median 52 versus. 120 months (p = 0.0003) of those without.An elevated prevalence of duplicate capsules in macro-textured prostheses is reconfirmed in addition to a novel symptom constellation that may assist with clinical diagnosis. Our study reinforces the aetiopathogenic influence of the elastomer in DC formation and reports DC for the first time in non-macrotextured implants. Single-surgeon cohort of 268 consecutive patients with 532 implants Statistically significant association of macro-textured devices with DC Statistically significant reduced duration of implantation of macro-textured devices First report of DC in non-macro-textured devices LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Large knowledge gaps concerning the effect of ocean surface waves on near-surface vertical distributions of temperature and humidity exist due to practical limitations and sensor fidelity challenges of direct measurements. Measurements of temperature and humidity are classically made using rocket- or radiosondes and fixed weather stations and can utilize a tethered profiling system. However, these measurement systems have limitations when obtaining wave-coherent measurements near the sea surface. Consequently, boundary layer similarity models are commonly employed to fill in near-surface measurement gaps despite the documented shortcomings of the models in this region. Thus, this manuscript presents a near-surface wave-coherent measurement platform that measures high-temporal-resolution vertical distributions of temperature and humidity down to ~0.3 m above the instantaneous sea surface. The design of the platform is described along with preliminary observations obtained during a pilot experiment. Ocean surface-wave phase-resolved vertical profiles are also demonstrated from the observations.

R-loops are three-stranded nucleotide structures consisting of a DNA:RNA hybrid and a displaced ssDNA non-template strand. Previous work suggests that R-loop formation is primarily determined by the thermodynamics of DNA:RNA binding, which are governed by base composition (e.g., GC skew) and transcription-induced DNA superhelicity. However, R-loops have been described at genomic locations that lack these properties, suggesting that they may serve other context-specific roles. To better understand the genetic determinants of R-loop formation, we have characterized the Drosophila melanogaster R-loop landscape across strains and between sexes using DNA:RNA immunoprecipitation followed by high-throughput sequencing (DRIP-seq). We find that R-loops are associated with sequence motifs that are G-rich or exhibit G/C skew, as well as highly expressed genes, tRNAs, and small nuclear RNAs, consistent with a role for DNA sequence and torsion in R-loop specification. However, we also find motifs associated with R-loops that are A/T-rich and lack G/C skew as well as a subset of R-loops that are enriched in polycomb-repressed chromatin. Differential enrichment analysis reveals a small number of sex-biased R-loops: while non-differentially enriched and male-enriched R-loops form at similar genetic features and chromatin states and contain similar sequence motifs, female-enriched R-loops form at unique genetic features, chromatin states, and sequence motifs and are associated with genes that show ovary-biased expression. Male-enriched R-loops are most abundant on the dosage-compensated X chromosome, where R-loops appear stronger compared to autosomal R-loops. R-loop-containing genes on the X chromosome are dosage-compensated yet show lower MOF binding and reduced H4K16ac compared to R-loop-absent genes, suggesting that H4K16ac or MOF may attenuate R-loop formation. Collectively, these results suggest that R-loop formation in vivo is not fully explained by DNA sequence and topology and raise the possibility that a distinct subset of these hybrid structures plays an important role in the establishment and maintenance of epigenetic differences between sexes.

We consider a finite population mixed model that accommodates response errors and show how to obtain optimal estimators of the finite population parameters in a pretest-posttest context. We illustrate the method with the estimation of the difference in gain between two interventions and consider a simulation study to compare the empirical version of the proposed estimator (obtained by replacing variance components with estimates) with the estimator obtained via covariance analysis usually employed in such settings. The results indicate that in many instances, the proposed estimator has a smaller mean squared error than that obtained from the standard analysis of covariance model.

Sporadic colorectal cancers arise from initiating mutations in APC, producing oncogenic β-catenin/TCF-dependent transcriptional reprogramming. Similarly, the tumor suppressor axis regulated by the intestinal epithelial receptor GUCY2C is among the earliest pathways silenced in tumorigenesis. Retention of the receptor, but loss of its paracrine ligands, guanylin and uroguanylin, is an evolutionarily conserved feature of colorectal tumors, arising in the earliest dysplastic lesions. Here, we examined a mechanism of GUCY2C ligand transcriptional silencing by β-catenin/TCF signaling.We performed RNA sequencing analysis of 4 unique conditional human colon cancer cell models of β-catenin/TCF signaling to map the core Wnt-transcriptional program. We then performed a comparative analysis of orthogonal approaches, including luciferase reporters, chromatin immunoprecipitation sequencing, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) knockout, and CRISPR epigenome editing, which were cross-validated with human tissue chromatin immunoprecipitation sequencing datasets, to identify functional gene enhancers mediating GUCY2C ligand loss.RNA sequencing analyses reveal the GUCY2C hormones as 2 of the most sensitive targets of β-catenin/TCF signaling, reflecting transcriptional repression. The GUCY2C hormones share an insulated genomic locus containing a novel locus control region upstream of the guanylin promoter that mediates the coordinated silencing of both genes. Targeting this region with CRISPR epigenome editing reconstituted GUCY2C ligand expression, overcoming gene inactivation by mutant β-catenin/TCF signaling.These studies reveal DNA elements regulating corepression of GUCY2C ligand transcription by β-catenin/TCF signaling, reflecting a novel pathophysiological step in tumorigenesis. They offer unique genomic strategies that could reestablish hormone expression in the context of canonical oncogenic mutations to reconstitute the GUCY2C axis and oppose transformation.

We present the results of the first Charged-Particle Transport Coefficient Code Comparison Workshop, which was held in Albuquerque, NM October 4-6, 2016. In this first workshop, scientists from eight institutions and four countries gathered to compare calculations of transport coefficients including thermal and electrical conduction, electron-ion coupling, inter-ion diffusion, ion viscosity, and charged particle stopping powers. Here, we give general background on Coulomb coupling and computational expense, review where some transport coefficients appear in hydrodynamic equations, and present the submitted data. Large variations are found when either the relevant Coulomb coupling parameter is large or computational expense causes difficulties. Understanding the general accuracy and uncertainty associated with such transport coefficients is important for quantifying errors in hydrodynamic simulations of inertial confinement fusion and high-energy density experiments., Comment: 45 pages, 17 figures

Molecular Dynamics (MD) is a powerful tool for simulating complex dynamical systems. MD is used across several disciplines and their sub-fields, e.g. biology, chemistry, material science. As a matter of fact for each of these research fields we can find MD codes, open-source or proprietary, optimized for the simulation of their respective dynamical systems. No such code exists for Non-Ideal Plasmas. This generates several difficulties for researchers. On one hand researchers are forced to modify existing codes and/or write their own. This requires an extensive knowledge of computing as all of the available codes have been developed in low-level languages, e.g. C or Fortran. Furthermore, the codes have been optimized for the simulation of systems other than non-ideal plasmas and as such are often difficult to modify. On the other hand most MD codes provide only a code for the simulation phase and lack pre-processing and/or post-processing analysis tools. Several open-source packages are available for post-processing, but again they are specific to systems other than non-ideal plasmas and are often developed in interpretative languages, e.g. Python.

Ultracold neutral plasmas 1 (UNPs) are strongly coupled, non- equilibrium systems created by photoionizing laser cooled atoms in a vacuum. As a result, experimental platforms are developed to elucidate the properties of UNPs such as their spatial expansion and temperature relaxation 2 . Data from these experiments are used to validate theories and computational models that aim to model UNPs. One such computational model derived from a multi-species BGK kinetic theory 3 .

Physical data are typically generated by experiments and computations in limited parameter regimes. When datasets generated using such disparate methods are combined into one dataset, the resulting dataset is typically sparse, with dense "islands" in a potentially high-dimensional parameter space, and predictions must be interpolated among such islands. Using plasma transport data as our example, we propose a multifidelity Gaussian-process regression framework that incorporates physical data from multiple sources at multiple fidelities. The impact of the proposed framework varies from little improvement over simpler approaches to qualitatively changing the prediction with consistently increased confidence in regions lacking high-fidelity data. By varying low- and high-fidelity data sources, we demonstrate an approach for determining when multifidelity Gaussian-process regression adds value over single-fidelity regression and therefore when its additional computational costs are merited. We also examine the case in which the outputs of the low- and high-fidelity models correspond to different physical quantities, one of which may be intrinsically computationally cheaper to compute. We conclude by analyzing strategies for sampling high-fidelity data for use in this framework, and we develop a simple sampling approach for reducing regression error across large gaps in data.

An ever-expanding hormetic database (HDB) was used to demonstrate that the median maximal hormetic stimulatory response (MHSR) of biphasic dose-response relationships increases in value with an increase in the number of stimulatory doses/concentrations that are administered below the estimated threshold/ZEP (zero equivalent point – i.e., the dose where the response crosses the control group value). With only one dose or concentration administered below the ZEP, the median MHSR for microbes (in vitro), animals (in vitro and in vivo), and plants (in vitro and in vivo) ranged between 120% and 125% of the control response. However, when individual agents having at least six doses below the ZEP were mined from the HDB (and a median MHSR then determined), the median MHSR increased to 160–190%. This progressive increase in the MHSR appears to be due to several factors, including (i) the enhanced capacity of additional doses in the stimulatory hormetic zone to better estimate the response optima, and (ii) enhanced variability due to the presence of more doses in the stimulatory zone. This study offers a novel perspective for improving research protocols, unraveling the limits of biological plasticity, understanding low-level stress biology, advancing human and ecological health, and enhancing human performance.

Background Metastatic paragangliomas are rare neuroendocrine tumors. Bony metastases most commonly occur in the ribs, vertebrae, and pelvis. Few cases of mandibular metastases have been reported. Methods A 75-year-old female presented with a 6-month history of an enlarging mandibular mass. A biopsy was consistent with a paraganglioma. Results Staging workup with 18 F-fluorodeoxyglucose positron emission tomography demonstrated 2 hypermetabolic intra-abdominal lesions adjacent to the inferior vena cava. These were confirmed as paraganglioma by biopsy and presumed as the primary lesions. The patient underwent left segmental mandibulectomy and neck dissection with osteocutaneous fibula free tissue reconstruction. Conclusion A rare case of malignant paraganglioma presenting as a mandibular metastasis is described. Nuclear medicine studies for paraganglioma are reviewed.

We present an open-source, performant, pure-python molecular dynamics (MD) suite for non-ideal plasmas. The code, Sarkas, aims to accelerate the research process by providing an MD code but also pre- and post-processing tools. Sarkas offers the ease of use of Python while employing the Numba library to obtain execution speeds comparable to that of compiled languages. The available tools in Sarkas include graphical displays of the equilibration process through a Jupyter interface and the ability to compute quantities such as, radial distribution functions, autocorrelation functions and Green-Kubo relations. Many force laws used to simulate plasmas are included in Sarkas, namely, pure Coulomb, Yukawa, and Moli\`ere pair-potentials. Sarkas also contains quantum statistical potentials and fast Ewald methods are included where necessary. An object-oriented approach allows for easy modification of Sarkas, such as adding new time integrators, boundary conditions and force laws.

The SAGA coactivator complex is essential for eukaryotic transcription and comprises four distinct modules, one of which contains the ubiquitin hydrolase USP22. In yeast, the USP22 ortholog deubiquitylates H2B, resulting in Pol II Ser2 phosphorylation and subsequent transcriptional elongation. In contrast to this H2B‐associated role in transcription, we report here that human USP22 contributes to the early stages of stimulus‐responsive transcription, where USP22 is required for pre‐initiation complex (PIC) stability. Specifically, USP22 maintains long‐range enhancer–promoter contacts and controls loading of Mediator tail and general transcription factors (GTFs) onto promoters, with Mediator core recruitment being USP22‐independent. In addition, we identify Mediator tail subunits MED16 and MED24 and the Pol II subunit RBP1 as potential non‐histone substrates of USP22. Overall, these findings define a role for human SAGA within the earliest steps of transcription., Loss of human USP22 affects the stability of the pre‐initiation complex, rather than histone H2B ubiquitylation, during stimulus‐responsive transcription.

OBJECTIVE: We determined the prevalence and correlates of cannabis use in Massachusetts after recreational use was passed, but before recreational cannabis stores opened. METHOD: A cross-sectional, population-based survey of Massachusetts adults, age 18 years or older, (n=3,022) was conducted in November–December, 2017. We estimated population-level prevalence and correlates of past 30-day cannabis use. RESULTS: 21.1% [95% CI: 18.6, 23.6] of Massachusetts adults reported past 30-day cannabis use. Among cannabis users, 56.0% [49.1, 62.9] reported non-medical cannabis use, 15.5% [12.1, 18.9] reported medical cannabis use, and 28.5% [22.3, 34.8] reported both types of use. Men were more likely than women to use cannabis (Risk Ratio: 1.3 [1.1, 1.6]), as were young adults (18–25 years old), those with lower socioeconomic status, non-parenting individuals, those who used alcohol (1.9 [1.4, 2.6]) or other substances (1.7 [1.3, 2.4]), and residents of Western Massachusetts (2.0 [1.3, 3.0]; ref: Boston area), the Northeast (1.8 [1.2, 2.7]), and the Southeast (1.8 [1.1, 2.7]). CONCLUSIONS: Cannabis is widely used in Massachusetts, with varying prevalence rates by gender, age, socioeconomic status, poly-substance use, and region. Findings may inform public health efforts and serve as a baseline for measuring health and social impacts of opening retail cannabis stores.

Background The variables correlated with problem gambling are routinely assessed and fairly well established. However, problem gamblers were all ‘at-risk’ and ‘recreational’ gamblers at some point. Thus, it is instructive from a prevention perspective to also understand the variables which discriminate between recreational gambling and at-risk gambling and whether they are similar or different to the ones correlated with problem gambling. This is the purpose of the present study. Method Between September 2013 to May 2014, a representative sample of 9,523 Massachusetts adults was administered a comprehensive survey of their past year gambling behavior and problem gambling symptomatology. Based on responses to the Problem and Pathological Gambling Measure, respondents were categorized as Non-Gamblers (2,523), Recreational Gamblers (6,271), At-Risk Gamblers (600), or Problem/Pathological Gamblers (129). With the reference category of Recreational Gambler, a series of binary logistic regressions were conducted to identify the demographic, health, and gambling related variables that differentiated Recreational Gamblers from Non-Gamblers, At-Risk-Gamblers, and Problem/Pathological Gamblers. Results The strongest discriminator of being a Non-Gambler rather than a Recreational Gambler was having a lower portion of friends and family that were regular gamblers. Compared to Recreational Gamblers, At-Risk Gamblers were more likely to: gamble at casinos; play the instant and daily lottery; be male; gamble online; and be born outside the United States. Compared to Recreational Gamblers, Problem and Pathological Gamblers were more likely to: play the daily lottery; be Black; gamble at casinos; be male; gamble online; and play the instant lottery. Importantly, having a greater portion of friends and family who were regular gamblers was the second strongest correlate of being both an At-Risk Gambler and Problem/Pathological Gambler. Conclusions These analyses offer an examination of the similarities and differences between gambling subtypes. An important finding throughout the analyses is that the gambling involvement of family and friends is strongly related to Recreational Gambling, At-Risk Gambling, and Problem/Pathological Gambling. This suggests that targeting the social networks of heavily involved Recreational Gamblers and At-Risk Gamblers (in addition to Problem/Pathological Gamblers) could be an important focus of efforts in problem gambling prevention.

Objectives Cigarette smoking, low physical activity, and sedentary behavior are modifiable risk factors for adverse pregnancy outcomes. However, only one study has evaluated predictors of these health risk behaviors among women at high risk for gestational diabetes mellitus (GDM). Therefore, our goal was to examine predictors of smoking, low physical activity, and sedentary behavior during pregnancy in an ethnically diverse high risk cohort. Methods This cross-sectional analysis utilized baseline data from the Behaviors Affecting Baby and You (B.A.B.Y.) study conducted among prenatal care patients at high risk for GDM (personal history of GDM or family history of diabetes and body mass index [BMI] ≥ 25 kg/m2). Smoking was assessed using questions from the Pregnancy Risk Assessment Monitoring System questionnaire and sedentary behavior (top vs. lower quartiles) and moderate/vigorous physical activity (bottom vs. upper quartile) via the Pregnancy Physical Activity Questionnaire. Results Participants (n = 400) enrolled at a mean of 12.4 (SD 3.6) weeks gestation. A total of 150 (44.1%) engaged in one, 37 (10.9%) in two, and 4 (1.2%) in three risk behaviors. Lower household income and not having children at home were each associated with a 2–6 fold increased odds of smoking, high sedentary behavior, and engaging in at least one risk behavior. Being married, Hispanic or of younger age was associated with a 2–6 fold reduced odds of smoking. BMI and personal history of GDM were not associated with risk behaviors. Conclusions for Practice Findings help characterize high risk groups and inform prenatal interventions targeting these health risk behaviors.

The characteristics of atomic-scale mixing are determined by diffusive processes driven by gradients. One such process is interdiffusion, a process driven by density gradients. We consider the various options for formulating interdiffusion in terms of Green–Kubo autocorrelation functions and the thermodynamic factor. Through models for the direct correlation function, we generalize expressions for the thermodynamic factor to include different electron and ion temperatures, electron degeneracy, finite-temperature exchange, and strong coupling. Additionally, a Gaussian autocorrelation function (GAF) is employed for a binary ionic mixture, yielding a simple analytic transport model for interdiffusion. The GAF model is shown to be accurate for moderately and strongly coupled plasmas.

Introduction: The Guillain-Barre syndrome is an acute infl ammatory autoimmune polyradiculoneuropathy and belongs among rare neurologic diseases. Since poliomyelitis has been almost completely eliminated, it is currently the most frequent cause of acute fl accid paralysis worldwide. The registry was formed in the Czech Republic in 2012 and is an important source of prospectively recorded data. Aim: The goal of the registry is to follow up the clinical profi le, treatment and 6-month prognosis of Guillain-Barre syndrome patients. Methods: The data are collected prospectively by persons delegated by neuromuscular centres in the Czech Republic. The clinical course is assessed on the basis of the GBS disability scale and muscle strength according to the Medical Research Council sum score for facial muscles and extremity muscles. Detailed clinical investigation is done on admission, before the treatment, immediately after the treatment, 1 month and 6 months after the end of the treatment. Results: We enrolled a total 272 cases of Guillain-Barre syndrome patients in the period from 1st January 2012 to 17th August 2016. We have complete data for 6 months in 137 of them. 52 were treated with intravenous human immunoglobulin and 85 with plasma exchange. A good clinical outcome after 6 months (ability to walk unassisted) was achieved in 85% of patients. Severe residual neurological defi cit persisted after 6 months in 11% of patients. The remaining 6 patients died. We did not fi nd any diff erence in the effi ciency of immunoglobulin vs. plasma exchange in the whole group, in the subgroup of the severely disabled patients and according to sex. Conclusion: Medical care centralisation and adherence to the standard of care lead to a good clinical outcome in Guillain-Barre syndrome patients, which is comparable with relevant sources.

Background Streptococcus pneumoniae infection is the most common cause of community-acquired pneumonia in adults. Invasive pneumococcal disease (IPD) carries a high case fatality rate. We investigated the lifespan of adults who recovered from IPD during a 32-year follow-up. Materials and Methods We determined whether adults discharged after an episode of IPD from hospitals affiliated with the Marshall University Joan C. Edwards School of Medicine in Huntington, West Virginia from 1983-2003 were alive on June 30, 2014. Lifespan was assessed by Kaplan-Meier methodology, Cox proportional hazards multivariate analysis, life expectancy using life tables for West Virginia, years of potential life lost and serotype occurrence. Results The study group comprised 155 adults who survived IPD. They had a mean age at discharge of 64.6 years, mean lifespan after IPD of 7.1 years, mean expected lifespan after IPD of 17.0 years, mean age at death of 71.6 years and a mean life expectancy of 81.6 years. Only 14 (9.0%) patients lived longer than their life expectancy. Of the 13 comorbid diseases analyzed, cancer and neurologic diseases and the number of comorbid diseases suffered by each patient were the significant variables associated with survival. The mean years of potential life lost was 9.936 years. Only serotype 12 of 31 serotypes recovered occurred more often in patients who survived for 11 or more years after discharge (relative risk = 3.44, 95% CI: 1.19-9.95). Conclusions The fact that most adult patients who recovered from IPD died before their documented life expectancy argues for the pernicious severity of IPD and the importance of immunization of adults with pneumococcal vaccines.

Background Worldwide, Streptococcus pneumoniae commonly causes community-acquired pneumonia, meningitis, septicemia and otitis media. Invasive pneumococcal infection (IPD) represents the most serious presentation, occurs in approximately 1 in 4 cases and engenders case fatality rates (CFR) in pneumonia of 20-25% and meningitis of 35-40%. We investigated IPD for 32 years in an American city to assess the effect of differing pneumococcal vaccines on serotype occurrence and CFR among children and adults. Methods In this retrospective study of IPD conducted from 1983-2014, consecutive pneumococcal strains were obtained from inpatients at 3 affiliated hospitals. Each hospital laboratory submitted to our research laboratory S pneumoniae strains recovered from blood and otherwise sterile sites for serotyping by Quellung and penicillin susceptibility tests by ETEST. Clinical data were abstracted from hospital medical records. Results IPD occurred among 193 children and 1,003 adults. The overall CFR among adults was 19.2%. Only 2 children died. From 1983-2004, PCV7 serotypes dominated, but after routine PCV7 immunization began in 2000, PCV7 serotypes decreased and nearly disappeared, including penicillin-resistant PCV7 serotypes, few IPD occurred among children and incidence rates declined markedly, which continued after PCV13 replaced PCV7 in 2010. The 11 additional serotypes in PPSV23 became dominant during the past 5 years. Nonvaccine serotypes emerged also. Only serotypes 6B, 15 and 35F showed a significant relative risk of death. Conclusions Community-wide usage of PCV7, then PCV13, changed the predominant serotypes. PCV7 serotypes and IPD among children almost disappeared and PPSV23 and nonvaccine serotypes became more dominant.

Emerging evidence indicates the deubiquitinase USP22 regulates transcriptional activation and modification of target substrates to promote pro-oncogenic phenotypes. Here, in vivo characterization of tumor-associated USP22 upregulation and unbiased interrogation of USP22-regulated functions in vitro demonstrated critical roles for USP22 in prostate cancer. Specifically, clinical datasets validated that USP22 expression is elevated in prostate cancer, and a novel murine model demonstrated a hyperproliferative phenotype with prostate-specific USP22 overexpression. Accordingly, upon overexpression or depletion of USP22, enrichment of cell-cycle and DNA repair pathways was observed in the USP22-sensitive transcriptome and ubiquitylome using prostate cancer models of clinical relevance. Depletion of USP22 sensitized cells to genotoxic insult, and the role of USP22 in response to genotoxic insult was further confirmed using mouse adult fibroblasts from the novel murine model of USP22 expression. As it was hypothesized that USP22 deubiquitylates target substrates to promote protumorigenic phenotypes, analysis of the USP22-sensitive ubiquitylome identified the nucleotide excision repair protein, XPC, as a critical mediator of the USP22-mediated response to genotoxic insult. Thus, XPC undergoes deubiquitylation as a result of USP22 function and promotes USP22-mediated survival to DNA damage. Combined, these findings reveal unexpected functions of USP22 as a driver of protumorigenic phenotypes and have significant implications for the role of USP22 in therapeutic outcomes. Significance: The studies herein present a novel mouse model of tumor-associated USP22 overexpression and implicate USP22 in modulation of cellular survival and DNA repair, in part through regulation of XPC.

Macroscopic simulations of dense plasmas rely on detailed microscopic information that can be computationally expensive and is difficult to verify experimentally. In this work, we delineate the accuracy boundary between microscale simulation methods by comparing Kohn-Sham density functional theory molecular dynamics (KS-MD) and radial pair potential molecular dynamics (RPP- MD) for a range of elements, temperature, and density. By extracting the optimal RPP from KS-MD data using force-matching, we constrain its functional form and dismiss classes of potentials that assume a constant power law for small interparticle distances. Our results show excellent agreement between RPP-MD and KS-MD for multiple metrics of accuracy at temperatures of only a few electron volts. The use of RPPs offers orders of magnitude decrease in computational cost and indicates that three-body potentials are not required beyond temperatures of a few eV. Due to its efficiency, the validated RPP-MD provides an avenue for reducing errors due to finite-size effects that can be on the order of $\sim20\%$.

The idea that a soothsayer may be able to know the unknown intrigues us, thanks in part to our natural fascination with the unknown.The unknown may be something that has happened in the past, but i...