Replicative history marks transcriptional and functional disparity in the CD8+ T cell memory pool.

Clonal expansion is a core aspect of T cell immunity. However, little is known with respect to the relationship between replicative history and the formation of distinct CD8+ memory T cell subgroups. To address this issue, we developed a genetic-tracing approach, termed the DivisionRecorder, that reports the extent of past proliferation of cell pools in vivo. Using this system to genetically 'record' the replicative history of different CD8+ T cell populations throughout a pathogen-specific immune response, we demonstrate that the central memory T (TCM) cell pool is marked by a higher number of prior divisions than the effector memory T cell pool, owing to the combination of strong proliferative activity during the acute immune response and selective proliferative activity after pathogen clearance. Furthermore, by combining DivisionRecorder analysis with single-cell transcriptomics and functional experiments, we show that replicative history identifies distinct cell pools within the TCM compartment. Specifically, we demonstrate that lowly divided TCM cells display enriched expression of stem-cell-associated genes, exist in a relatively quiescent state, and are superior in eliciting a proliferative recall response upon activation. These data provide the first evidence that a stem-cell-like memory T cell pool that reconstitutes the CD8+ T cell effector pool upon reinfection is marked by prior quiescence.

Measuring in-hospital quality multidimensionally by integrating patients', kin's and healthcare professionals' perspectives: development and validation of the FlaQuM-Quickscan.

BACKGROUND: Measuring quality is essential to drive improvement initiatives in hospitals. An instrument that measures healthcare quality multidimensionally and integrates patients', kin's and professionals' perspectives is lacking. We aimed to develop and validate an instrument to measure healthcare quality multidimensionally from a multistakeholder perspective. METHODS: A multi-method approach started by establishing content and face validity, followed by a multi-centre study in 17 Flemish (Belgian) hospitals to assess construct validity through confirmatory factor analysis, criterion validity through determining Pearson's correlations and reliability through Cronbach's alpha measurement. The instrument FlaQuM-Quickscan measures 'Healthcare quality for patients and kin' (part 1) and 'Healthcare quality for professionals' (part 2). This bipartite instrument mirrors 15 quality items and 3 general items (the overall quality score, recommendation score and intention-to-stay score). A process evaluation was organised to identify effective strategies in instrument distribution by conducting semi-structured interviews with quality managers. RESULTS: By involving experts in the development of quality items and through pilot testing by a multi-stakeholder group, the content and face validity of instrument items was ensured. In total, 13,615 respondents (5,891 Patients/kin and 7,724 Professionals) completed the FlaQuM-Quickscan. Confirmatory factor analyses showed good to very good fit and correlations supported the associations between the quality items and general items for both instrument parts. Cronbach's alphas supported the internal consistency. The process evaluation revealed that supportive technical structures and approaching respondents individually were effective strategies to distribute the instrument. CONCLUSIONS: The FlaQuM-Quickscan is a valid instrument to measure healthcare quality experiences multidimensionally from an integrated multistakeholder perspective. This new instrument offers unique and detailed data to design sustainable quality management systems in hospitals. Based on these data, hospital management and policymakers can set quality priorities for patients', kin's and professionals' care. Future research should investigate the transferability to other healthcare systems and examine between-stakeholders and between-hospitals variation.

HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling.

Burkitt lymphoma (BL) is an aggressive B-cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Because of their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Targeted therapies for BL are therefore needed. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We found that inhibitors of heat shock protein 90 (HSP90) induced apoptosis in BL cells in vitro at concentrations that did not affect normal B cells. By global proteomic and phosphoproteomic profiling, we show that, in BL, HSP90 inhibition compromises the activity of the pivotal B-cell antigen receptor (BCR)-proximal effector spleen tyrosine kinase (SYK), which we identified as an HSP90 client protein. Consistently, expression of constitutively active TEL-SYK counteracted the apoptotic effect of HSP90 inhibition. Together, our results demonstrate that HSP90 inhibition impairs BL cell survival by interfering with tonic BCR signaling, thus providing a molecular rationale for the use of HSP90 inhibitors in the treatment of BL.

Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leukemia.

Acute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved in recruitment and retention of leukemia-initiating cells within this niche. Various drugs targeting this pathway have entered clinical trials. To evaluate CXCR4 imaging in acute myeloid leukemia, we first tested CXCR4 expression in patient-derived primary blasts. Flow cytometry revealed that high blast counts in patients with acute myeloid leukemia correlate with high CXCR4 expression. The wide range of CXCR4 surface expression in patients was reflected in cell lines of acute myeloid leukemia. Next, we evaluated the CXCR4-specific peptide Pentixafor by positron emission tomography imaging in mice harboring CXCR4 positive and CXCR4 negative leukemia xenografts, and in 10 patients with active disease. [(68)Ga]Pentixafor-positron emission tomography showed specific measurable disease in murine CXCR4 positive xenografts, but not when CXCR4 was knocked out with CRISPR/Cas9 gene editing. Five of 10 patients showed tracer uptake correlating well with leukemia infiltration assessed by magnetic resonance imaging. The mean maximal standard uptake value was significantly higher in visually CXCR4 positive patients compared to CXCR4 negative patients. In summary, in vivo molecular CXCR4 imaging by means of positron emission tomography is feasible in acute myeloid leukemia. These data provide a framework for future diagnostic and theranostic approaches targeting the CXCR4/CXCL12-defined leukemia-initiating cell niche.

The PROactive innovative conceptual framework on physical activity.

Although physical activity is considered an important therapeutic target in chronic obstructive pulmonary disease (COPD), what "physical activity" means to COPD patients and how their perspective is best measured is poorly understood. We designed a conceptual framework, guiding the development and content validation of two patient reported outcome (PRO) instruments on physical activity (PROactive PRO instruments). 116 patients from four European countries with diverse demographics and COPD phenotypes participated in three consecutive qualitative studies (63% male, age mean±sd 66±9 years, 35% Global Initiative for Chronic Obstructive Lung Disease stage III-IV). 23 interviews and eight focus groups (n = 54) identified the main themes and candidate items of the framework. 39 cognitive debriefings allowed the clarity of the items and instructions to be optimised. Three themes emerged, i.e. impact of COPD on amount of physical activity, symptoms experienced during physical activity, and adaptations made to facilitate physical activity. The themes were similar irrespective of country, demographic or disease characteristics. Iterative rounds of appraisal and refinement of candidate items resulted in 30 items with a daily recall period and 34 items with a 7-day recall period. For the first time, our approach provides comprehensive insight on physical activity from the COPD patients' perspective. The PROactive PRO instruments' content validity represents the pivotal basis for empirically based item reduction and validation.

Introducing the Biosimilar Paradigm to Neurology: The Totality of Evidence for the First Biosimilar Natalizumab.

A biosimilar medicine is a successor to a reference ('originator'/'original-brand') biologic medicine brought to market once the patent and exclusive marketing rights for the reference have expired. Biosimilar natalizumab (PB006 [biosim-NTZ]; developed by Polpharma Biologics S.A. and marketed globally as Tyruko®; Sandoz) has been developed as a successor to reference natalizumab (Tysabri® [ref-NTZ]; Biogen) and is the first US Food and Drug Administration (FDA)-approved and European Medicines Agency (EMA)-approved biosimilar in neurology. As per the FDA and EMA indications for ref-NTZ, biosim-NTZ is approved to treat relapsing forms of multiple sclerosis (USA, EU) and Crohn's disease (USA only). Approval of biosim-NTZ was based on the 'totality of evidence', a comprehensive body of data collected during the development process, demonstrating similarity to its reference medicine. The foundational step of demonstrating structural and functional similarity between biosim-NTZ and ref-NTZ confirmed identical primary and indistinguishable higher order structures, as well as matching binding affinity to α4ß1/α4ß7 integrins. Following the confirmation of matching structure and function, pharmacokinetic/pharmacodynamic similarity of biosim-NTZ to ref-NTZ in healthy subjects was demonstrated, with no clinically meaningful differences identified in safety and immunogenicity. A comparative, double-blind, randomized study (Antelope) was also conducted in patients with relapsing-remitting multiple sclerosis and demonstrated matching efficacy, safety, and immunogenicity with no clinically meaningful differences between biosim-NTZ and ref-NTZ. This review presents the totality of evidence that confirmed the biosimilarity of biosimilar natalizumab to its reference medicine, which supported its approval by the FDA and the EMA. [Graphical plain language summary available].

The Role of ß-Dystroglycan in Nuclear Dynamics.

Dystroglycan is a ubiquitously expressed heterodimeric cell-surface laminin receptor with roles in cell adhesion, signalling, and membrane stabilisation. More recently, the transmembrane ß-subunit of dystroglycan has been shown to localise to both the nuclear envelope and the nucleoplasm. This has led to the hypothesis that dystroglycan may have a structural role at the nuclear envelope analogous to its role at the plasma membrane. The biochemical fraction of myoblast cells clearly supports the presence of dystroglycan in the nucleus. Deletion of the dystroglycan protein by disruption of the DAG1 locus using CRISPR/Cas9 leads to changes in nuclear size but not overall morphology; moreover, the Young's modulus of dystroglycan-deleted nuclei, as determined by atomic force microscopy, is unaltered. Dystroglycan-disrupted myoblasts are also no more susceptible to nuclear stresses including chemical and mechanical, than normal myoblasts. Re-expression of dystroglycan in DAG1-disrupted myoblasts restores nuclear size without affecting other nuclear parameters.

Pseudogenes: pseudo-functional or key regulators in health and disease?

Pseudogenes have long been labeled as "junk" DNA, failed copies of genes that arise during the evolution of genomes. However, recent results are challenging this moniker; indeed, some pseudogenes appear to harbor the potential to regulate their protein-coding cousins. Far from being silent relics, many pseudogenes are transcribed into RNA, some exhibiting a tissue-specific pattern of activation. Pseudogene transcripts can be processed into short interfering RNAs that regulate coding genes through the RNAi pathway. In another remarkable discovery, it has been shown that pseudogenes are capable of regulating tumor suppressors and oncogenes by acting as microRNA decoys. The finding that pseudogenes are often deregulated during cancer progression warrants further investigation into the true extent of pseudogene function. In this review, we describe the ways in which pseudogenes exert their effect on coding genes and explore the role of pseudogenes in the increasingly complex web of noncoding RNA that contributes to normal cellular regulation.

Raising "Antiracist Disruptors": Illuminating Socialization Practices that Support Antiracism in Multiracial Households.

Although an emerging body of literature has advanced our knowledge of how monoracial parents can support their multiracial children in understanding the ethnic-racial identities they hold, there is a dearth of research exploring how parents socialize their children towards antiracism. Drawing from ten interviews with monoracial parents of multiracial children, this paper illuminates how parents leverage multiracial socialization practices, as identified in previous academic research, to instill an antiracist orientation in their children. Using consensual qualitative analyses, we find that although all parents had a vested interest in the wellbeing and identity development of their multiracial children, parents qualitatively differed in their ability and willingness to instill an antiracist orientation in their children. Specifically, parents in our sample exhibited five approaches to multiracial socialization, ranging from those that reinforced dominant racial ideologies to those that explicitly aimed to prepare youth to become antiracist activists. We also describe how monoracial parents' lived experiences are implicated in their engagement in multiracial socialization practices, especially those that better position them to prepare their children to engage in antiracism. Our findings illuminate how monoracial parents may engage in a repertoire of strategies in order to foster antiracism in multiracial children, molding the next generation of "antiracist disruptors."

Wearable Technologies Using Peripheral Neuromodulation to Enhance Mobility and Gait Function in Older Adults-A Narrative Review.

BACKGROUND: Mounting evidence suggests that wearable technologies using peripheral neuromodulation can provide novel ways of improving mobility and gait function in various patient populations including older adults. The purpose of this narrative review is to provide an overview of wearable technologies/devices to improve mobility and gait function through noninvasive peripheral neuromodulation in older adults over the age of 65 and to indicate the suggested mechanism of action behind these technologies. METHODS: We performed searches for articles and conference abstracts written in English, using the following databases: Embase Classic+Embase from 1947 to July 15, 2021; Ovid MEDLINE; Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions from 1946 to July 15, 2021; PubMed; and Scopus. RESULTS: Forty-one technologies met the inclusion/exclusion criteria. We found that the primary implementation of the 41 technologies can be divided into 3 main categories: sensory substitution, sensory augmentation (open loop, closed loop), and motor stimulation. Using these technologies, various aspects of mobility are treated or addressed, including, gait function, fall risk, foot drop, navigating environment, and postural control. CONCLUSIONS: This narrative review summarizes wearable technologies that are currently commercially available and in stages of research and development. Overall, studies suggest that wearable peripheral neuromodulation technologies can improve aspects of mobility for older adults. Existing literature suggests that these technologies may lead to physiological changes in the brain through sensory reweighting or other neuroplastic mechanisms to enhance the performance of mobility and gait function in older adults over the age of 65.

The effect of tactile and verbal guidance during scapulothoracic exercises: An EMG and kinematic investigation.

BACKGROUND: Clinician-led training through tactile and verbal guidance to improve muscle activity and joint motion are a common but understudied focus of therapeutic interventions for shoulder pain. The purpose of this study was to determine if clinician guidance changes scapulothoracic muscle activity and kinematics compared to unguided shoulder exercises. METHODS: Eleven participants with shoulder pain were studied. Electromyographic (EMG) sensors were placed on the serratus anterior and upper and lower trapezii. Scapulothoracic and sternoclavicular kinematics were collected using electromagnetic sensors. Five common resisted shoulder exercises were performed with the following guidance: unguided, combined (verbal and tactile cues), and verbal guidance only. One-way repeated measures ANOVAs determined the effect of guidance versus unguided conditions for each exercise. RESULTS: Nine of ten combinations of exercise and guidance techniques demonstrated a significant effect of guidance for either muscle activity or joint kinematics. The guidance condition with the most frequent significant improvements across all variables was the combined condition. The exercises with the most frequent significant improvements across all variables were the external rotation exercises. Variables improved most frequently were: upper:lower trapezius EMG ratio (up to 11%), sternoclavicular elevation (up to 6°) and scapulothoracic internal rotation positioning (up to 8°), and sternoclavicular retraction displacement (up to 5°). CONCLUSION: Shoulder muscle activity and kinematics during exercises can be modified by tactile and verbal guidance. Most improvements in muscle activity occurred with verbal guidance during external rotation exercises. Most improvements in joint positioning and movement occurred with combined guidance during external rotation exercises.

Extended effects of a wearable sensory prosthesis on gait, balance function and falls after 26 weeks of use in persons with peripheral neuropathy and high fall risk-The walk2Wellness trial.

Background: We recently reported that individuals with impaired plantar sensation and high fall risk due to sensory peripheral neuropathy (PN) improved gait and balance function following 10 weeks of use of Walkasins®, a wearable lower limb sensory prosthesis that provides directional specific mechanical tactile stimuli related to plantar pressure measurements during standing and walking (RxFunction Inc., Eden Prairie, MN, United States). Here, we report 26-week outcomes and compare pre- and in-study fall rates. We expected improvements in outcomes and reduced fall rates reported after 10 weeks of use to be sustained. Materials and methods: Participants had clinically diagnosed PN with impaired plantar sensation, high fall risk (Functional Gait Assessment, FGA score < 23) and ability to sense tactile stimuli above the ankle at the location of the device. Additional outcomes included 10 m Gait Speed, Timed Up and Go (TUG), Four-Stage Balance Test, and self-reported outcomes, including Activities-Specific Balance Confidence scale and Vestibular Disorders Activities of Daily Living Scale. Participants tracked falls using a calendar. Results: We assessed falls and self-reported outcomes from 44 individuals after 26 weeks of device use; 30 of them conducted in-person testing of clinical outcomes. Overall, improvements in clinical outcomes seen at 10 weeks of use remained sustained at 26 weeks with statistically significant increases compared to baseline seen in FGA scores (from 15.0 to 19.2), self-selected gait speed (from 0.89 to 0.97 m/s), and 4-Stage Balance Test (from 25.6 to 28.4 s), indicating a decrease in fall risk. Non-significant improvements were observed in TUG and fast gait speed. Overall, 39 falls were reported; 31 of them did not require medical treatment and four caused severe injury. Participants who reported falls over 6 months prior to the study had a 43% decrease in fall rate during the study as compared to self-report 6-month pre-study (11.8 vs. 6.7 falls/1000 patient days, respectively, p < 0.004), similar to the 46% decrease reported after 10 weeks of use. Conclusion: A wearable sensory prosthesis can improve outcomes of gait and balance function and substantially decreases incidence of falls during long-term use. The sustained long-term benefits in clinical outcomes reported here lessen the likelihood that improvements are placebo effects. Clinical trial registration: ClinicalTrials.gov, identifier #NCT03538756.

Patients' and kin's perspective on healthcare quality compared to Lachman's multidimensional quality model: Focus group interviews.

OBJECTIVES: To identify key attributes of healthcare quality relevant to patients and kin and to compare them to Lachman's multidimensional quality model. METHODS: Four focus groups with patients and kin were conducted using a semi-structured interview guide and a purposive sampling method. Classical content analysis and constant comparison method were used to focus data analysis on individual and group level. RESULTS: Communication with patients, kin and professionals emerged as a new dimension from interview transcripts. Other identified key attributes largely corresponded with Lachman's multidimensional quality model. They were mainly classified in dimensions: 'Partnership and Co-Production', 'Dignity and Respect' and 'Effectiveness'. Technical quality dimensions were linked to organisational aspects of care in terms of staffing levels and time. The dimension 'Eco-friendly' was not addressed by patients or kin. CONCLUSIONS: The results enhance the comprehension of healthcare quality and contribute to its academic understanding by validating Lachman's multidimensional quality model from patients' and kin's perspective. The model robustness is increased by including communication as a quality dimension surrounding technical domains and core values. PRACTICE IMPLICATIONS: The key attributes can serve as a holistic framework for healthcare organisations to design their quality management system. An instrument can be developed to measure key attributes.

A comprehensive systematic review of the development process of 104 patient-reported outcomes (PROs) for physical activity in chronically ill and elderly people.

BACKGROUND: Capturing dimensions of physical activity relevant to patients may provide a unique perspective for clinical studies of chronically ill patients. However, the quality of the development of existing instruments is uncertain. The aim of this systematic review was to assess the development process of patient-reported outcome (PRO) instruments including their initial validation to measure physical activity in chronically ill or elderly patient populations. METHODS: We conducted a systematic literature search of electronic databases (Medline, Embase, Psychinfo, Cinahl) and hand searches. We included studies describing the original development of fully structured instruments measuring dimensions of physical activity or related constructs in chronically ills or elderly. We broadened the population to elderly because they are likely to share physical activity limitations. At least two reviewers independently conducted title and abstract screening and full text assessment. We evaluated instruments in terms of their aim, items identification and selection, domain development, test-retest reliability, internal consistency, validity and responsiveness. RESULTS: Of the 2542 references from the database search and 89 from the hand search, 103 full texts which covered 104 instruments met our inclusion criteria. For almost half of the instruments the authors clearly described the aim of the instruments before the scales were developed. For item identification, patient input was used in 38% of the instruments and in 32% adaptation of existing scales and/or unsystematic literature searches were the only sources for the generation of items. For item reduction, in 56% of the instruments patient input was used and in 33% the item reduction process was not clearly described. Test-retest reliability was assessed for 61%, validity for 85% and responsiveness to change for 19% of the instruments. CONCLUSIONS: Many PRO instruments exist to measure dimensions of physical activity in chronically ill and elderly patient populations, which reflects the relevance of this outcome. However, the development processes often lacked definitions of the instruments' aims and patient input. If PROs for physical activity were to be used in clinical trials more attention needs to be paid to the establishment of content validity through patient input and to the assessment of their evaluative measurement properties.

Coming Out of the Closet, Also on the News? A Longitudinal Content Analysis of Patterns in Visibility, Tone and Framing of LGBTs on Television News (1986-2017).

This study documents the results of a longitudinal content analysis of television news about LGBT people in terms of visibility, active representation, tone and framing in Flanders (1986-2017). While attention for LGBT issues has increased over time, LGBTs are not more likely to be visually represented or granted a voice. Gay men are more often actively represented than lesbians and transgender people. News remains negatively biased, although news stories in which LGBT people are depicted as the cause of negativity have become less prevalent. Patterns in framing have shifted: Deviance and abnormality frames have decreased in favor of a rise in equal rights and victim frames. Patterns in tone and framing were similar for gay men, lesbians and transgender people. Results suggest that journalists have shifted from problematizing homosexuality to problematizing homophobia. Implications of news as a source of mass-mediated contact to promote tolerance toward LGBT people are discussed.

The Effects of a Wearable Sensory Prosthesis on Gait and Balance Function After 10 Weeks of Use in Persons With Peripheral Neuropathy and High Fall Risk - The walk2Wellness Trial.

BACKGROUND: Sensory peripheral neuropathy (PN) is associated with gait, balance problems and high fall risk. The walk2Wellness trial investigates effects of long-term, home-based daily use of a wearable sensory prosthesis on gait function, balance, quality of life and fall rates in PN patients. The device (Walkasins®, RxFunction Inc., MN, United States) partially substitutes lost nerve function related to plantar sensation providing directional tactile cues reflecting plantar pressure measurements during standing and walking. We tested the null hypothesis that the Functional Gait Assessment (FGA) score would remain unchanged after 10 weeks of use. METHODS: Participants had PN with lost plantar sensation, gait and balance problems, an FGA score < 23 (high fall risk), and ability to sense tactile stimuli above the ankle. Clinical outcomes included FGA, Gait Speed, Timed Up&Go (TUG) and 4-Stage Balance Test. Patient-reported outcomes included Activities-Specific Balance Confidence (ABC) scale, Vestibular Disorders Activities of Daily Living Scale, PROMIS participation and satisfaction scores, pain rating, and falls. Evaluations were performed at baseline and after 2, 6, and 10 weeks. Subjects were not made aware of changes in outcomes. No additional balance interventions were allowed. RESULTS: Forty-five participants of 52 enrolled across four sites completed in-clinic assessments. FGA scores improved from 15.0 to 19.1 (p < 0.0001), normal and fast gait speed from 0.86 m/s to 0.95 m/s (p < 0.0001) and 1.24 m/s to 1.33 m/s (p = 0.002), respectively, and TUG from 13.8 s to 12.5 s (p = 0.012). Four-Stage Balance Test did not improve. Several patient-reported outcomes were normal at baseline and remained largely unchanged. Interestingly, subjects with baseline ABC scores lower than 67% (high fall risk cut-off) increased their ABC scores (49.9% to 59.3%, p = 0.01), whereas subjects with ABC scores above 67% showed a decrease (76.6% to 71.8%, p = 0.019). Subjects who reported falls in the prior 6 months (n = 25) showed a decrease in the number of fall-risk factors (5.1 to 4.3, p = 0.023) and a decrease in fall rate (13.8 to 7.4 falls/1000 days, p = 0.014). Four pre-study non-fallers (n = 20) fell during the 10 weeks. CONCLUSION: A wearable sensory prosthesis presents a new way to treat gait and balance problems and manage falls in high fall-risk patients with PN. TRIAL REGISTRATION: ClinicalTrials.gov (#NCT03538756).

The intracellular domain of ß-dystroglycan mediates the nucleolar stress response by suppressing UBF transcriptional activity.

ß-dystroglycan (ß-DG) is a key component of multiprotein complexes in the plasma membrane and nuclear envelope. In addition, ß-DG undergoes two successive proteolytic cleavages that result in the liberation of its intracellular domain (ICD) into the cytosol and nucleus. However, stimuli-inducing ICD cleavage and the physiological relevance of this proteolytic fragment are largely unknown. In this study we show for the first time that ß-DG ICD is targeted to the nucleolus where it interacts with the nuclear proteins B23 and UBF (central factor of Pol I-mediated rRNA gene transcription) and binds to rDNA promoter regions. Interestingly DG silencing results in reduced B23 and UBF levels and aberrant nucleolar morphology. Furthermore, ß-DG ICD cleavage is induced by different nucleolar stressors, including oxidative stress, acidosis, and UV irradiation, which implies its participation in the response to nucleolar stress. Consistent with this idea, overexpression of ß-DG elicited mislocalization and decreased levels of UBF and suppression of rRNA expression, which in turn provoked altered ribosome profiling and decreased cell growth. Collectively our data reveal that ß-DG ICD acts as negative regulator of rDNA transcription by impeding the transcriptional activity of UBF, as a part of the protective mechanism activated in response to nucleolar stress.

Direct and indirect photolysis of polycyclic aromatic hydrocarbons in nitrate-rich surface waters.

The photolysis of three polycyclic aromatic hydrocarbons (PAHs)-pyrene, phenanthrene, and naphthalene-were studied in waters taken from creosote-contaminated sites in Gary (IN, USA) and Wilmington (NC, USA). Direct photolysis of all PAHs was observed under simulated solar radiation, with pyrene degrading at a faster rate than either phenanthrene or naphthalene. Phenanthrene degradation, when compared to its direct photolysis rate, increased in Gary water but decreased in Wilmington water. Analysis of the waters for dissolved organic carbon (DOC) and nitrate revealed higher levels of DOC in the Wilmington sample (9.29 mg/L) compared with the Gary sample (6.73 mg/L), as well as significantly less nitrate (0.046 mM vs 0.205 mM for the Gary sample). The slightly lower rate of phenanthrene degradation observed for the Wilmington sample, corrected for light attenuation effects, is statistically the same as that in the direct photolysis experiments. Therefore, we attribute the lower rate of degradation in the presence of Wilmington water to light screening by DOC, but we believe the faster reaction rate observed for the Gary water results from hydroxyl radical (OH*) chemistry generated by nitrate photolysis. Indeed, degradation of the target compound increased when nitrate (at 0.2 and 0.4 mM) was added to the Wilmington sample, further corroborating this conclusion. Overall photoreaction rates decreased for the lower-molecular-weight PAHs, because the fastest naphthalene photolytic rate was roughly two orders of magnitude slower than that of pyrene.

Publisher Correction: Retrograde trafficking of ß-dystroglycan from the plasma membrane to the nucleus.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.