Reconsidering the Model of Trim5α Assembly: The Role of the Linker2 (l2) Region in Trim5α Assembly

The TRIM5α protein from rhesus macaques (TRIM5αrh) exhibits a remarkable ability to potently inhibit infection by Human Immunodeficiency Virus Type-1 (HIV-1). Extensive studies have shown that TRIM5α is capable of self-associating at many levels, eventually leading to the formation of a hexameric assembly that can superimpose on the hexameric lattice of the HIV-1 capsid. The mechanism underlying the self-association of TRIM5α and the molecular determinants of self-association remain to be completely understood. In this study, we show that the Linker 2 (L2) region of TRIM5rh is important for dimerization and higher order self-association, both of which are independent processes. Additionally, fluorescence resonance energy transfer (FRET) analysis suggests that an antiparallel dimer configuration is the basic unit of TRIM5α, consistent with the recently published crystal structure of the CCL2 region of TRIM25 by Sanchez et al. We propose a homology model of the CCL2 fragment of TRIM5α based on the structure of the TRIM25 CCL2 region. In this model the Helix 3 of the L2 region folds back onto Helix 1 (CC domain), possibly ensuring correct binding of the SPRY domain to the HIV-1 core. These studies reveal previously unknown determinants in the L2 region that govern self-association of TRIM5α

Men and maternal care: how men make sense of their experiences with a partner's pregnancy, labor, and delivery

Men often report wanting to be involved in a partner's pregnancy, labor, and delivery but may feel unsure of what to do or if they are allowed to participate. Existing studies describe men's participation and are mostly from non-communication disciplines, such as midwifery. This dissertation, guided by sensemaking theory, aimed to provide a communicative perspective to men's experiences with maternal health. Sensemaking theory examines the communicative process of making sense of lived experiences and the factors that influence an individual's sensemaking. The influences of societal expectations, as outlined in the U.S. master narrative of birth, were also examined. Sixteen men with partners who had recently given birth were interviewed and asked about how they participated in, and made sense of, their experiences with a partner's pregnancy, labor. and delivery. Data were analyzed through a hermeneutic phenomenological lens with the intention of describing and interpreting the lived experiences of these participants. Participants made sense of their experience by engaging in the process of noting memorable moments, placing boundaries on those moments, and labeling (explicitly and implicitly) the role they played. Participants fell into one of three roles (lead character, background character, and supportive character), often depending on their partners' needs. Most participants labeled themselves in a different role at different points, indicating that men's roles change throughout the process. When asked to story their partner's pregnancy, labor, and delivery, most told incomplete or incoherent stories. This could be due to their lack of practice telling the story or an expectation that men are not supposed to talk about maternal health. Additionally, participants discussed expectations of a normal pregnancy, feeling in control of the process, and being seen but not heard. These expectations reflected the U.S. master birth narrative which is characterized as a pronatalist (i.e., belief that posits all adults will desire to become parents and assumes all adults are able to get and sustain a pregnancy) narrative that privileges a medicalized model of birth. However, this sample was predominantly white, indicating that the master U.S. birth narrative may only reflect the experiences of a predominantly white population. This sheds light on a need for additional research examining the experiences of BIPOC women and their partners in maternal health. Practitioners and educators should encourage fathers or other support partners to be involved in maternal health. Participants who utilized doulas or midwives felt strongly that other people should do the same, and felt that this external support was vital for them to be able to support their partner and engage in pregnancy, labor, and delivery. Many participants felt pregnancy was supposed to be a time for them to prepare for parenthood but lacked the resources to do so. Prenatal educators should provide more information for parents to aid their transition from delivering a baby to parenting one. These findings extend understanding of men's experiences in maternal health by adding a communicative lens to this context. These findings also expand the timeframe by analyzing how men make sense of and engage with pregnancy, labor, and delivery and how that engagement or sensemaking may change over time, rather than only focusing on the stagnant role played by men in labor and delivery only. These findings also extend sensemaking theory by examining a family and health context and by examining the impact of societal expectations on men's sensemaking and engagement with pregnancy, labor, and delivery.Includes bibliographical references

Mellom visshet og uvisshet- en studie av risikopersepsjon og unge kvinners valg om hormonell prevensjon

I nyere tid har det blitt observert en nedgang i salget av hormonell prevensjon, en økning i abortraten, og en økning i salget av nødprevensjon. Foruten nødprevensjon, er endringen i prevensjonsvaner og stigning i abortraten tydelig blant unge kvinner. Parallelt med statistikkene, er det en bevegelse på sosiale medier som viser en skepsis mot hormonell prevensjon, og som er ledet av unge kvinner uten noen medisinsk bakgrunn. Selv om det er for tidlig å stadfeste en sammenheng, kan det være at risikopersepsjonen til unge kvinner påvirker deres valg om hormonell prevensjon. Følgelig er oppgavens problemstilling: Hvordan påvirker unge kvinners risikopersepsjonen valg om hormonell prevensjon? For å besvare problemstillingen er det samlet inn data fra et gruppeintervju med fire unge kvinner, tre individuelle intervju med helsepersonell, et individuelt intervju med en journalist, og ett dokument. Funn fra oppgaven tyder på at unge kvinners risikopersepsjon påvirker valg om hormonell prevensjon. Vanlige bivirkninger som påvirkning av psykisk helse er fremtredende som en risiko, og utgjør en bekymring som påvirker valg om hormonell prevensjon. God livskvalitet kan synes å være en prioritet for unge kvinner i deres valg om hormonell prevensjon, og vanlige bivirkninger kan dermed bli en trussel på tross av at de er ufarlige. De empiriske funnene tyder på at unge kvinner oppfatter risikokommunikasjonen fra helsepersonell som manglende rundt informasjon om vanlige bivirkninger, siden de oppfatter kompetansen på hormonell prevensjon som begrenset. Gruppeintervjuet indikerer at unge kvinner i mangel på informasjon gitt av helsepersonell, heller søker ut informasjon på internettet, noe som kan påvirke unge kvinners risikopersepsjonen gjennom en sosial forsterking av risiko

Interorganizational collaboration in a Norwegian prison - challenges and opportunities arising from interagency meetings

Peer reviewe

A Patient Activities of Daily Living Scale for Amyotrophic Lateral Sclerosis

Background: Motor neuron disorders are rare, progressive neurodegenerative diseases which affect multiple domains of motor function. The ability to assess function from home using an electronic medical record (EMR) would facilitate pragmatic studies. Objective: To develop a Patient Activity of Daily Living scale for Amyotrophic Lateral Sclerosis and other motor neuron disorders (PADL-ALS) to support large pragmatic trials. Methods: The Greater Plains Collaborative Clinical Data Research Network (GPC) developed and tested the feasibility of using the PADL-ALS.  We convened patient and caregiver focus groups and in-person meetings to recommend changes to the ALS Functional Rating Scale-Revised (ALSFRS-R), which clarified language and added questions about pseudobulbar affect, pain, and faith.  Feasibility was determined by conducting a survey of participants identified using EMR-computable phenotypes and returned via patient-preferred modalities. Results: Surveys were distributed to 1079 participants at nine GPC health systems.  The survey response rate was 44.4% (range 12.9-57.66%): male to female ratio 1.56; 84% self-identified as a patient with ALS.  Patient respondents used computers or tablets more frequently than caregivers responding on their behalf.  The PADL-ALS correlated to clinic-performed ALSFRS-R within 4 weeks of survey completion (n=33, rho=0.93, Kansas only).  The pseudobulbar affect question correlated to functional motor burden.  Over 80% agreed to be contacted for future research opportunities. Conclusion:  We demonstrated the feasibility of determining functional burden with the PADL-ALS using an EMR-computable phenotype.  Future directions include implementing the PADL-ALS to answer pragmatic questions about ALS care

Photophysiological cycles in Arctic krill are entrained by weak midday twilight during the Polar Night

Light plays a fundamental role in the ecology of organisms in nearly all habitats on Earth and is central for processes such as vision and the entrainment of the circadian clock. The poles represent extreme light regimes with an annual light cycle including periods of Midnight Sun and Polar Night. The Arctic Ocean extends to the North Pole, and marine light extremes reach their maximum extent in this habitat. During the Polar Night, traditional definitions of day and night and seasonal photoperiod become irrelevant since there are only “twilight” periods defined by the sun’s elevation below the horizon at midday; we term this “midday twilight.” Here, we characterize light across a latitudinal gradient (76.5° N to 81° N) during Polar Night in January. Our light measurements demonstrate that the classical solar diel light cycle dominant at lower latitudes is modulated during Arctic Polar Night by lunar and auroral components. We therefore question whether this particular ambient light environment is relevant to behavioral and visual processes. We reveal from acoustic field observations that the zooplankton community is undergoing diel vertical migration (DVM) behavior. Furthermore, using electroretinogram (ERG) recording under constant darkness, we show that the main migratory species, Arctic krill (Thysanoessa inermis) show endogenous increases in visual sensitivity during the subjective night. This change in sensitivity is comparable to that under exogenous dim light acclimations, although differences in speed of vision suggest separate mechanisms. We conclude that the extremely weak midday twilight experienced by krill at high latitudes during the darkest parts of the year has physiological and ecological relevance

RNF40 regulates gene expression in an epigenetic context-dependent manner

Background Monoubiquitination of H2B (H2Bub1) is a largely enigmatic histone modification that has been linked to transcriptional elongation. Because of this association, it has been commonly assumed that H2Bub1 is an exclusively positively acting histone modification and that increased H2Bub1 occupancy correlates with increased gene expression. In contrast, depletion of the H2B ubiquitin ligases RNF20 or RNF40 alters the expression of only a subset of genes. Results Using conditional Rnf40 knockout mouse embryo fibroblasts, we show that genes occupied by low to moderate amounts of H2Bub1 are selectively regulated in response to Rnf40 deletion, whereas genes marked by high levels of H2Bub1 are mostly unaffected by Rnf40 loss. Furthermore, we find that decreased expression of RNF40-dependent genes is highly associated with widespread narrowing of H3K4me3 peaks. H2Bub1 promotes the broadening of H3K4me3 to increase transcriptional elongation, which together lead to increased tissue-specific gene transcription. Notably, genes upregulated following Rnf40 deletion, including Foxl2, are enriched for H3K27me3, which is decreased following Rnf40 deletion due to decreased expression of the Ezh2 gene. As a consequence, increased expression of some RNF40-“suppressed” genes is associated with enhancer activation via FOXL2. Conclusion Together these findings reveal the complexity and context-dependency whereby one histone modification can have divergent effects on gene transcription. Furthermore, we show that these effects are dependent upon the activity of other epigenetic regulatory proteins and histone modifications

Impact of different infliximab dose regimens on treatment response and drug survival in 462 patients with psoriatic arthritis: results from the nationwide registries DANBIO and ICEBIO.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The aim of this study was to describe dose regimens, dose escalation and clinical outcomes in TNF-α inhibitor (TNFi)-naive patients with PsA treated with infliximab in routine rheumatology care.We conducted an observational cohort study based on the nationwide Danish Rheumatologic Database (DANBIO) and Center for Rheumatology Research (ICEBIO) registries. Stratified by country, characteristics of patients treated with ≤3 mg infliximab/kg body weight, 3-5 mg/kg or ≥5 mg/kg every 8 weeks were described. Outcomes were evaluated by ACR 20%, 50% and 70% (ACR20/50/70) responses and European League Against Rheumatism good response after 6 months, disease activity after 12 months, Kaplan-Meier plots and regression analyses.Four hundred and sixty-two patients (376 Danish, 86 Icelandic) received treatment with infliximab. In Danish patients, the starting dose was ≤3 mg/kg in 110 patients (29%), 3-5 mg/kg in 157 (42%), ≥5 mg/kg in 38 (10%) and unregistered in 71 (19%). In Icelandic patients, corresponding numbers were 64 (74%), 17 (27%), 0 (0%) and 5 (6%). Patients with a higher body weight received lower doses per kilogram. Danish patients received higher doses than Icelandic patients at baseline [median 3.1 (interquartile range 3.0-3.8) vs 2.3 (2.1-2.9) mg/kg, P 70% of Icelandic and Danish PsA patients treated with infliximab received sustained doses below the 5 mg/kg every 8 weeks recommended in international guidelines. Lower starting doses did not affect drug survival or response

Telomerase and pluripotency factors jointly regulate stemness in pancreatic cancer stem cells

To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patientsThis research was funded by a Max Eder Fellowship of the German Cancer Aid (111746), a German Cancer Aid Priority Program ‘Translational Oncology’ 70112505, by a Collaborative Research Centre grant (316249678—SFB 1279) of the German Research Foundation, and by a Hector Foundation Cancer Research grant (M65.1) to P.C.H., B.S.J. is supported by a Rámon y Cajal Merit Award (RYC- 2012-12104) from the Ministerio de Economía y Competitividad, Spain and a Coordinated grant (GC16173694BARB) from the Fundación Asociación Española Contra el Cáncer (AECC). K.W. is supported by a Baustein 3.2 by Ulm University