Impact of etoposide and ASCT on survival among patients aged <65 years with stage II to IV PTCL: a population-based cohort study.

Patients aged <65 years with peripheral T-cell lymphoma (PTCL) are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Although the addition of etoposide (CHOEP) and consolidation with autologous stem cell transplantation (ASCT) are preferred in some countries, randomized trials are lacking. This nationwide population-based study assessed the impact of etoposide and ASCT on overall survival (OS) among patients aged 18 to 64 years with stage II to IV anaplastic large-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (NOS) diagnosed between 1989 and 2018 using the Netherlands Cancer Registry. Patients were categorized into 2 calendar periods, representing pre- and post-eras of etoposide and ASCT, respectively. A total of 1427 patients were identified (ALCL, 35%; AITL, 21%; and PTCL NOS, 44%). OS increased from 39% in the period from 1989 to 2009 to 49% in the period of 2009 to 2018 (P < .01). Five-year OS was superior for patients treated with CHOEP vs CHOP (64% and 44%, respectively; P < .01). When adjusted for subtype, International Prognostic Index score, and ASCT, the risk of mortality was similar between the 2 groups, except for patients with ALK+ ALCL, for whom the risk of mortality was 6.3 times higher when treated with CHOP vs CHOEP. Patients undergoing consolidation with ASCT had superior 5-year OS of 81% compared with 39% for patients not undergoing ASCT (P < .01), regardless of whether complete remission was achieved. In patients aged <65 years with advanced-stage ALK- ALCL, AITL, or PTCL, the use of ASCT consolidation, but not the addition of etoposide, was associated with improved OS.

Impact of comorbidity on health-related quality of life in newly diagnosed patients with lymphoma or multiple myeloma: results from the PROFILES-registry.

With the increasing prevalence of comorbidity in an ageing population, it is crucial to better understand the impact of comorbidity on health-related quality of life (HRQoL) after lymphoma or multiple myeloma (MM) diagnosis. We included 261 newly diagnosed patients (67% response rate) diagnosed with lymphoma or MM between October 2020 and March 2023 in a longitudinal survey. The European Organisation for Research and Treatment of Cancer (EORTC) questionnaires were used to measure generic and disease-specific HRQoL. Evidence-based guidelines for interpretation of the EORTC questionnaires were used to identify clinical importance. Patients were classified as having 'no comorbidity', 'mild comorbidity' (e.g. arthrosis or rheumatism), or 'moderate-severe comorbidity' (e.g. heart or lung disease), using the adapted self-administered comorbidity questionnaire. At diagnosis, the mean age was 64 years, 63% were male and 38% reported no comorbidity, 33% mild comorbidity, and 29% moderate-severe comorbidity. Patients with mild or moderate-severe comorbidity reported clinically relevant worse HRQoL at diagnosis than patients without comorbidity. One year post-diagnosis most outcomes showed clinically relevant improvement, irrespective of comorbidity. However, outcomes of physical functioning (ß=-7.9, p < 0.05), global health status (ß=-7.6, p < 0.05), bone pain (ß = 8.1 to 9.1, p < 0.05), muscle/joint pain (ß = 14.5 to 18.8, p < 0.01) and muscle weakness (ß = 10.4 to 15.6, p < 0.05) improved less among those with comorbidity, and clinically relevant differences between comorbidity groups persisted over time. With clinically relevant worse HRQoL at diagnosis and less recovery of HRQoL during the first year after diagnosis in patients with comorbidity, consideration of both prognosis and HRQoL is important when making treatment decisions.

To stand out or to conform: Stereotypes and meta-stereotypes as barriers in the transition to sustainable diets.

What factors hinder the reduction of meat and/or dairy intake? In this study, we explored the perceived barriers that meat and/or dairy reducers experienced when shifting their diets. We particularly focused on how meat and/or dairy reducers were affected by their beliefs about how omnivores stereotype vegans (i.e., meta-stereotypes), as meta-stereotypes have not been previously explored in this context. Through open-ended questions in an online survey, we explored the experiences and perceived barriers among female meat and/or dairy reducers (n = 272), as well as their perceptions of vegans (i.e., stereotypes and meta-stereotypes), and how these perceptions affected their lived experiences. We analysed the data using reflexive thematic analysis and generated six themes. We highlighted perceptions of cost (Theme 1) and perceptions of health concerns (Theme 2) as the most dominant barriers to the reduction of meat and/or dairy intake. Regarding (meta) stereotypes, participants' perceptions of vegans were shaped by personal experiences and encounters with vegans (Theme 3), and how participants related to vegans was sometimes reflected in the language they used to describe vegans (Theme 4). Participants felt that they, or reducers more generally, were occasionally judged as vegans (Theme 5), which might influence participants' choices and conformity to eating norms (Theme 6). Meta-stereotypes may play a role in polarised dietary group perceptions, and we discuss how they are shaped by social identity processes as well as by aspects of Western food systems.

CRY2 missense mutations suppress P53 and enhance cell growth.

Disruption of circadian rhythms increases the risk of several types of cancer. Mammalian cryptochromes (CRY1 and CRY2) are circadian transcriptional repressors that are related to DNA-repair enzymes. While CRYs lack DNA-repair activity, they modulate the transcriptional response to DNA damage, and CRY2 can promote SKP1 cullin 1-F-box (SCF)FBXL3-mediated ubiquitination of c-MYC and other targets. Here, we characterize five mutations in CRY2 observed in human cancers in The Cancer Genome Atlas. We demonstrate that two orthologous mutations of mouse CRY2 (D325H and S510L) accelerate the growth of primary mouse fibroblasts expressing high levels of c-MYC. Neither mutant affects steady-state levels of overexpressed c-MYC, and they have divergent impacts on circadian rhythms and on the ability of CRY2 to interact with SCFFBXL3 Unexpectedly, stable expression of either CRY2 D325H or of CRY2 S510L robustly suppresses P53 target-gene expression, suggesting that this may be a primary mechanism by which they influence cell growth.

Comparison of autologous and allogeneic hematopoietic cell transplantation strategies in patients with primary plasma cell leukemia, with dynamic prediction modeling.

Primary plasma cell leukemia (pPCL) is a rare and challenging malignancy. There are limited data regarding optimum transplant approaches. We therefore undertook a retrospective analysis from 1998-2014 of 751 patients with pPCL undergoing one of four transplant strategies; single autologous transplant (single auto), single allogeneic transplant (allo-first) or a combined tandem approach with an allogeneic transplant following an autologous transplant (auto-allo) or a tandem autologous transplant (auto-auto). To avoid time bias, multiple analytic approaches were employed including Cox models with time-dependent covariates and dynamic prediction by landmarking. Initial comparisons were made between patients undergoing allo-first (n=70) versus auto-first (n=681), regardless of a subsequent second transplant. The allo-first group had a lower relapse rate (45.9%, 95% confidence interval [95% CI]: 33.2-58.6 vs. 68.4%, 64.4-72.4) but higher non-relapse mortality (27%, 95% CI: 15.9-38.1 vs. 7.3%, 5.2-9.4) at 36 months. Patients who underwent allo-first had a remarkably higher risk in the first 100 days for both overall survival and progression-free survival. Patients undergoing auto-allo (n=122) had no increased risk in the short term and a significant benefit in progression-free survival after 100 days compared to those undergoing single auto (hazard ratio [HR]=0.69, 95% CI: 0.52- 0.92; P=0.012). Auto-auto (n=117) was an effective option for patients achieving complete remission prior to their first transplant, whereas in patients who did not achieve complete remission prior to transplantation our modeling predicted that auto-allo was superior. This is the largest retrospective study reporting on transplantation in pPCL to date. We confirm a significant mortality risk within the first 100 days for allo-first and suggest that tandem transplant strategies are superior. Disease status at time of transplant influences outcome. This knowledge may help to guide clinical decisions on transplant strategy.

"I know it's just pouring it from the tap, but it's not easy": Motivational processes that underlie water drinking.

Water drinking behaviour is under-researched despite the prevalence and adverse health consequences of underhydration. We conducted a qualitative exploration into the motivational processes underlying water drinking, informed by a grounded cognition perspective on desire and motivated behaviour. We interviewed and analysed data from 60 participants stratified by age, gender, and education level using thematic analysis, to generate three key themes. "Water as situated habits," suggests that participants form and maintain situated water drinking habits, so that within certain situations they regularly drink water. However, participants who situated their water intake only in one key situation (e.g., work routine), had low and inconsistent intake when they left this situation. Some situations happened so infrequently during the day (e.g., before bed) that participants' daily water intake was low. Many participants reported drinking water in reaction to thirst cues, but these were easily suppressed or ignored, so that water drinking was inconsistent. Participants who saw drinking water as part of their self-identity had consistent and high water intake across a variety of situations. "Knowledge and attitudes," suggests that few participants had knowledge or attitudes that promoted water intake (e.g., perceived water as positive or understood the importance of hydration). "Strategies underlying attempts to increase intake" suggests that many participants lacked insight into strategies to increase water intake, although they spontaneously discussed attempts to drink more. This lead to ineffective attempts at behaviour change. Participants' mentions of dehydration and their responses to a urine colour chart suggested that many participants were possibly underhydrated. Our findings suggest that interventions and practitioners attempting to increase water intake need to increase knowledge about the importance of hydration, and encourage individuals to develop effective situated water drinking habits.

Bortezomib maintenance after R-CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial.

Rituximab-containing induction followed by autologous stem cell transplantation (ASCT) is the standard first-line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo-immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high-dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow-up of 77·5 months for patients still alive, 5-year event-free survival (EFS) was 51% (95% CI 42-59%); 5-year overall survival (OS) was 73% (95% CI 65-80%). The median follow-up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5-year EFS of 63% (95% CI 44-78%) and 5-year OS of 90% (95% CI 72-97%). The patients randomised to observation had 5-year PFS of 60% (95% CI, 40-75%) and OS of 90% (95% CI 72-97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.

Treatment of patients with MYC rearrangement positive large B-cell lymphoma with R-CHOP plus lenalidomide: results of a multicenter HOVON phase II trial.

Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).

Nutritional Intake and Bone Health Among Adults With Probable Undiagnosed, Untreated Celiac Disease: What We Eat in America and NHANES 2009-2014.

Objective: The aim was to evaluate differences in nutritional intake of calcium, vitamin D, and phosphorus; serologic indices of these nutrients; and bone health among adults with and without probable, undiagnosed celiac disease (CD).Method: Cross-sectional data from What We Eat in America and the National Health and Nutrition Examination Survey 2009-2014 including self-reported dietary and supplement intake from one day of 24-hour recalls, serologic indicators, and dual x-ray absorptiometry scans were analyzed in adults with probable undiagnosed CD, who tested positive on the immunoglobulin A endomysial antibody assay (n = 48) and controls (n = 13,634). Statistical analysis included multiple linear regression modeling controlled for age, sex, race/ethnicity, energy intake, and poverty income ratio.Results: The prevalence of probable undiagnosed CD was 1 in 285. Probable CD status was associated with a 251.6 mg (95% confidence interval [CI], 72.3-432.9) higher daily total calcium intake. The total dietary and supplement intake of those with probable CD was significantly higher in calcium density (103.4 mg/1,000 kcal; 95% CI, 25.6-181.1) and phosphorus density (46.7 mg/1,000 kcal; 95% CI, 3.1-90.3). Probable CD status was associated with higher dairy consumption by 0.7 cups per day (95% CI, 0.2-1.2) and higher serum phosphorus concentrations (4.0 mg/dL vs 3.8 mg/dL, p = 0.011). No differences in serum calcium, vitamin D, or alkaline phosphatase levels were observed between groups. Probable CD status was also associated with a -0.1 g/cm2 (95% CI, -0.2 to -0.0) lower femur bone mineral density (BMD) and a -0.1 g/cm2 (95% CI, -0.1 to -0.0) lower femoral neck BMD. No differences in total spine BMD were observed.Conclusions: Adults with probable undiagnosed CD had lower bone density than adults without CD, despite also reporting higher total calcium intake and nutritional density of both calcium and phosphorus.

Silver nanoparticles are lethal to the ciliate model Tetrahymena and safe to the pike silverside Chirostoma estor.

Ciliate ectoparasites are one of the most important groups of pathogens in fish culture, and the traditional treatments are sometimes harmful to the fish and the environment. Thus, the search for novel compounds that are effective at low concentrations and safe for fish are necessary to optimise treatments in aquaculture. The antiprotozoal capacity of silver nanoparticles (AgNPs) against the ciliate Tetrahymena has been documented; however, their toxicity may vary with the synthesis methodology and nanoparticle size. The objectives of this study were a) to evaluate the acute toxicity in vitro of two AgNPs (Argovit™ and UTSA) on Tetrahymena sp., a biological model for ciliated ectoparasites of fish and b) to test the safety of lethal and higher doses of UTSA AgNPs for ciliates on the fish C. estor. Light microscopy and scanning electron microscopy (SEM) were used to determine whether AgNPs affected the structure of the cell surface of Tetrahymena. The mortality, histopathological alterations and metagenomics of the fish were used to determine the major effects of UTSA AgNPs. In Tetrahymena, the median lethal concentration (LC50) for Argovit™ was 2501 ± 1717 ng/L at 15 min and 796 ± 510 ng/L at 60 min, while the LC50 for UTSA AgNPs was 4 ± 2 and 1 ± 0.6 ng/L at 15 min and 60 min, respectively. A concentration of 3300 ng/L Argovit™ and 10.6 ng/L UTSA AgNPs for 15 and 60 min, respectively, was 100% effective against Tetrahymena. After 60 min of exposure to 0.25 and 0.50 ng/L UTSA AgNPs, the number of cilia significantly reduced, there were small holes on the cell surface, and the cellular membrane was ruptured. In fish exposed to lethal (10.6 ng/L) and higher (31.8 and 95.4 ng/L) doses of UTSA, the AgNPs did not affect fish survival after 96 h, and there were no signs of histopathological damage or gut microbial changes. This study is the first report on microscopic and ultrastructural changes in Tetrahymena after exposure to significantly low concentrations of UTSA AgNPs with antiprotozoal efficacy without evidence of harmful effects on fish. These results provide the basis for further studies of both pet aquarium and commercial fish that may validate these findings at a larger experimental scale, taking into account AgNPs bioaccumulation, safety for human consumption and environmental impact.

Regulation of signaling pathways by ß-elemene in cancer progression and metastasis.

Entry of ß-elemene into various phases of clinical trials advocates its significance as a premium candidate likely to gain access to mainstream medicine. Based on the insights gleaned from decades of research, it seems increasingly transparent that ß-elemene has shown significant ability to modulate multiple cell signaling pathways in different cancers. We partition this multicomponent review into how ß-elemene strategically modulates various signal transduction cascades. We have individually summarized regulation of tumor necrosis factor related apoptosis-inducing ligand, signal transducers and activators of transcription, transforming growth factor/SMAD, NOTCH, and mammalian target of rapamycin pathways by ß-elemene. Last, we will discuss the results of clinical trials of ß-elemene and how effectively we can use these findings to stratify patients who can benefit most from ß-elemene.

Efficient Copper-Catalyzed Multicomponent Synthesis of N-Acyl Amidines via Acyl Nitrenes.

Direct synthetic routes to amidines are desired, as they are widely present in many biologically active compounds and organometallic complexes. N-Acyl amidines in particular can be used as a starting material for the synthesis of heterocycles and have several other applications. Here, we describe a fast and practical copper-catalyzed three-component reaction of aryl acetylenes, amines, and easily accessible 1,4,2-dioxazol-5-ones to N-acyl amidines, generating CO2 as the only byproduct. Transformation of the dioxazolones on the Cu catalyst generates acyl nitrenes that rapidly insert into the copper acetylide Cu-C bond rather than undergoing an undesired Curtius rearrangement. For nonaromatic dioxazolones, [Cu(OAc)(Xantphos)] is a superior catalyst for this transformation, leading to full substrate conversion within 10 min. For the direct synthesis of N-benzoyl amidine derivatives from aromatic dioxazolones, [Cu(OAc)(Xantphos)] proved to be inactive, but moderate to good yields were obtained when using simple copper(I) iodide (CuI) as the catalyst. Mechanistic studies revealed the aerobic instability of one of the intermediates at low catalyst loadings, but the reaction could still be performed in air for most substrates when using catalyst loadings of 5 mol %. The herein reported procedure not only provides a new, practical, and direct route to N-acyl amidines but also represents a new type of C-N bond formation.

Rituximab-PECC induction followed by 90 Y-ibritumomab tiuxetan consolidation in relapsed or refractory DLBCL patients who are ineligible for or have failed ASCT: results from a phase II HOVON study.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after, or ineligible for, autologous stem cell transplantation (ASCT) have a dismal prognosis. This phase II study evaluated treatment with R-PECC (rituximab, prednisolone, etoposide, chlorambucil, lomustine), every 28 days for 4 cycles in 62 patients, followed by radio-immunotherapy consolidation with 90 Y-ibritumomab tiuxetan in responsive patients. Primary endpoints were failure-free survival (FFS) and incidence of grade ≥3 adverse events from start of 90 Y-ibritumomab tiuxetan. The overall response rate after R-PECC was 50%. Twenty-nine of 31 responsive patients proceeded to 90 Y-ibritumomab tiuxetan. Five out of 15 partial remission patients converted to complete remission after 90 Y-ibritumomab tiuxetan. One-year FFS and overall survival (OS) from start of 90 Y-ibritumomab tiuxetan was 52% (95% confidence interval [CI], 33-68%) and 62% (95% CI, 42-77%), respectively. One-year FFS and OS from start of R-PECC was 28% (95% CI, 17-39%) and 49% (95% CI, 36-61%), respectively. Toxicities of R-PECC and 90 Y-ibritumomab tiuxetan were mainly haematological. In conclusion, for relapsed DLBCL patients the largely oral R-PECC regimen achieves promising response rates, combined with an acceptable safety profile. Consolidation with 90 Y-ibritumomab tiuxetan resulted in long-term response durations in approximately one third of the patients that received it.

Microfluidic fabrication of vesicles with hybrid lipid/nanoparticle bilayer membranes.

Hybrid lipid/nanoparticle membranes are suitable model systems both to study the complex interactions between nanoparticles and biological membranes, and to demonstrate technological concepts in cellular sensing and drug delivery. Unfortunately, embedding nanoparticles into the bilayer membrane of lipid vesicles is challenging due to the poor control over the vesicle fabrication process of conventional methodologies and the fragility of the modified lipid bilayer assembly. Here, the utility of water-in-oil-in-water double emulsion drops with ultrathin oil shells as templates to form vesicles with hybrid lipid/nanoparticle membranes is reported. Moreover, upon bilayer formation, which occurs through dewetting of the oil solvent from the double emulsion drops, a phase separation is observed in the vesicle membrane, with solid-like nanoparticle-rich microdomains segregated into a continuous fluid-like nanoparticle-poor phase. This phase coexistence evidences the complex nature of the interactions between nanoparticles and lipid membranes. In this context, this microfluidic-assisted fabrication strategy may play a crucial role in thoroughly understanding such interactions given the uniform membrane properties of the resulting productions. Furthermore, the high encapsulation efficiency of both the vesicle membrane and core endows these vesicles with great potential for sensing applications and drug delivery.

Ethnic differences in response to directive vs. non-directive brief intervention for subsyndromal depression.

OBJECTIVE: Analog research suggests that directive interventions might increase treatment engagement for non-symptomatic Asian American (AA) students; however, no studies have assessed whether directiveness improves therapy processes or clinical outcomes for AAs with mental health symptoms. This study tested the comparative efficacy of brief directive vs. non-directive intervention for AAs and European Americans (EAs) with subsyndromal depression. METHOD: Participants were randomly assigned directive, non-directive, or cultural values interview conditions, and assessed three times over six months. Directive and non-directive treatment involved meeting with a therapist for a single, 20-minute session to receive psychoeducation and personalized feedback on depressive symptoms and coping strategies. Cultural values participants also met with a therapist. RESULTS: Although results were mixed for the overall sample, directive treatment was generally superior to non-directive treatment and cultural values at addressing depressive symptoms, coping behavior, and working alliance. Ethnicity did moderate treatment effects for some outcomes, but in an unexpected manner. At six-month follow-up, the directive intervention was more effective than cultural values at reducing depressive symptoms for AAs; however, the cultural values condition was more effective than the non-directive intervention at reducing depressive symptoms for EAs. CONCLUSION: Mixed evidence was found for directiveness as an Asian-specific treatment enhancement. Clinical or methodological significance of this article: This article adds to a complicated body of research and clinical work aiming to inform best practices for ethnic minorities. We found some evidence that a directive therapeutic style may be a "culturally invariant" clinical technique that could be beneficial to Asian American and European American populations alike. Yet, other findings suggest that directiveness might be uniquely advantageous for Asian Americans, particularly for long-term improvement of depressive symptoms.

DMPC vesicle structure and dynamics in the presence of low amounts of the saponin aescin.

Vesicle shape and bilayer parameters are studied by small-angle X-ray (SAXS) and small-angle neutron (SANS) scattering in the presence of the saponin aescin. We confirm successful incorporation of aescin molecules by analysis of the radii of gyration RG and study furthermore the impact of aescin incorporation on bilayer thickness parameters from the neutron and X-ray perspective. Additionally, the bending elasticity (κ) of these 1,2-dimyristoyl-sn-glycero-3-phosphocholine vesicle bilayers is studied in the presence of aescin. Neutron spin-echo spectroscopy (NSE) allows to detect subtle changes in the dynamics and κ of lipid membranes. Changes of κ are detectable at temperatures below and above the main phase transition temperature Tm of the lipid. The impact of aescin is much more significant below Tm. It has been found that below Tm the addition of aescin to the vesicles decreases the value of κ and softens the bilayer. Above Tm the value of κ increases with increasing aescin content and the bilayer becomes more rigid. Altogether, we demonstrate by analysis of the structure and dynamics of the vesicles that the impact of aescin strongly depends on the lipid state. Below Tm the membrane becomes fluidized and softer, above Tm solidified and stiffer compared to a DMPC membrane without additive at similar conditions.

Developmental Dynamics of X-Chromosome Dosage Compensation by the DCC and H4K20me1 in C. elegans.

In Caenorhabditis elegans, the dosage compensation complex (DCC) specifically binds to and represses transcription from both X chromosomes in hermaphrodites. The DCC is composed of an X-specific condensin complex that interacts with several proteins. During embryogenesis, DCC starts localizing to the X chromosomes around the 40-cell stage, and is followed by X-enrichment of H4K20me1 between 100-cell to comma stage. Here, we analyzed dosage compensation of the X chromosome between sexes, and the roles of dpy-27 (condensin subunit), dpy-21 (non-condensin DCC member), set-1 (H4K20 monomethylase) and set-4 (H4K20 di-/tri-methylase) in X chromosome repression using mRNA-seq and ChIP-seq analyses across several developmental time points. We found that the DCC starts repressing the X chromosomes by the 40-cell stage, but X-linked transcript levels remain significantly higher in hermaphrodites compared to males through the comma stage of embryogenesis. Dpy-27 and dpy-21 are required for X chromosome repression throughout development, but particularly in early embryos dpy-27 and dpy-21 mutations produced distinct expression changes, suggesting a DCC independent role for dpy-21. We previously hypothesized that the DCC increases H4K20me1 by reducing set-4 activity on the X chromosomes. Accordingly, in the set-4 mutant, H4K20me1 increased more from the autosomes compared to the X, equalizing H4K20me1 level between X and autosomes. H4K20me1 increase on the autosomes led to a slight repression, resulting in a relative effect of X derepression. H4K20me1 depletion in the set-1 mutant showed greater X derepression compared to equalization of H4K20me1 levels between X and autosomes in the set-4 mutant, indicating that H4K20me1 level is important, but X to autosomal balance of H4K20me1 contributes slightly to X-repression. Thus H4K20me1 is not only a downstream effector of the DCC [corrected].In summary, X chromosome dosage compensation starts in early embryos as the DCC localizes to the X, and is strengthened in later embryogenesis by H4K20me1.

Aescin Incorporation and Nanodomain Formation in DMPC Model Membranes.

The saponin aescin from the horse chestnut tree is a natural surfactant well-known to self-assemble as oriented-aggregates at fluid interfaces. Using model membranes in the form of lipid vesicles and Langmuir monolayers, we study the mixing properties of aescin with the phase-segregating phospholipid 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC). The binary membranes are experimentally studied on different length scales ranging from the lipid headgroup area to the macroscopic scale using small-angle X-ray scattering (SAXS), photon correlation spectroscopy (PCS), and differential scanning calorimetry (DSC) with binary bilayer vesicles and Langmuir tensiometry (LT) with lipid monolayers spread on the surface of aescin solutions. The binary interaction was found to strongly depend on aescin concentration in two well differentiated concentration regimes. Below 7 mol %, the results reveal phase segregation of nanometer-sized aescin-rich domains in an aescin-poor continuous bilayer. Above this concentration, aescin-aescin interactions dominate, which inhibit vesicle formation but lead to the formation of new membrane aggregates of smaller sizes. From LT studies in monolayers, the interaction of aescin with DMPC was shown to be stronger in the condensed phase than in the liquid expanded phase. Furthermore, a destructuring role was revealed for aescin on phospholipid membranes, similar to the fluidizing effect of cholesterol and nonsteroidal anti-inflammatory drugs (NSAIDs) on lipid bilayers.