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UNFOLDER (Unfavorable Young Low-Risk Densification of R-Chemo Regimens) is an international phase-3 trial in patients 18–60 years with aggressive B-cell lymphoma and intermediate prognosis defined by age-adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R-CHOP-14 or 6× R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso[lo]ne) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET). Primary endpoint was event-free survival (EFS). A total of 695 of 700 patients were eligible for the intention-to-treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R-CHOP-21: 155; R-CHOP-14: 150) and 162 to observation (R-CHOP-21: 81, R-CHOP-14: 81). Two hundred twenty-eight patients not qualifying for radiotherapy were randomized for R-CHOP-14 versus R-CHOP-21. After a median observation of 66 months 3-year EFS was superior in the radiotherapy-arm versus observation-arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression-free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R-CHOP-14 and R-CHOP-21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005-005218-19).

Crystalline and 3D continuous mesoporous quaternary CsTaWO6 semiconductors are prepared with different degrees of long‐range periodic order and local order, respectively, to investigate the influence of periodic pore order on the photocatalytic performance in hydrogen evolution of mesoporous photocatalysts. The degree of long‐range order of the mesopores is changed by modifying the ratio between metal precursors and soft polymer template poly(isoprene‐b‐styrene‐b‐ethylene oxide) (PI‐b‐PS‐b‐PEO; ISO) in the sol–gel synthesis. Long‐range periodic order is found to have no appreciable advantage compared with an only locally ordered continuous pore system. On the contrary, nonperiodically ordered mesopores result in higher activity toward photocatalytic hydrogen evolution, even with slightly smaller pore diameter and lower cumulative pore volume. Most importantly, it is shown that pore connectivity and heterogeneous pore systems in mesoporous photocatalysts play a major role for hydrogen evolution when other parameters are confirmed to be not rate limiting.

Porous polymer-derived membranes are useful for applications ranging from filtration and separation technologies to energy storage and conversion. Combining block copolymer (BCP) self-assembly with the industrially scalable, non-equilibrium phase inversion technique (SNIPS) yields membranes comprising periodically ordered top surface structures supported by asymmetric, hierarchical substructures that together overcome performance tradeoffs typically faced by materials derived from equilibrium approaches. This review first reports on recent advances in understanding the top surface structural evolution of a model SNIPS-derived system during standard membrane formation. Subsequently, the application of SNIPS to multicomponent systems is described, enabling pore size modulation, chemical modification, and transformation to non-polymeric materials classes without compromising the structural features that define SNIPS membranes. Perspectives on future directions of both single-component and multicomponent membrane materials are provided. This points to a rich and fertile ground for the study of fundamental as well as applied problems using non-equilibrium-derived asymmetric porous materials with tunable chemistry, composition, and structure.

Real-time quantum feedback control can be used to cool quantum systems to their motional ground states, but this has been so far achieved via classical probe fields. Here the authors report feedback cooling of a mechanical oscillator using a squeezed field, reporting higher cooling rate over classical light.

Experimental auctions have not been widely used in Africa. However, auctions are important tools for evaluating new products and technologies. To increase the quality of these experiments, we explore an alternative first-price bidding mechanism that is more similar to African market exchanges and we analyze factors likely to affect bidding. Experiments with African consumers show that the proposed first-price mechanism has no advantage over conventional second-price mechanisms. Results show high and significant cash-in-hand, experimenter, and time of day effects in main rounds, and significant ordering effects in test rounds. These effects need to be carefully considered when applying the Becker-DeGroot-Marschak mechanism in Africa.

We propose an optomechanical setup allowing quantum mechanical correlation, entanglement and steering of two ultrashort optical pulses. The protocol exploits an indirect interaction between the pulses mediated optomechanically by letting both interact twice with a highly noisy mechanical system. We prove that significant entanglement can be reached in the bad cavity limit, where the optical decay rate exceeds all other damping rates of the optomechanical system. Moreover, we demonstrate that the protocol generates a quantum non-demolition interaction between the ultrashort pulses which is the basic gate for further applications.

Nature Communications 7: Article number: 13628 (2014); Published 29 November 2016; Updated 3 February 2017 This Article contains a typographical error in the second line of the right column on page 4, in which the exponent ‘−1’ incorrectly appears before the final closing parenthesis. The correct equation is

It is becoming increasingly common in the mining industry for either crushed ore or filtered mine waste to be stacked to a significant height (>100 m) in a moist state with little compaction, resulting in deposits that can be potentially loose and unsaturated. This paper presents a case history describing the characterization of stacked filtered tailings at a mine site in South America. Cone penetration tests with pore pressure and seismic velocity measurements (SCPTu) were carried out along with selected drilling, sampling, and laboratory testing. Compression wave velocity ([V.sub.p]) and shear wave velocity ([V.sub.s]) profiles were obtained and compared with laboratory values on reconstituted saturated and unsaturated samples. Results indicate that shear wave velocity is sensitive to suction hardening effects and appears to capture the correct unsaturated in situ behavior. The cone resistance, which is a large strain measurement, can destroy the beneficial effects of suction hardening and appears to be insensitive to the unsaturated in situ behavior, but may capture the correct behavior after the beneficial effects of suction are removed if the soil becomes saturated. Key words: tailings, unsaturated, cone penetration test (CPT), seismic, case history. Il est de plus en plus courant dans l'industrie miniere d'empiler soit le minerai concasse ou les residus miniers filtres a une hauteur significative (>100 m) dans un etat humide avec peu de compaction entrainant des depots qui peuvent etre potentiellement laches et non satures. Cet article presente une etude de cas decrivant la caracterisation des residus filtres empiles sur un site minieren Amerique du Sud. Des essais de penetration au cone de lapressioninterstitielle et avec des mesures de vitesse sismique (<< SCPTu >>) ont ete effectues ainsi que certains forages, echantillonnages et essais en laboratoire. Les profils de la vitesse de l'onde de compression ([V.sub.p]) et la vitesse de l'onde de cisaillement ([V.sub.s]) ont ete obtenus et compares aux valeurs obtenues en laboratoire sur des echantillons satures et insatures reconstitues. Les resultats indiquent que la vitesse de l'onde de cisaillement est sensible aux effets de durcissement par succion et semble capter le comportement correct in situ non sature. La resistance du cone, qui est une mesure de grande deformation, peut detruire les effets benefiques du durcissement par succion et ne semble pas sensible au comportement in situ insature, mais peut capturer le comportement correct apres les effets benefiques de la succion sont supprimes si le sol se sature. [Traduit par la Redaction] Mots-cles: residus, non sature, essai de penetration au cone (<< CPT >>), sismique, histoire de cas., Introduction In the mining industry, it is becoming more common for either crushed ore or filtered mine waste to be stacked to a significant height (>100 m) in a moist [...]

Abstract The generation of antibody-drug conjugates with optimal functionality depends on many parameters. These include binder epitope, antibody format, linker composition, conjugation site(s), drug-to-antibody ratio, and conjugation method. The production of matrices that cover all possible parameters is a major challenge in identifying optimal antibody-drug conjugates. To address this bottleneck, we adapted our Format Chain Exchange technology (FORCE), originally established for bispecific antibodies, toward the generation of binder-format-payload matrices (pair-FORCE). Antibody derivatives with exchange-enabled Fc-heterodimers are combined with payload-conjugated Fc donors, and subsequent chain-exchange transfers payloads to antibody derivatives in different formats. The resulting binder-format-conjugate matrices can be generated with cytotoxic payloads, dyes, haptens, and large molecules, resulting in versatile tools for ADC screening campaigns. We show the relevance of pair-FORCE for identifying optimal HER2-targeting antibody-drug conjugates. Analysis of this matrix reveals that the notion of format-defines-function applies not only to bispecific antibodies, but also to antibody-drug conjugates.

Abstract Although there have been advances in understanding colorectal cancer (CRC) pathogenesis, significant gaps still exist, highlighting the need for deeper insights. Dysregulated protein homeostasis, including perturbations in the epidermal growth factor receptor (EGFR) pathway, remains a focal point in CRC pathogenesis. Within this context, the roles of ubiquitin ligases and deubiquitinases have attracted attention, but exploration of their precise contributions is still in its early stages. To address this gap, we investigated the involvement of the deubiquitinase USP10 in CRC. Our in vitro and in vivo study reveals a new paradigm in CRC biology and unravels a novel mechanistic axis, demonstrating for the first time the involvement of inositol polyphosphate 4-phosphatase type II B (INPP4B) in USP10-mediated CRC modulation. Specifically, our study demonstrates that the loss of USP10 results in reduced sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and osimertinib. This is accompanied by a decrease in the activation of the AKT1/PKB pathway upon EGF stimulation, which is mediated by INPP4B. Importantly, in vivo xenograft experiments validate these findings and highlight the crucial role of USP10, particularly in conjunction with INPP4B, in driving CRC progression. The findings enhance our understanding of CRC pathobiology and reveal a new regulatory axis involving USP10 and INPP4B in CRC progression. This unique insight identifies USP10 and INPP4B as potential therapeutic targets in CRC.

Abstract Background N6-methyladenosine (m6A), the most abundant internal modification on eukaryotic mRNA, and N6, 2′-O-dimethyladenosine (m6Am), are epitranscriptomic marks that function in multiple aspects of posttranscriptional regulation. Fat mass and obesity-associated protein (FTO) can remove both m6A and m6Am; however, little is known about how FTO achieves its substrate selectivity. Results Here, we demonstrate that ZBTB48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of ZBTB48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. ZBTB48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Conclusions Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which ZBTB48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.

Long-term research in grassland biodiversity experiments has provided empirical evidence that ecological and evolutionary processes are intertwined in determining both biodiversity–ecosystem functioning (BEF) and biodiversity–stability relationships. Focusing on plant diversity, we hypothesize that multifunctional stability is highest in high-diversity plant communities and that biodiversity–stability relationships increase over time due to a variety of forms of ecological complementarity including the interaction with other biota above and below ground. We introduce the multiple-mechanisms hypothesis of biodiversity–stability relationships suggesting that it is not an individual mechanism that drives long-term biodiversity effects on ecosystem functioning and stability but that several intertwined processes produce increasingly positive ecosystem effects. The following six mechanisms are important. Low-diversity plant communities accumulate more plant antagonists over time (1), and use resources less efficiently and have more open, leaky nutrient cycles (2). Conversely, high-diversity plant communities support a greater diversity and activity of beneficial interaction partners across trophic levels (3); diversify in their traits over time and space, within and across species, to optimize temporal (intra- and interannual) and spatial complementarity (4), create a more stable microclimate (5), and foster higher top-down control of aboveground and belowground herbivores by predators (6). In line with the observation that different species play unique roles in ecosystems that are dynamic and multifaceted, the particular mechanism contributing most to the higher performance and stability of diverse plant communities might differ across ecosystem functions, years, locations, and environmental change scenarios. This indicates “between-context insurance” or “across-context complementarity” of different mechanisms. We introduce examples of experiments that will be conducted to test our hypotheses and which might inspire additional work.

Abstract Disruption of alternative splicing frequently causes or contributes to human diseases and disorders. Consequently, there is a need for efficient and sensitive reporter assays capable of screening chemical libraries for compounds with efficacy in modulating important splicing events. Here, we describe a screening workflow employing dual Nano and Firefly luciferase alternative splicing reporters that affords efficient, sensitive, and linear detection of small molecule responses. Applying this system to a screen of ~95,000 small molecules identified compounds that stimulate or repress the splicing of neuronal microexons, a class of alternative exons often disrupted in autism and activated in neuroendocrine cancers. One of these compounds rescues the splicing of several analyzed microexons in the cerebral cortex of an autism mouse model haploinsufficient for Srrm4, a major activator of brain microexons. We thus describe a broadly applicable high-throughput screening system for identifying candidate splicing therapeutics, and a resource of small molecule modulators of microexons with potential for further development in correcting aberrant splicing patterns linked to human disorders and disease.

Porous polymer-derived membranes are useful for applications ranging from filtration and separation technologies to energy storage and conversion. Combining block copolymer (BCP) self-assembly with the industrially scalable, non-equilibrium phase inversion technique (SNIPS) yields membranes comprising periodically ordered top surface structures supported by asymmetric, hierarchical substructures that together overcome performance tradeoffs typically faced by materials derived from equilibrium approaches. This review first reports on recent advances in understanding the top surface structural evolution of a model SNIPS-derived system during standard membrane formation. Subsequently, the application of SNIPS to multicomponent systems is described, enabling pore size modulation, chemical modification, and transformation to non-polymeric materials classes without compromising the structural features that define SNIPS membranes. Perspectives on future directions of both single-component and multicomponent membrane materials are provided. This points to a rich and fertile ground for the study of fundamental as well as applied problems using non-equilibrium-derived asymmetric porous materials with tunable chemistry, composition, and structure. [ABSTRACT FROM AUTHOR]

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis.

Abstract Background Point-of-care ultrasound (POCUS) is a critical diagnostic tool in various medical settings, yet its instruction in medical education is inconsistent. The Rapid Ultrasound for Shock and Hypotension (RUSH) protocol is a comprehensive diagnostic tool, but its complexity poses challenges for teaching and learning. This study evaluates the effectiveness of a single-day training in RUSH for medical students by assessing their performance in clinical scenarios. Methods In this prospective single-center observational proof-of-concept study, 16 medical students from Saarland University Medical Center underwent a single-day training in RUSH, followed by evaluations in clinical settings and on a high-fidelity simulator. Performance was assessed using a standardized scoring tool and time to complete the RUSH exam. Knowledge gain was measured with pre- and post-training written exams, and diagnostic performance was evaluated with an objective structured clinical examination (OSCE). Results Students demonstrated high performance in RUSH exam views across patients (median performance: 85–87%) and improved scanning times, although not statistically significant. They performed better on simulators than on live patients. Written exam scores significantly improved post-training, suggesting a gain in theoretical knowledge. However, more than a third of students could not complete the RUSH exam within five minutes on live patients. Conclusions Single-day RUSH training improved medical students’ theoretical knowledge and simulator performance but translating these skills to clinical settings proved challenging. The findings suggest that while short-term training can be beneficial, it may not suffice for clinical proficiency. This study underscores the need for structured and possibly longitudinal training programs to ensure skill retention and clinical applicability.

Introduction Mesenchymal stromal cells (MSCs) play a crucial role in promoting tissue regeneration and healing, particularly in bone tissue. Both smoking and nicotine use are known to delay and inhibit the healing process in patients. This study aims at delineating these cellular effects by comparing the impact of nicotine alone to cigarette smoke with equivalent nicotine content, and shedding light on potential differences in the healing process. Methods We examined how cigarette smoke and nicotine affect the migration, proliferation, and osteogenic differentiation of human patient-derived MSCs in vitro , as well as the secretion of cytokines IL-6 and IL-8. We measured nicotine concentration of the cigarette smoke extract (CSE) to clarify the role of the nicotine in the effect of the cigarette smoke. Results MSCs exposed to nicotine-concentration-standardized CSE exhibited impaired wound healing capability, and at high concentrations, increased cell death. At lower concentrations, CSE dose-dependently impaired migration, proliferation, and osteogenic differentiation, and increased IL-8 secretion. Nicotine impaired proliferation and decreased PINP secretion. While there was a trend for elevated IL-6 levels by nicotine in undifferentiated MSCs, these changes were not statistically significant. Exposure of MSCs to equivalent concentrations of nicotine consistently elicited stronger responses by CSE and had a more pronounced effect on all studied parameters. Our results suggest that the direct effect of cigarette smoke on MSCs contributes to impaired MSC function, that adds to the nicotine effects. Conclusions Cigarette smoke extract reduced the migration, proliferation, and osteogenic differentiation in MSCs in vitro , while nicotine alone reduced proliferation. Cigarette smoke impairs the osteogenic and regenerative ability of MSCs in a direct cytotoxic manner. Cytotoxic effect of nicotine alone impairs regenerative ability of MSCs, but it only partly explains cytotoxic effects of cigarette smoke. Direct effect of cigarette smoke, and partly nicotine, on MSCs could contribute to the smoking-related negative impact on long-term bone health, especially in bone healing.

Abstract The pituitary functions as a master endocrine gland that secretes hormones critical for regulation of a wide variety of physiological processes including reproduction, growth, metabolism and stress responses. The distinct hormone-producing cell lineages within the pituitary display remarkable levels of cell plasticity that allow remodeling of the relative proportions of each hormone-producing cell population to meet organismal demands. The molecular mechanisms governing pituitary cell plasticity have not been fully elucidated. Our recent studies have implicated a role for the Musashi family of sequence-specific mRNA binding proteins in the control of pituitary hormone production, pituitary responses to hypothalamic stimulation and modulation of pituitary transcription factor expression in response to leptin signaling. To date, these actions of Musashi in the pituitary appear to be mediated through translational repression of the target mRNAs. Here, we report Musashi1 directs the translational activation, rather than repression, of the Prop1, Gata2 and Nr5a1 mRNAs which encode key pituitary lineage specification factors. We observe that Musashi1 further directs the translational activation of the mRNA encoding the glycolipid Neuronatin (Nnat) as determined both in mRNA reporter assays as well as in vivo. Our findings suggest a complex bifunctional role for Musashi1 in the control of pituitary cell function.

We combine farm accounting data with high‐resolution meteorological data, and climate scenarios to estimate climate change impacts and adaptation potentials at the farm level. To do so, we adapt the seminal model of Moore and Lobell (2014) who applied panel data econometrics to data aggregated from the farm to the regional (subnational) level. We discuss and empirically investigate the advantages and challenges of applying such models to farm‐level data, including issues of endogeneity of explanatory variables, heterogeneity of farm responses to weather shocks, measurement errors in meteorological variables, and aggregation bias. Empirical investigations into these issues reveal that endogeneity due to measurement errors in temperature and precipitation variables, as well as heterogeneous responses of farms toward climate change may be problematic. Moreover, depending on how data are aggregated, results differ substantially compared to farm‐level analysis. Based on data from Austria and two climate scenarios (Effective Measures and High Emission) for 2040, we estimate that the profits of farms will decline, on average, by 4.4% (Effective Measures) and 10% (High Emission). Adaptation options help to considerably ameliorate the adverse situation under both scenarios. Our results reinforce the need for mitigation and adaptation to climate change. [ABSTRACT FROM AUTHOR]