bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Vitamin K in Bone and Muscle Metabolism
Authors: Alonso N. , Meinitzer A. , Fritz-Petrin E. , Enko D. , Herrmann M.
Published: February 2022

Vitamin K, a cofactor for the γ-glutamyl carboxylase enzyme, is required for the post-translational activation of osteocalcin and matrix Gla protein, which play a key role in bone and muscle homeostasis. In vivo and in vitro models for osteoporosis and sarcopenia suggest the vitamin K could exert a positive effect in both conditions. In bone, it increases osteoblastogenesis, whilst decreases osteoclast formation and function. In muscle, it is associated with increased satellite cell proliferation and migration and might play a role in energy metabolism. Observational trials suggest that high levels of vitamin K are associated with increased bone mineral density and reduced fracture risk. However, interventional studies for vitamin K supplementation yielded conflicting results. Clinical trials in sarcopenia suggest that vitamin K supplementation could improve muscle mass and function. One of the main limitations on the vitamin K studies are the technical challenges to measure its levels in serum. Thus, they are obtained from indirect sources like food questionnaires, or levels of undercarboxylated proteins, which can be affected by other environmental or biological processes. Although current research appoints to a beneficial effect of vitamin K in bone and muscle, further studies overcoming the current limitations are required in order to incorporate this supplementation in the clinical management of patients with osteosarcopenia.
Evaluation of Safety‐Related Outcomes of One‐Segment and More‐Than‐One‐Segment High‐Level Hepatectomy in Hepatocellular Carcinoma Based on the Japanese Board Certification System
Authors: Hojo Akihisa , Nakayama Hisashi , Okamura Yukiyasu , Higaki Tokio , Moriguchi Masamichi , Aramaki Osamu , Yamazaki Shitaro , Takayama Tadatoshi
Published: February 2022

Background

We evaluated the impact of the Japanese board certification system for expert surgeons (JBCSES) on complications and survival outcomes in hepatectomy for hepatocellular carcinoma.

Methods

The postoperative outcomes of 493 patients who underwent high‐level liver surgery involving one‐segment (OSeg) hepatectomy and more‐than‐one‐segment (MOSeg) resection were compared before and after JBCSES establishment. After the establishment of the JBCSES, the patients’ postoperative outcomes were compared using propensity score matching (PSM) to determine the influence of expert surgeons.

Results

The establishment of the JBCSES was associated with a decrease in the overall postoperative complication rates after high‐level liver surgery from 50.2 to 38.1% (P = 0.008) and a decrease in Clavien–Dindo class ≥ IIIb complications from 10.2 to 5.0% (P = 0.035). The 90‐day mortality rate decreased from 5.1 to 0.7% (P = 0.003), and the 5‐year survival rate increased from 51.4 to 63.9% (P = 0.009). Using PSM, a comparison of OSeg hepatectomies that involved expert surgeons (n = 48) and those that did not (n = 48) showed significantly lower intraoperative blood loss in surgeries involving an expert surgeon (mean, 340 vs. 473 mL; P = 0.033). There were no significant differences in complication rates or long‐term prognosis between these groups. A comparison of MOSeg hepatectomies that involved expert surgeons (n = 26) and those that did not (n = 26) showed no significant difference in surgical factors, complications, or overall survival between the two groups.

Conclusions

After establishment of the JBCSES, postoperative complication rates and mortality rates decreased and survival rates increased following liver surgery. Expert surgeon participation significantly decreased intraoperative blood loss during OSeg hepatectomies.
90-yttrium-ibritumomab tiuxetan as first-line treatment for follicular lymphoma: updated efficacy and safety results at an extended median follow-up of 9.6 years
Authors: Rieger Kathrin , De Filippi Rosaria , Lindén Ola , Viardot Andreas , Hess Georg , Lerch Kristina , Neumeister Peter , Stroux Andrea , Peuker Caroline A. , Pezzutto Antonio , Pinto Antonello , Keller Ulrich , Scholz Christian W.
Published: February 2022

Radioimmunotherapy with 90-yttrium-ibritumomab tiuxetan (90Y-IT) as first-line treatment in patients with follicular lymphoma (FL) demonstrated promising results with a complete remission (CR) rate of 56% and a median progression-free survival (PFS) of 26 months, when initially analyzed after a median follow-up of 30.6 months. The aim of this long-term follow-up was to investigate whether clinical benefits were maintained and new safety signals appeared. Fifty-nine patients, aged ≥ 50 years, with FL grade 1 to 3A in stages II to IV were treated with 90Y-IT as first-line therapy. If CR without evidence of minimal residual disease (MRD), partial response or stable disease was achieved 6 months after treatment, patients were observed without further treatment. Patients with CR but persisting MRD received consolidation therapy with rituximab. The primary endpoint was the clinical response rate. Secondary endpoints were time to progression, safety, and tolerability. After a median follow-up of 9.6 years, median PFS was 3.6 years, and 8-year PFS was 38.3%. Median overall survival (OS) was not reached during the extended follow-up, and 8-year OS amounted to 69.2%. Age 65 years and above or disease progression within 24 months of treatment were significantly associated with shorter OS. An important finding was the lack of new safety signals. In particular, no increase in secondary malignancies or transformation into aggressive lymphoma was observed compared to trials with a similar follow-up. In summary, 90Y-IT as first-line treatment demonstrates a favorable safety profile and long-term clinical activity in a substantial fraction of FL patients in need of therapy. ClinicalTrials.gov Identifier: NCT00772655.
Yeast Stn1 promotes MCM to circumvent Rad53 control of the S phase checkpoint
Authors: Gasparayan Hovik , Caridi Chris , Julius Jeff , Feng Wenyi , Bachant Jeff , Nugent Constance I.
Published: February 2022

Treating yeast cells with the replication inhibitor hydroxyurea activates the S phase checkpoint kinase Rad53, eliciting responses that block DNA replication origin firing, stabilize replication forks, and prevent premature extension of the mitotic spindle. We previously found overproduction of Stn1, a subunit of the telomere-binding Cdc13–Stn1–Ten1 complex, circumvents Rad53 checkpoint functions in hydroxyurea, inducing late origin firing and premature spindle extension even though Rad53 is activated normally. Here, we show Stn1 overproduction acts through remarkably similar pathways compared to loss of RAD53, converging on the MCM complex that initiates origin firing and forms the catalytic core of the replicative DNA helicase. First, mutations affecting Mcm2 and Mcm5 block the ability of Stn1 overproduction to disrupt the S phase checkpoint. Second, loss of function stn1 mutations compensate rad53 S phase checkpoint defects. Third Stn1 overproduction suppresses a mutation in Mcm7. Fourth, stn1 mutants accumulate single-stranded DNA at non-telomeric genome locations, imposing a requirement for post-replication DNA repair. We discuss these interactions in terms of a model in which Stn1 acts as an accessory replication factor that facilitates MCM activation at ORIs and potentially also maintains MCM activity at replication forks advancing through challenging templates.
Impact of linewidth enhancement factor and gain suppression on chirp characteristics of high-speed laser diode and performance of 40 Gbps optical fiber links
Authors: Fouad Nada , Mohamed Tarek , Mahmoud Alaa
Published: February 2022

We present a simulation study on the chirping characteristics of a directly modulated 40 Gbps laser diode and evaluate its performance for use in high-speed optical fiber links. The effects of the linewidth enhancement factor (α) and gain suppression on the laser chirp and the maximum fiber transmission length are investigated. The chirp characteristics include the frequency peak-to-peak chirp of the time-varying frequency and shift of the emission wavelength. The performance of 40 Gbps optical fiber link is evaluated in terms of the eye diagram and quality factor of the received signal, which helps in predicting the maximum fiber length that achieves error-free transmission. The results show that whenαincreases from 1 to 10, the overshoots of the relaxation oscillations become strong, resulting in a sharp increase in laser peak-to-peak chirp from 21.8 to 205 GHz. The increase of gain suppression factor formε = 0.5 × 10–17cm3toε = 5 × 10–17cm3dampens out the overshoots and slightly reduces the peak-to-peak chirp from 19.5 to 193.3 GHz. Although the gain suppression works to reduce the laser chirp, it causes a significant wavelength shift relative to the emission wavelength of the non-modulated laser, which degrades the efficiency of the laser diode. On the other hand, the gain suppression is shown to increase the degree of eye-opening and the correspondingQ-factor of the fiber link on a reverse action of the linewidth enhancement factor. As fiber length increases, the influences ofαand ε on chirp characteristics become more significant. The maximum fiber length (Lmax) is shown to decrease with the increase inαand/orε; when α increases from 1 to 10,Lmaxdecreases from 5.89 to 0.78 km atε = 5 × 10–17cm3, and decreases from 2.52 to 0.3 km atε = 0.5 × 10–17cm3.
The radiation adaptive response and priming dose influence: the quantification of the Raper–Yonezawa effect and its three-parameter model for postradiation DNA lesions and mutations
Authors: Fornalski Krzysztof W. , Adamowski Łukasz , Dobrzyński Ludwik , Jarmakiewicz Rafał , Powojska Aleksandra , Reszczyńska Joanna
Published: February 2022

The priming dose effect, called also the Raper–Yonezawa effect or simply the Yonezawa effect, is a special case of the radiation adaptive response phenomenon (radioadaptation), which refers to: (a) faster repair of direct DNA lesions (damage), and (b) DNA mutation frequency reduction after irradiation, by applying a small priming (conditioning) dose prior to the high detrimental (challenging) one. This effect is observed in many (but not all) radiobiological experiments which present the reduction of lesion, mutation or even mortality frequency of the irradiated cells or species. Additionally, the multi-parameter model created by Dr. Yonezawa and collaborators tried to explain it theoretically based on experimental data on the mortality of mice with chronic internal irradiation. The presented paper proposes a new theoretical approach to understanding and explaining the priming dose effect: it starts from the radiation adaptive response theory and moves to the three-parameter model, separately for two previously mentioned situations: creation of fast (lesions) and delayed damage (mutations). The proposed biophysical model was applied to experimental data—lesions in human lymphocytes and chromosomal inversions in mice—and was shown to be able to predict the Yonezawa effect for future investigations. It was also found that the strongest radioadaptation is correlated with the weakest cellular radiosensitivity. Additional discussions were focussed on more general situations where many small priming doses are used.
Evaluation of peripapillary vascular flow in patients with Thyroid-Associated Ophthalmopathy (TAO) by OCT Angiography
Authors: Del Noce Chiara , Roda Matilde , Valsecchi Nicola , Guandalini Sofia , Di Geronimo Natalie , Schiavi Costantino , Traverso Carlo Enrico , Vagge Aldo
Published: February 2022

Purpose

To evaluate changes in peripapillary vascular blood flow indices (PVBFI) in patients with thyroid-associated ophthalmopathy (TAO) using OCT angiography (OCTA) technology.

Methods

Patients with TAO and control subjects matched for age and sex were included in the study. Eye examination, Clinical Activity Score (CAS) evaluation and OCTA scan analysis (Topcon ImageNet 6; DRI OCT Triton, Topcon Corporation) were performed. In particular, PVBFI of the superficial capillary plexus (SCP), deep capillary plexus (DCP), outer retina (OR) and choriocapillaris (CC) layers were obtained by OCTA and extracted from 8-bit greyscale OCT images using the ImageJ software package.

Results

Twenty-six patients with TAO (19 females, mean age 54.7 ± 5.2 and 7 males, mean age 51.4 ± 16.3) were compared with 26 healthy subjects (15 females, mean age 48.2 ± 14.1 and 11 males, mean age 53.1 ± 15.2). Both DCP-PVBF and CC-PVBFI were significantly reduced in TAO patients compared to control eyes (28.6 ± 2.1 vs. 29.7 ± 0.93, p = 0.002; 46.5 ± 1.72 vs. 47.2 ± 1.2, p = 0.019 respectively); on the other hand, no statistically significant differences were found in SCP-PVBFI and OR-PVBFI in TAO patients compared to healthy subjects (p > 0.05). Also, CC-PVBFI was associated with elevated values of CAS (p = 0.018) and ROC curve showed that patients with elevated CC-PVBFI were correlated with active TAO (CAS > 3) (p = 0.012).

Conclusions

TAO disease may be associated with changes in DCP-PVBFI and CC-PVBFI; also, CC-PVBFI seems to correlate with disease activity.
Implications of the study of subglacial volcanism and glaciovolcanic cave systems
Authors: Sobolewski Linda , Stenner Christian , Williams-Jones Glyn , Anitori Roberto , Davis Richard E. , Pflitsch Andreas
Published: February 2022

Glacial environments can have significant impacts on the surrounding landscape and nearby populations when affected by volcanic activity. As such, glaciovolcanic interactions and related hazards have received substantial attention during the last few decades. In contrast, the study of void spaces created by these interactions—glaciovolcanic cave systems—remains underrepresented. This review outlines the global distribution of glaciovolcanic caves and describes examples of both historical and ongoing research advances, most of which are limited to volcanoes of the Cascade Volcanic Arc and Antarctica. Examples range from a largely static fumarolic ice cave system in the crater of Mount Rainier to glaciovolcanic cave genesis and evolution in the crater of Mount St. Helens, where the advancing glacier ice is interacting with ongoing fumarolic activity and generating new cave systems. This review includes various volcanic subfields and also brings together additional disciplines including speleology, microbiology, and astrobiology. Due to the importance of glaciovolcanic caves in the hydrothermal cycle of volcanic systems, the global fight against antibiotic resistance, and their implications for understanding volcano-ice interactions beyond Earth, research on these systems is expanding. Kamchatka, Alaska, and Iceland have notable potential for further studies, while known research sites still hold open questions, including better understanding of the environmental parameters affecting cave genesis and persistence, the effect of glaciovolcanic cave development on underlying hydrothermal systems, and cataloging the biodiversity of glaciovolcanic cave environments.
Revisiting the Evaluation of Hydraulic Transmissivity of Elliptical Rock Fractures in Triaxial Shear-Flow Experiments
Authors: Ji Yinlin , Hofmann Hannes , Rutter Ernest H. , Xiao Fei , Yang Lining
Published: February 2022

Highlights

• A novel numerical approach has been proposed to retrieve the hydraulic transmissivity of elliptical rock fractures in triaxial shear-flow experiments.

• The accuracy of different methods for estimation of hydraulic transmissivity of elliptical rock fractures has been evaluated and discussed.

• The numerical approach and electrical analogy are recommended for accurate evaluation of hydraulic transmissivity of elliptical rock fractures.
Not just a background: pH buffers do interact with lanthanide ions—a Europium(III) case study
Authors: Mandal Poulami , Kretzschmar Jerome , Drobot Björn
Published: February 2022

The interaction between Eu(III) ion and different pH buffers, popular in biology and biochemistry, viz. HEPES, PIPES, MES, MOPS, and TRIS, has been studied by solution nuclear magnetic resonance spectroscopy (NMR) and time-resolved laser-induced fluorescence spectroscopy (TRLFS) techniques. The Good’s buffers reveal non-negligible interaction with Eu(III) as determined from their complex stability constants, where the sites of interaction are the morpholine and piperazine nitrogen atoms, respectively. In contrast, TRIS buffer shows practically no affinity towards Eu(III). Therefore, when investigating lanthanides, TRIS buffer should be preferred over Good’s buffers.

Graphical abstract
“Passive or interactive virtual reality? The effectiveness for pain and anxiety reduction in pediatric patients”
Authors: Ferraz-Torres Marta , San Martín-Rodríguez Leticia , García-Vivar Cristina , Soto-Ruiz Nelia , Escalada-Hernández Paula
Published: February 2022

Invasive techniques such as venipuncture are painful procedures causing stress and anxiety, both in pediatric patients and in their carers. For this reason, efforts are being made to develop mitigating strategies for the patient’s pain and anxiety during the performance. To analyze and evaluate the effectiveness of the use of Virtual Reality distraction techniques as a measure of pain and anxiety reduction in pediatric patients and their parents. In addition, the effects of two modes of Virtual Reality (passive vs. interactive) were compared. A quasi-experimental study was carried out in the pediatric emergency department of a tertiary referral hospital in north Spain. The participants were children who underwent venipuncture for blood extraction and vascular cannulation. From the 124 patients, 51.6% (n = 64) were girls and 48.4% (n = 60) were boys (p = 0.574). The mean age was 8.4 years (SD: 4.1). The mean level of pain experienced was 2.33 (SD: 0.76) in the interactive VR group (n = 88) versus 2.67 (SD: 1.35) in patients with passive VR (n = 36) (p = 0.008); being the presence of anxiety in 27.3% (n = 24) of the cases treated with interactive Virtual Reality and in 88.9% (n = 32) of the patients with passive Virtual Reality (p = 0.000). The virtual reality is an effective method to reduce pain and anxiety levels in pediatric patients, with the effectiveness of interactive virtual reality and its use in the population aged 7–15 years being greater.
In systemic sclerosis TAPSE/sPAP ratio is correlated with ventilatory efficiency and exercise capacity assessed by CPET
Authors: Colalillo Amalia , Pellicano Chiara , Romaniello Antonella , Rosato Edoardo
Published: February 2022

Objectives

The aim of the study was to evaluate the correlation between cardiopulmonary exercise testing (CPET) parameters and right ventricular echocardiographic parameters for pulmonary arterial hypertension screening in a cohort of systemic sclerosis (SSc) patients. Methods forty SSc patients were examined using CPET and resting transthoracic echocardiography. CPET parameters analyzed were minute ventilation/carbon dioxide production (VE/VCO2) slope and maximum oxygen uptake (VO2 max); echocardiographic parameters were systolic pulmonary artery pressure (sPAP), tricuspid annular plane systolic excursion (TAPSE), and TAPSE/sPAP ratio. Results a positive correlation was observed between VE/VCO2 slope and age (r = 0.415, p < 0.01) and sPAP (r = 0.461, p < 0.01), conversely, a negative correlation was found between VE/VCO2 slope and TASPE/sPAP ratio (r = − 0.521, p = 0.001). VO2 max showed an inverse correlation with age (r = − 0.367, p < 0.05) and sPAP (r = − 0.387, p < 0.05) and a positive correlation with TAPSE/sPAP ratio (r = 0.521, p < 0.01). On stepwise linear regression analysis, VE/VCO2 slope was significantly correlated with TAPSE/sPAP ratio (β coefficient = − 0.570; p < 0.0001), as well as VO2 max was significantly correlated with TAPSE/sPAP ratio (β coefficient = 0.518; p = 0.001). Conclusion in SSc patients, TAPSE/sPAP ratio is the echocardiographic parameter of RV function which showed the best correlation with ventilatory efficiency and exercise capacity.
EU Fiscal Rules: A Look Back and the Way Forward
Authors: Regling Klaus
Published: February 2022

The decline of “natural real interest rates” during the last three decades is a common phenomenon in all advanced economies and can be explained by a number of structural factors: the downward trend in potential growth; population ageing, which has led to higher savings rates in many countries; and the rising inequality in the distribution of wealth, which also increases the average savings rate.
The Economics of Fiscal Rules and Debt Sustainability
Authors: Beetsma Roel
Published: February 2022

Because they exert cross-border spillover effects, fiscal policies of individual EU member states are a common concern for the entire EU.
EU Fiscal Governance Reforms: A Perspective of Independent Fiscal Institutions
Authors: Barnes Sebastian
Published: February 2022

The fiscal framework needs in practice to achieve a balance between, on the one hand, effective budgetary rules that allow governments to commit to sound policies and, on the other, judgements and discretion in how these are applied so that the framework adequately reflects the complexity of the situations that countries may find themselves in.
How Large Is the Risk of Stagflation in the Eurozone?
Authors: Demary Markus , Hüther Michael
Published: February 2022

The rapid recovery of demand combined with supply constraints has led to rising prices during the past months. This is evident in oil and gas markets, but also in international trade, which has been thrown out of step by bottlenecks at Asian ports. This situation creates a trade-off for the European Central Bank, because a more expansionary monetary policy cannot mitigate the supply bottlenecks and supply-side restrictions, while a more restrictive monetary policy would slow down the economic recovery. For this reason, key interest rate hikes in the eurozone are not to be expected for 2022. If the supply-side factors become persistent and wage policy tries to pass the price effects on, monetary policy will be forced to become restrictive.
International Inequality and the COVID-19 Pandemic
Authors: Dauderstädt Michael
Published: February 2022

The lockdowns and stimulus programmes that governments have adopted to fight the COVID-19 pandemic and the associated economic crisis have affected the distribution of income and production within and between countries. Considering both, current evidence indicates that the EU-wide and global inequality of disposable income did not change dramatically in 2020. However, the unequal impact on the wealth and health of people is likely to worsen income inequality in the future.
Do the COVID-19 Crisis, Ageing and Climate Change Put Swiss Fiscal Sustainability at Risk?
Authors: Brändle Thomas , Bruchez Pierre-Alain , Colombier Carsten , Baur Martin , Hohl Lukas
Published: February 2022

The ongoing coronavirus pandemic crisis as well as demographic and climate change pose major challenges for public finances. This article deals with the implications of demographic trends in Switzerland, i.e. the progressive ageing of the population and its impact on the country’s public finances in the long run. As the analysis shows, the brunt of the demographic burden is borne by the old-age pension scheme, health and long-term care. This article also addresses the financial ramifications of the COVID-19 crisis and shows the need for economic policy action over the longer term to ensure the sustainability of public finances in Switzerland. Furthermore, a qualitative assessment of climate change is included, as it constitutes an additional major long-term challenge for public finances.
Measuring the relative development and integration of EU countries’ capital markets using composite indicators and cluster analysis
Authors: Gucciardi Gianluca
Published: February 2022

The paper proposes a set of metrics and a methodology to measure the progress that European Union Member States are making towards the development and integration of capital markets. It identifies a set of indicators and analyzes the performance of these countries over the 2007–2018 period using a composite indicator approach (in both a static and dynamic environment), based on the six priorities related to achieving a well-functioning and integrated European capital market included in the European Commission Capital Markets Union Action Plan. The author uses robust clustering to identify groups of countries and tracks their development over time. He finds that the process of capital market development and integration process has started but is not completed and that it is mainly associated with countries’ adherence to European increasing trends driven by the benchmarks rather than the policy actions of countries aimed at catching up with the best performers.
Pseudo-T2 mapping for normalization of T2-weighted prostate MRI
Authors: Sørland Kaia Ingerdatter , Sunoqrot Mohammed R. S. , Sandsmark Elise , Langørgen Sverre , Bertilsson Helena , Trimble Christopher G. , Lin Gigin , Selnæs Kirsten M. , Goa Pål E. , Bathen Tone F. , Elschot Mattijs
Published: February 2022

Objective

Signal intensity normalization is necessary to reduce heterogeneity in T2-weighted (T2W) magnetic resonance imaging (MRI) for quantitative analysis of multicenter data. AutoRef is an automated dual-reference tissue normalization method that normalizes transversal prostate T2W MRI by creating a pseudo-T2 map. The aim of this study was to evaluate the accuracy of pseudo-T2s and multicenter standardization performance for AutoRef with three pairs of reference tissues: fat/muscle (AutoRefF), femoral head/muscle (AutoRefFH) and pelvic bone/muscle (AutoRefPB).

Materials and methods

T2s measured by multi-echo spin echo (MESE) were compared to AutoRef pseudo-T2s in the whole prostate (WP) and zones (PZ and TZ/CZ/AFS) for seven asymptomatic volunteers with a paired Wilcoxon signed-rank test. AutoRef normalization was assessed on T2W images from a multicenter evaluation set of 1186 prostate cancer patients. Performance was measured by inter-patient histogram intersections of voxel intensities in the WP before and after normalization in a selected subset of 80 cases.

Results

AutoRefFH pseudo-T2s best approached MESE T2s in the volunteer study, with no significant difference shown (WP: p = 0.30, TZ/CZ/AFS: p = 0.22, PZ: p = 0.69). All three AutoRef versions increased inter-patient histogram intersections in the multicenter dataset, with median histogram intersections of 0.505 (original data), 0.738 (AutoRefFH), 0.739 (AutoRefF) and 0.726 (AutoRefPB).

Discussion

All AutoRef versions reduced variation in the multicenter data. AutoRefFH pseudo-T2s were closest to experimentally measured T2s.
Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors
Authors: Waqar Saiama N. , Robinson Clifford , Olszanski Anthony J. , Spira Alexander , Hackmaster Melissa , Lucas Luisa , Sponton Laura , Jin Hulin , Hering Ursula , Cronier Damien , Grinberg Marianna , Seithel-Keuth Annick , Diaz-Padilla Ivan , Berlin Jordan
Published: February 2022

Background. Ataxia telangiectasia mutated (ATM) kinase orchestrates DNA double strand break (DSB) repair; ATM inhibitors may therefore enhance the therapeutic effect of DSB-inducing treatments such as radiotherapy (RT). M3541 is an orally administered selective inhibitor of ATM. Methods. This phase I dose-escalation study evaluated the maximum-tolerated dose (MTD), recommended phase II dose(s) (RP2D), safety, pharmacokinetics (PK) and antitumor activity of M3541 in combination with fractionated palliative RT in patients with solid tumors. Fifteen patients received palliative RT (30 Gy in 10 fractions) and escalating doses of M3541 (50–300 mg administered on RT fraction days) guided by a Bayesian 2-parameter logistic regression model with overdose control. Results. Doses of M3541 up to 300 mg/fraction day were well tolerated. One patient (200 mg group) experienced two dose-limiting toxicities (urinary tract infection, febrile neutropenia) that resolved with antibiotics. All patients reported ≥ 1 treatment-emergent adverse event (TEAE) but none led to treatment discontinuation. No grade ≥ 4 TEAEs were reported and there was no indication of a dose effect for any TEAE. Three patients (20.0%; 95% confidence interval 4.3–48.1) had confirmed complete or partial response. M3541 total plasma levels did not increase with dose following single or repeated dosing. No relationship was observed between dose and changes in the ratio of phosphorylated to total ATM or in immune cell counts. Conclusions. The MTD and RP2D could not be established as the study closed early due to the absence of a dose–response relationship and non-optimal PK profile. No further clinical development of M3541 was pursued. (Trial registration number ClinicalTrials.gov NCT03225105. Registration date July 21, 2017).
Epistemic Beliefs in Science—A Systematic Integration of Evidence From Multiple Studies
Authors: Schiefer Julia , Edelsbrunner Peter A. , Bernholt Andrea , Kampa Nele , Nehring Andreas
Published: February 2022

Recent research has integrated developmental and dimensional perspectives on epistemic beliefs by implementing an approach in which profiles of learners’ epistemic beliefs are modeled across multiple dimensions. Variability in study characteristics has impeded the comparison of profiles of epistemic beliefs and their relations with external variables across studies. We examined this comparability by integrating data on epistemic beliefs about the source, certainty, development, and justification of knowledge in science from six studies comprisingN = 10,932 German students from elementary to upper secondary school. Applying latent profile analyses to these data, we found that profiles of epistemic beliefs that were previously conceptualized were robust across multiple samples. We found indications that profiles of epistemic beliefs homogenize over the course of students’ education, are related to school tracking, and demonstrate robust relations with students’ personal characteristics and socioeconomic background. We discuss implications for the theory, assessment, and education of epistemic beliefs.
Pivotal discrepancy measures for Bayesian modelling of spatio-temporal data
Authors: Morris Lindsay R. , Sibanda Nokuthaba
Published: February 2022

Within the field of geostatistics, Gaussian processes are a staple for modelling spatial and spatio-temporal data. Statistical literature is rich with estimation methods for the mean and covariance of such processes (in both frequentist and Bayesian contexts). Considerably less attention has been paid to developing goodness-of-fit tests for assessment of model adequacy. Jun et al. (Environmetrics 25(8):584–595, 2014) introduced a statistical test that uses pivotal discrepancy measures to assess goodness-of-fit in the Bayesian context. We present a modification and generalization of their statistical test. The initial method involves spatial partitioning of the data, followed by evaluation of a pivotal discrepancy measure at each posterior draw to obtain a posterior distribution of pivotal statistics. Order statistics from this distribution are used to obtain approximate p-values. Jun et al. (Environmetrics 25(8):584–595, 2014) use arbitrary partitions based on pre-existing spatial boundaries. The partitions are made to be of equal size. Our contribution is two-fold. We use K-means clustering to create the spatial partitions and we generalise Jun et al.’s approach to incorporate unequal partition sizes. Observations from a spatial or spatio-temporal process are partitioned using an appropriate feature vector that incorporates the geographic location of the observations into subsets (not necessarily of the same size). The method’s viability is illustrated in a simulation study, and in an application to hoki (Macruronus novaezelandiae) catch data from a survey of the sub-Antarctic region.
Value Promotion and the Explanation of Evidential Standards
Authors: Magalotti Tricia
Published: February 2022

While it is commonly accepted that justified beliefs must be strongly supported by evidence and that support comes in degrees, the question of how much evidential support one needs in order to have a justified belief remains. In this paper, I consider how the question about degrees of evidential support connects with recent debates between consequentialist and deontological explanations of epistemic norms. I argue that explaining why strong, but not conclusive, evidential support is required for justification should be one explanandum that such theories seek to explain. Furthermore, I argue that foundational theories that appeal to the promotion of epistemic value (especially consequentialism, but perhaps also some versions of epistemic deontology) are better suited to provide such an explanation.
Diving beetle (Coleoptera: Dytiscidae) community dissimilarity reveals how low landscape connectivity restricts the ecological value of urban ponds
Authors: Liao Wenfei , Venn Stephen , Niemelä Jari
Published: February 2022

Context

Structural and functional connectivity, as subconcepts of landscape connectivity, are key factors in biodiversity conservation and management. Previous studies have focused on the consequences of connectivity for populations of terrestrial organisms, which may not be appropriate for aquatic organisms.

Objectives

As landscape connectivity critically affects the potential value of ponds for biodiversity, here we used diving beetles (Dytiscidae), an indicator taxon of wetland biodiversity, to investigate how structural connectivity affects functional connectivity to aquatic invertebrates in an urban landscape.

Methods

We assessed pairwise similarities of dytiscid community, i.e. the variation of species composition between clustered and isolated ponds in the Helsinki Metropolitan Area, Finland. We investigated how dytiscid community similarity is affected by Euclidean distances between ponds, as an indicator of structural connectivity.

Results

We found that clustered ponds shared more species than isolated ponds. Dytiscid species community similarity responded negatively to increasing Euclidean distance between ponds. Effectively dispersing species were widely distributed across the landscape, while poor dispersers were scarcely distributed in the same landscape.

Conclusions

Structural connectivity determines which species are able to disperse successfully, with poor dispersers restricted to well-connected ponds. The different responses of effective dispersers and poor dispersers to the same structural connectivity indicate that functional connectivity determines species composition. We recommend providing well-connected aquatic habitats in urban landscapes and the implementation of measures to reduce isolation of wetland assemblages. Even clustered ponds need dispersal from other habitats to ensure their contribution to urban biodiversity.
Equity financing incentive and corporate disclosure: new causal evidence from SEO deregulation
Authors: Chen Jun , Li Ningzhong , Zhou Xiaolu
Published: February 2022

We provide new causal evidence for the impact of equity financing incentive on firms’ voluntary disclosure decisions by exploring the 2008 seasoned equity offering deregulation, which exogenously facilitates small firms’ access to public equity financing and increases their equity issuance incentives without changing their business and information environments. We argue that the heightened equity financing incentive due to the deregulation can motivate a firm to increase disclosures even in the period without actual equity issuance, because such disclosures, by signaling a commitment to disclosure, could reduce the cost of equity in case the firm issues equity in the future. Consistent with this argument, we find that, benchmarking against control firms that are not affected by the deregulation, an average treatment firm that is affected by the deregulation but does not issue equity provides more management earnings forecasts in the post-deregulation period. The effect is mainly driven by repeated forecasters and is more pronounced for firms with greater equity financing needs and firms with higher information asymmetry in the equity market.
Solid Lubrication on Hard Metal Specimens with Micropits Under Normal and Elevated Temperatures
Authors: Dawari Christopher K. , Mönkkönen Kari , Suvanto Mika , Saarinen Jarkko J.
Published: February 2022

Solid lubrication in tribological applications was studied on hard metal specimens with micropits fabricated using metal injection molding (MIM). This study investigated synergy effects of paraffin wax mixed with 5 wt% MoS2 on the lubricating potential both under normal and elevated temperatures. Pin-on-plate sliding tests were performed on a CSM tribometer in which WC–Co pins oscillated against microstructured and flat reference WC–Co specimens under 10 N applied normal load. Surface morphology characterization of test specimens was carried out before and after tribological tests using scanning electron microscopy. Solid paraffin wax displayed enhanced lubrication compared to solid paraffin wax mixed with 5 wt% MoS2 on micropit specimens under normal temperature. On the contrary, under heating conditions, solid paraffin mixed with 5 wt% MoS2 significantly reduced the dynamic coefficient of friction (COF) values for both flat and micropit specimens. The results showed that the micropits in textured specimens can be used as a reservoir for the lubricant that can significantly reduce friction compared to flat reference specimens.

Graphical Abstract
Optimising Operational Reliability and Performance in Aerobic Passive Mine Water Treatment: the Multistage Westfield Pilot Plant
Authors: Opitz Joscha , Bauer Martin , Eckert Jutta , Peiffer Stefan , Alte Matthias
Published: February 2022

A three-stage pilot system was implemented for passive treatment of circumneutral, ferruginous seepage water at a former opencast lignite mine in southeast Germany. The pilot system consisted of consecutive, increasingly efficient treatment stages with settling ponds for pre-treatment, surface-flow wetlands for polishing and sediment filters for purification. The overall objective of the multistage approach was to demonstrate applicability and operational reliability for successive removal of iron as the primary contaminant broadly following Pareto’s principle in due consideration of the strict site-specific effluent limit of 1 mg/L. Average inflow total iron concentration was 8.4(± 2.4) mg/L, and effluent concentration averaged 0.21(± 0.07) mg/L. The bulk iron load (≈69%) was retained in settling ponds, thus effectively protecting wetlands and sediment filter from overloading. In turn, wetlands and sediment filters displayed similar discrete treatment efficiency (≈73% each) relative to settling ponds and thus proved indispensable to reliably meet regulatory requirements. Moreover, the wetlands were found to additionally stimulate and enhance biogeochemical processes that facilitated effective removal of secondary contaminants such as Mn and NH4. The sediment filters were found to reliably polish particulate and redox-sensitive compounds (Fe, As, Mn, NH4, TSS) whilst concomitantly mitigating natural spatiotemporal fluctuations that inevitably arise in open systems. Both treatment performance and operational reliability of the multistage pilot system were comparable to the conventional treatment plant currently operated on site. Altogether the study fully confirmed suitability of the multistage passive setup as a long-term alternative for seepage water treatment on site and provided new insights into the performance and interrelation of consecutive treatment stages. Most importantly, it was demonstrated that strategically combining increasingly efficient components may be used for optimisation of treatment performance and operational reliability whilst providing an opportunity to minimise land consumption and overall costs.
Effects of organic matter degradation in cohesive sediment: linking sediment rheology to spatio-temporal patterns of organic matter degradability
Authors: Zander F. , Shakeel A. , Kirichek A. , Chassagne C. , Gebert J.
Published: February 2022

Purpose

Sediment organic matter (SOM) influences settling and thus the rheological behavior of suspended particles by enhancing flocculation or reducing surface charges by forming organo-mineral complexes that facilitate particle–particle interactions in consolidating sediments. It was, therefore, assumed that the microbial degradation of SOM and its spatio-temporal variability would affect sediment rheological properties and enhance port maintenance dredging and navigability of ports and waterways.

Methods

To investigate this effect, samples were taken at six locations along a transect of 30 river kilometers through the Port of Hamburg, Germany, during nine sampling campaigns within two years. The collected samples were divided into different layers based on the differences in visual consistency and strength. For analysis of SOM degradability, the samples were incubated in the laboratory for 250 days in glass bottles under aerobic and anaerobic conditions following the evolution of gas composition (CH4, CO2) and pressure in the bottle headspace over time. Yield stress was analyzed before and after the dissolved organic matter (DOM) decay using a rheometer with Couette geometry. Standard properties of solids and pore water were also analyzed.

Results

Shear strength decreased upon SOM decay under both anaerobic and aerobic conditions. Under anaerobic conditions, organic matter decay reduced static and fluidic yield stresses to an average of 74% and 79% of the fresh sample values. Consolidated layers at lower depths showed the highest absolute decrease in fluidic yield stress of up to –110 Pa due to a larger absolute amount of degradable organic matter in these layers in connection to higher bulk density. Pronounced spatial trends with higher changes in yield stress at upstream locations and lower yield stress changes at downstream locations coincided with a decreasing gradient of SOM degradability from upstream to downstream. Seasonal trends indicated that the investigation area is impacted by temporally changing factors.

Conclusion

The availability of easily degradable organic matter significantly affects sediment strength, especially under the anaerobic conditions, even when the mass loss of organic matter mass loss is small. Seasonal variability in yield stress changes upon SOM decay indicate that the site-specific responses were modulated by overarching seasonal effects impacting the entire investigation area. It was assumed that during an anaerobic decay, the formation of gas bubbles added an additional physical component to the effect of biological SOM decay.
Multi-Cue Kinetic Model with Non-Local Sensing for Cell Migration on a Fiber Network with Chemotaxis
Authors: Conte Martina , Loy Nadia
Published: February 2022

Cells perform directed motion in response to external stimuli that they detect by sensing the environment with their membrane protrusions. Precisely, several biochemical and biophysical cues give rise to tactic migration in the direction of their specific targets. Thus, this defines a multi-cue environment in which cells have to sort and combine different, and potentially competitive, stimuli. We propose a non-local kinetic model for cell migration in which cell polarization is influenced simultaneously by two external factors: contact guidance and chemotaxis. We propose two different sensing strategies, and we analyze the two resulting transport kinetic models by recovering the appropriate macroscopic limit in different regimes, in order to observe how the cell size, with respect to the variation of both external fields, influences the overall behavior. This analysis shows the importance of dealing with hyperbolic models, rather than drift-diffusion ones. Moreover, we numerically integrate the kinetic transport equations in a two-dimensional setting in order to investigate qualitatively various scenarios. Finally, we show how our setting is able to reproduce some experimental results concerning the influence of topographical and chemical cues in directing cell motility.
Nitrous oxide-induced myeloneuropathy: an emerging public health issue
Authors: McCormick John P. , Sharpe Sophie , Crowley Karen , Dudley Alexander , O’Laoi Ruadhan , Barry Michael , Owens Lisa , Doherty Colin P. , Redmond Janice , Yeung Sarah-Jane
Published: February 2022

Increasing use of nitrous oxide as a recreational drug has been reported among young adults in western countries over the past decade. We present two cases of young males presenting to the Emergency Department (ED) of a large urban university hospital in Dublin with progressive neurological dysfunction related to nitrous oxide use. We review the pathophysiology, clinical features and treatment of nitrous oxide neurotoxicity. It is important that clinicians are aware of this evolving public health issue and are able to recognize the clinical features of this rare presentation, which may become more common in Irish EDs and GP surgeries as nitrous oxide abuse becomes more prevalent.
Stem Cell-Based Tissue Engineering for the Treatment of Burn Wounds: A Systematic Review of Preclinical Studies
Authors: Lukomskyj Alissa Olga , Rao Nikitha , Yan Lei , Pye Jasmine Sarah , Li Haiyan , Wang Bin , Li Jiao Jiao
Published: February 2022

Burn wounds are a devastating type of skin injury leading to severe impacts on both patients and the healthcare system. Current treatment methods are far from ideal, driving the need for tissue engineered solutions. Among various approaches, stem cell-based strategies are promising candidates for improving the treatment of burn wounds. A thorough search of the Embase, Medline, Scopus, and Web of Science databases was conducted to retrieve original research studies on stem cell-based tissue engineering treatments tested in preclinical models of burn wounds, published between January 2009 and June 2021. Of the 347 articles retrieved from the initial database search, 33 were eligible for inclusion in this review. The majority of studies used murine models with a xenogeneic graft, while a few used the porcine model. Thermal burn was the most commonly induced injury type, followed by surgical wound, and less commonly radiation burn. Most studies applied stem cell treatment immediately post-burn, with final endpoints ranging from 7 to 90 days. Mesenchymal stromal cells (MSCs) were the most common stem cell type used in the included studies. Stem cells from a variety of sources were used, most commonly from adipose tissue, bone marrow or umbilical cord, in conjunction with an extensive range of biomaterial scaffolds to treat the skin wounds. Overall, the studies showed favourable results of skin wound repair in animal models when stem cell-based tissue engineering treatments were applied, suggesting that such strategies hold promise as an improved therapy for burn wounds.

Graphical abstract
Tetrahydrobiopterin induces proteasome inhibitor resistance and tumor progression in multiple myeloma
Authors: Zhang Hua , Chen Jintong , Zhang Mingyue , Zhao Munan , Zhang Luyao , Liu Bin , Wang Siqing
Published: February 2022

Multiple myeloma (MM) still remains an incurable disease due to widespread drug resistance and high frequency of relapse. In this study, we found that tetrahydrobiopterin (BH4) promotes MM cell proliferation and tumor growth in vivo. BH4 also increases MM bortezomib (Bor) resistance in vitro and in vivo. We show that BH4 increases the expressions of USP7 and USP46 in MM cells, which are responsible for MM Bor resistance primed by BH4. BH4 promotes the degradation of P53 and the activation of NF-κB signaling through the up-regulation of USP7 and USP46. Furthermore, the inhibition of USPs increases the therapeutic effects of Bor in MM tumor bearing mice. Our results demonstrate the important role of BH4 in MM Bor resistance and tumor progression in vivo. These findings could potentially have clinical implications.