bluuebunny/crossref_metadata_2025 huggingface dataset:
RETRACTED ARTICLE: Evaluation of problems and countermeasures in marketing teaching based on cloud computing data aggregation algorithm
Authors: Shen Weinan
Published: April 2023

In this study, we present a highly practical marketing course. Through learning marketing, we can cultivate students’ ability to analyze, solve and practice problems. Therefore, this paper would study the problems encountered in the marketing course through cloud computing technology and propose corresponding countermeasures, so as to better improve students’ ability to analyze and solve problems and enhance the effectiveness of the classroom. This paper also analyzed the data aggregation algorithm based on Particle Swarm Optimization (PSO) algorithm. The results showed that when other conditions were the same, only 6 students approve of the traditional marketing teaching mode, accounting for 12%; there were 44 people who did not approve, accounting for 88%. This number was more than half; 49 students recognized the optimized marketing teaching mode, accounting for 98%; there was 1 person who did not approve, accounting for 2%. The proportion of people who did not approve after optimization was far less than that of the traditional model, which showed that cloud computing data aggregation algorithm could find out the problems in marketing teaching and provide correct countermeasures to solve them, so that the teaching model could be optimized. (1) The data aggregation algorithm based on cloud computing has a good optimization effect on the evaluation of marketing teaching problems and countermeasures, indicating a new direction for future research. (2) The combination of cloud computing and data aggregation algorithm is not only a novel research perspective, but also a perfect idea. (3) Marketing course is a very important course in today’s society. The study of its teaching problems and countermeasures evaluation will help students improve their learning efficiency and enhance their ability to adapt to the society.
Sharpening of graded diamond grinding wheels
Authors: Denkena Berend , Bergmann Benjamin , Raffalt Daniel
Published: April 2023

Grinding the flutes of cemented carbide end mill cutters results in high and uneven radial wear of the grinding wheel. This is a consequence of the varying geometrical contact conditions over the grinding wheel width. Decreased manufacturing accuracy regarding the tool target geometry is the consequence. To compensate for this, the dressing intervals must be shortened. High non-productive times and an additionally reduction of the grinding layer results from this. The higher non-productive times reduce the productivity of the grinding process and, in conjunction with the shorter lifetime of the grinding tool, thus increase the costs per work piece. It has already been shown that load-adapted grinding wheels can reduce uneven radial wear up to 50%. The adaptation of the wear behaviour to non-uniform engagement conditions causes non-uniform radial wear to occur again under uniform engagement conditions. Uniform engagement conditions occur during grinding wheel sharpening. Therefore, the present study investigates the influence of sharpening on the grinding tool topography. For this purpose, sharpening tests are carried out on four differently graded grinding wheels. For comparability, the tests are also carried out on two non-graded grinding wheels. In the present work, the surface parameters are evaluated with regard to their suitability for analysing the sharpening condition of graded grinding wheels. The grain protrusion derived from this is subsequently used for evaluation. For this, a dependency on the grain concentration is proven and the grain protrusions are shown over the grinding wheel widths. From this, sharpening parameters are determined that enable reproducible sharpening of graded grinding wheels.
Effects of Microbial Inoculants and Organic Amendments on Wheat Nutrition and Development in a Variety of Soils
Authors: Moreno-Lora Aurora , Velasco-Sánchez Ángel , Delgado Antonio
Published: April 2023

Manipulation of soil microbial communities through inoculants or amendments can improve crop nutrition. However, to what extent these benefits vary depending on soil properties is not yet understood. Thus, here we studied the effects of microbial inoculants and the application of labile organic C on the yield and uptake of micronutrients and P in wheat (Triticum durum) in different soils. The application of Bacillus subtilis QST713, Trichoderma asperellum strain T34, and cellulose was tested in ten soils varying greatly in properties in a pot experiment. Microbial inoculants and cellulose increased dry matter (between 5 and 10%) and grain yield (between 15 and 20%), regardless of the soil. Some treatments triggered nutrient mobilization mechanisms such as phosphatase and oxalate production. However, total Zn and P in plants did not increase with treatments, and their effect on Fe and Mn varied depending on soils. The effect of B. subtilis and T. asperellum improving Fe uptake by plants decreased with increasing pH and also with decreased microbial activity in soil. Inoculants and cellulose increased the Zn harvest index and decreased the P-to-Zn ratio in grains independently of the soil. This was probably ascribable to changes in the distribution of phytohormones in plants. Microorganisms and cellulose improved wheat yield, the portion of absorbed Zn accumulated in grains, and grain quality. These effects did not depend on the soil. However, the effect on Fe and Mn nutrition was affected by soil pH and microbial activity.
The development of active optical clock
Authors: Zhang Jia , Shi Tiantian , Miao Jianxiang , Chen Jingbiao
Published: April 2023

The atomic clocks, whether operating at optical or microwave region, can be divided into two categories according to their working mode, namely the passive clocks and active clocks. The passive clocks, whose standard frequency is locked to an ultra-narrow atomic spectral line, such as laser cooled Cs beam or lattice trapped Sr atoms, depend on the spontaneous emission line. On the contrary, the active clocks, in which the atoms are used as the gain medium, are based on the stimulated emission radiation, their spectrum can be directly used as the frequency standard. Up to now, the active hydrogen maser has been the most stable microwave atomic clocks. Also, the Sr superradiant active atomic clock is prospects for a millihertz-linewidth laser. Moreover, the optical clocks are expected to surpass the performance of microwave clocks both in stability and uncertainty, since their higher working frequency. The active optical clock has the potential to improve the stability of the best clocks by 2 orders of magnitude. In this work, we introduce the development of active optical clocks, and their types is classified according to the energy-level structure of atoms for stimulated radiation.
Analysis of in situ performance of rooftop PV system in Seoul, South Korea
Authors: Singh Ravneet , Nam A. Young , Park Jong Jun , Kim Young Il
Published: April 2023

This paper presents a study of a 98.1 kW-PV system facing south at an inclined angle of 15º on the roof of a university building in Seoul, South Korea (latitude 37.63° N and longitude 127.1° E). The system performance was analyzed for 2 years from Sep. 2015 to Aug. 2017. The average electrical power output was 0.59 kWh/(m2·day) with a 16.9% average annual efficiency for the 1st year which further decreased to 0.58 kWh/(m2·day) with average annual efficiency of 17.6% in the 2nd year. The annual irradiance was 3.50 kWh/(m2·day) for the 1st year and 3.31 kWh/(m2·day) for the 2nd year with a total annual output generation of 105.4 MWh and 103.5 MWh, respectively. Average daily power generations were 2.93 and 2.89 kWh/(kWp·day) for 2 years, respectively, with an annual performance ratio range of 80 ~ 90%. Predicted module temperatures show a good correlation with measured temperatures. Predicted and measured output values show a strong correlation. During the 1st year at a maximum module temperature of 60ºC, power output loss was found to be 13.3%, while in the 2nd year at a maximum module temperature of 57ºC, the power output loss observed was 12.2%.
Particle-resolved simulation of antidunes in free-surface flows
Authors: Schwarzmeier Christoph , Rettinger Christoph , Kemmler Samuel , Plewinski Jonas , Núñez-González Francisco , Köstler Harald , Rüde Ulrich , Vowinckel Bernhard
Published: April 2023

The interaction of supercritical turbulent flows with granular sediment beds is challenging to study both experimentally and numerically. This challenging task has hampered advances in understanding antidunes, the most characteristic bedform of supercritical flows. This article presents the first numerical attempt to simulate upstream-migrating antidunes with geometrically resolved particles and a liquid–gas interface. Our simulations provide data at a resolution higher than laboratory experiments, and they can therefore provide new insights into the mechanisms of antidune migration and contribute to a deeper understanding of the underlying physics. To manage the simulations’ computational costs and physical complexity, we employ the cumulant lattice Boltzmann method in conjunction with a discrete element method for particle interactions, as well as a volume-of-fluid scheme to track the deformable free surface of the fluid. By reproducing two flow configurations of previous experiments (Pascal et al., Earth Surf. Process. Landf., vol. 46, issue 9, 2021, pp. 1750–1765), we demonstrate that our approach is robust and accurately predicts the antidunes’ amplitude, wavelength and celerity. Furthermore, the simulated wall shear stress, a key parameter governing sediment transport, is in excellent agreement with the experimental measurements. The highly resolved data of fluid and particle motion from our simulation approach open new perspectives for detailed studies of morphodynamics in shallow supercritical flows.
Caught in the Net: Fish, Ships, and Oil in the GDR-Poland Territorial Waters Dispute, 1949–1989
Authors: Tompkins Andrew S.
Published: April 2023

The 1945 Potsdam Agreement established a new border between Poland and Germany at the so-called “Oder-Neisse line,” but it left unsettled the question of the maritime boundary on the Baltic Sea. Until 1989, the water border remained a matter of dispute between the German Democratic Republic and the Polish People's Republic socialist allies otherwise at pains to demonstrate unity in geopolitical matters—especially with regard to their shared “border of peace and friendship.” In the intervening decades, East German fishermen and Polish ship captains repeatedly ran afoul of the invisible water border, the importance of which increased as UN conventions on the Law of the Sea affected fishing, shipping, drilling, and security matters. This article examines the diplomatic dispute over territorial waters in relation to its environmental dimensions and social consequences, demonstrating how the challenges of governing transnational space in a water environment greatly complicated everyday life for water users as well as the border work of both states.
Beyond clinical and cost-effectiveness: The contribution of qualitative research to health technology assessment
Authors: Germeni Evi , Szabo Shelagh
Published: April 2023

Recent developments in health technology assessment (HTA), including the promotion of a new and internationally accepted definition of HTA, have highlighted the need to go beyond clinical and cost-effectiveness to fully understand the potential value of health technologies. Multidisciplinary efforts to generate patient-focused evidence relevant to HTA, using both quantitative and qualitative approaches, are needed. Although it has been more than 20 years since opportunities for qualitative methods to inform HTA were first discussed, their use remains infrequent. The goal of this article is to resurrect the debate about the value of qualitative research in HTA. Drawing on examples from published literature, we propose five key areas where qualitative methods can contribute to HTA, complementary to studies of clinical and cost-effectiveness: (i) assessing acceptability and subjective value; (ii) understanding perspectives and providing context; (iii) reaching the groups other methods cannot reach; (iv) laying the groundwork for subsequent quantitative exercises; and (v) contributing to economic model development.
Health technology assessment of tests for SARS-CoV-2 and treatments for COVID-19: A proposed approach and best-practice recommendations
Authors: Elvidge Jamie , Summerfield Ashley , Knies Saskia , Németh Bertalan , Kaló Zoltán , Goettsch Wim , Dawoud Dalia M.
Published: April 2023

Objectives

To develop best-practice guidance for health technology assessment (HTA) agencies when appraising diagnostic tests for SARS-CoV-2 and treatments for COVID-19.

Methods

We used a policy sandbox approach to develop best-practice guidance for HTA agencies to approach known challenges associated with assessing tests and treatments for COVID-19. The guidance was developed by a multi-stakeholder workshop of twenty-one participants representing HTA agencies, clinical and patient experts, academia, industry, and a payer, from across Europe and North America. The workshop was supported by extensive background work to identify the key challenges, including: targeted reviews of existing COVID-related methods guidance for assessing interventions and clinical guidelines, engagement with clinical experts, a survey and workshop of HTA agencies, a systematic review of published economic evaluations, and a workshop of health economic modelers.

Results

We suggest HTA agencies should consider using other types of evidence (e.g., real world) where high-quality randomized controlled trials may be lacking and healthcare systems would value timely HTA outputs. A “living” HTA approach may be useful, given the context of an evolving disease, scientific understanding and evidence base, allowing for decisions to be efficiently revisited in response to new information; particularly, if supported by a common “disease model” for COVID-19. Innovative ways of engaging with the public and clinicians, and early engagement with regulators and payers, are recommended.

Conclusions

HTA agencies should consider the elements of this guidance that are most suited to their existing processes to enable them to assess the effectiveness and value of interventions for COVID-19.
Election hacking, the rule of sovereignty, and deductive reasoning in customary international law
Authors: Wheatley Steven
Published: April 2023

This article considers the international laws applicable to irresponsible state behaviour in cyberspace through the lens of the problem of election hacking. The rule of sovereignty has taken centre stage in these discussions and is said to be preferred to the non-intervention rule because it evades the problem of coercion. Proponents of the cyber rule of sovereignty contend that there is such a rule; opponents reject the existence of the rule as a matter of existing law. The objective here is to explore the methodologies involved in the identification of the cyber rule of sovereignty under customary international law. The work first frames the debate in the language of regulative and constitutive rules, allowing us to show that a regulative rule of sovereignty can, logically, and necessarily, be deduced from the constitutive rule of sovereignty. The content of the regulative rule can also be deduced from the constitutive rule of sovereignty, but it has a more limited scope than claimed by the proponents of the rule, notably the Tallinn Manual 2.0. The rule of sovereignty prohibits state cyber operations carried out on the territory of the target state and remote cyber operations which involve the exercise of sovereign authority on that territory, e.g., police evidence-gathering operations. The rule of sovereignty does not, however, prohibit other remote, ex situ state cyber operations, even those targeting ICTs used for governmental functions, including the conduct of elections. The rule of sovereignty is not, then, the solution to the problem of election hacking.
Inside the treaty interpreter’s mind: An experimental linguistic approach to international law
Authors: Pirker Benedikt , Skoczeń Izabela
Published: April 2023

One particularly intense critical debate over interpretation in international law concerns the role of moral factors – specifically, the degree to which such factors influence legal interpretation, and how the law should deal with them. A formalist approach argues that moral considerations should be excluded as non-legal; a critical legal studies approach suggests they are an inevitable part of the functioning of international law and must therefore be acknowledged; and an inclusivist approach would suggest their influence is permissible, albeit only under certain circumstances. In this article, we are concerned with the question of whether moral factors influence interpretation at all, taking international treaties as the object of study. To address this question, we take a novel approach, proposing an experimental linguistic framework to test whether linguistic categorizations (originally developed for the analysis of everyday language) can be successfully applied to treaty interpretation, relying on both laypersons and experts as participants. Although some caveats must be made, the experiments deliver clear results: both groups are influenced by morals in their interpretation of international treaty norms. On this basis, we draw conclusions regarding (i) how the process of interpretation of international law operates; and (ii) what the institutions managing that process, such as courts, should factor-in when deliberating their decisions. By adopting this novel perspective, we also contribute to linguistic and experimental approaches to international law at the methodological level.
Ableism in the college of international lawyers: On disabling differences in the professional field
Authors: Kulamadayil Lys
Published: April 2023

In the wake of the #metoo and #blacklivesmatter movements, the masculine and ‘methodologically white’ nature of the core of the international legal profession has received renewed attention, and attempts to diversify it are well underway. Absent from the conversations that accompany such diversification efforts are reflections on the pervasiveness of ableism in the profession. Ableism describes implicit assumptions about the species-typical condition of the human body and the ways in which it interacts with the material and social world. The importance of ableism in excluding and marginalizing persons with disabling differences in international legal academia has widely been overlooked. This neglect simultaneously contributes to ableist re-productions of the profession and affects how international law understands and governs disability.
Clique-factors in graphs with sublinear -independence number
Authors: Han Jie , Hu Ping , Wang Guanghui , Yang Donglei
Published: April 2023

Given a graph

$G$

and an integer

$\ell \ge 2$

, we denote by

$\alpha _{\ell }(G)$

the maximum size of a

$K_{\ell }$

-free subset of vertices in

$V(G)$

. A recent question of Nenadov and Pehova asks for determining the best possible minimum degree conditions forcing clique-factors in

$n$

-vertex graphs

$G$

with

$\alpha _{\ell }(G) = o(n)$

, which can be seen as a Ramsey–Turán variant of the celebrated Hajnal–Szemerédi theorem. In this paper we find the asymptotical sharp minimum degree threshold for

$K_r$

-factors in

$n$

-vertex graphs

$G$

with

$\alpha _\ell (G)=n^{1-o(1)}$

for all

$r\ge \ell \ge 2$

.
Religious tolerance in the Arab Gulf states: Christian organizations, soft power, and the politics of sustaining the “family–state” beyond the rentier model
Authors: Monier Elizabeth
Published: April 2023

The states of the Arabian Gulf present a novel case for the examination of relations between authoritarian governance and Christian organizations. The economic clout of the Gulf states has been central to political stability and legitimacy but they are increasingly seeking to expand and consolidate the soft power and resilience through political and diplomatic initiatives. This article examines how the Christian organizations established in recent decades by large migrant communities are incorporated into this strategy and how they are responding. It argues that religious tolerance has formed a central discourse in governmental policies and narratives that construct the Gulf states as modern progressive nations, despite their unique political systems based mainly on constitutional monarchies with limited political participation. This constructs local Christian communities as a source of soft power, despite their position as a religious minority.
The Contribution of Anammox to Nitrogen Removal Is Greater in Bulk Soils Than in Rhizosphere Soils in Riparian Wetlands Along the Yangtze River
Authors: Deng Danli , Ding Bangjing , He Gang , Ji Mingfei , Yang Yuyi , Liu Guihua , Zhang Quanfa , Liu Wenzhi
Published: April 2023

The importance of denitrification and anaerobic ammonium oxidation (anammox) in removing nitrogen (N) from upland runoff has been well documented in riparian wetlands. However, the relative contributions of denitrification and anammox to N removal in the rhizosphere and non‐rhizosphere soils of riparian zones remain unclear. Here, we explored the denitrification and anammox rates in the rhizosphere and bulk soils (0–5 and 10–15 cm) of 39 riparian wetlands along the Yangtze River using the 15N isotope pairing technique. Additionally, we used a quantitative polymerase chain reaction assay to determine the abundance of soil denitrifying and anammox bacteria using nosZ and hzsB genes, respectively. The results showed that both denitrification and anammox rates were significantly higher in rhizosphere soils than in bulk soils, suggesting that the rhizosphere environment is favorable for N removal. The contribution of anammox constituted over half (62.53% ± 1.49%) of the N loss and was greater in bulk soils (68.57% ± 1.42%) than in rhizosphere soils (55.64% ± 2.42%). Higher nosZ and hzsB gene abundances were also observed in rhizosphere soils than in bulk soils. Denitrification and anammox rates were significantly regulated by edaphic properties, microbial abundance, and plant biomass. The structural equation model further revealed that soil pH and N availability could affect denitrification and anammox rates both directly and indirectly by altering nosZ and hzsB gene abundance. Overall, this study highlights that the rhizosphere is a control point for N removal and harbors more functional microbes than bulk soils. Therefore, revegetation may effectively enhance the N removal function of riparian wetlands along the Yangtze River.
On the Seasonal and Spatial Dependence of Extreme Warm Days in Antarctica
Authors: Xu Min , Yang Qinghua , Clem Kyle R. , Yu Lejiang , Hu Xiaoming
Published: April 2023

The spatial distribution of trends in temperature extremes over Antarctica remains largely unknown. Here we investigate the seasonal and spatial characteristics of extreme warm occurrence across Antarctica. The Antarctic inland areas show significant positive trends in the number of extreme warm days in austral spring and summer. The trends in the seasonal mean of daily maximum temperature show strong coherence with the trends in extreme warm occurrences. In addition, the long‐term longwave radiation, water vapor flux and regional atmospheric circulation changes are closely connected to the trends of extreme warm days in all seasons outside of summer; the summer longwave radiation and interior wind trends show little coherence with warm extreme trends, indicating other processes at play driving extreme warm days in summer.
Wave and Particle Analysis of Z‐Mode and O‐Mode Emission in the Jovian Inner Magnetosphere
Authors: Menietti J. D. , Yoon P. H. , Averkamp T. F. , Kurth W. S. , Faden J. B. , Allegrini F. , Kollmann P. , Bolton S. J.
Published: April 2023

We report some of the most intense Z‐mode and O‐mode observations obtained by the Juno spacecraft while in orbit about Jupiter in a low to mid‐latitude region near the inner edge of the Io torus. We have been able to estimate the density of the plasma in this region based on the lower frequency cutoff of the observed Z‐mode emission. The results are compatible with the electron density measurements of the Jovian Auroral Distributions Experiment (JADE), on board the Juno spacecraft, if we account for unmeasured cold plasma. Direction‐finding measurements indicate that the Z‐ and O‐mode emission have distinct source regions. We have also used the measured phase space density of the JADE and the Jupiter energetic particle detector instruments to calculate estimated local growth rates of the observed O‐mode and Z‐mode emission assuming a loss cone instability and quasilinear analysis. The results suggest the emissions were observed near, but not within, a source region, and the free energy source is consistent with a loss cone. We have thus carried out the quasilinear wave analysis of the assumed remote Z‐ and O‐mode wave growths. It is shown that the remotely generated waves, propagated through an inhomogeneous medium to the satellite location, may account for the observed wave characteristics. The importance of Z‐mode in accelerating electrons in the inner Jovian magnetosphere makes these new wave mode confirmations at Jupiter of particular interest.
A Common Language for Reporting Earthquake Intensities
Authors: Wald David , Loos Sabine , Spence Robin , Goded Tatiana , Hortacsu Ayse
Published: April 2023

Scientists are working together to establish a standardized international scale for measuring and reporting the intensities and impacts of earthquake shaking.
Twelve-month effectiveness of telephone and SMS support to mothers with children aged 2 years in reducing children’s BMI: a randomized controlled trial
Authors: Wen Li Ming , Xu Huilan , Phongsavan Philayrath , Rissel Chris , Hayes Alison , Taki Sarah , Buchanan Limin , Simone Lisa , Moreton Renee , Baur Louise A.
Published: April 2023

Background/objectives

Few quality intervention studies have assessed whether a combined telephone and short message service (SMS) intervention to mothers is effective in reducing BMI and obesity risk behaviors of children at 3 years of age. This study aimed to assess effectiveness of telephone and SMS support in reducing children’s body mass index (BMI) and obesity risk behaviors.

Subjects/Methods

A randomized controlled trial (RCT) with 662 women of 2-year-old children (with the proportion of overweight and obesity being similar to the general population) was conducted in Sydney, Australia, March 2019–October 2020. The mothers in the intervention group received three telephone support sessions plus SMS messages and mailed-intervention-booklets over a 12 months period i.e., 24–26, 28–30, and 32–34 months of the child’s age. Mothers in the control group received usual care and two mailed booklets on information not related to the intervention. The primary outcome was child’s BMI at 3 years of age. Secondary outcomes were children’s dietary and activity behaviors. All outcome measures were based on mothers’ self-report using standardized tools due to COVID-19 pandemic restrictions.

Results

537 (81%) mothers completed the post-intervention assessment at 3 years with only 470 (71%) children having weight and height measures. Multiple imputation analysis showed no statistically significant difference in mean BMI between the groups. Children in the intervention group were more likely not to eat in front of the TV [AOR 1.79 (95% CI 1.17–2.73), P = 0.008], more likely to meet the dietary recommendations [AOR 1.73 (95% CI 0.99–3.02), P = 0.054] and meet the activity recommendations [AOR 1.72 (95% CI 1.11–2.67), P = 0.015] than those in the control group respectively. Among those with an annual household income (<AUD$80,000), the intervention was significantly associated with a lower mean BMI [16.26 (SD 2.22) kg.m−2] in the intervention group than [16.84 (SD 2.37)] in the control, a difference of −0.59 kg/m2 (95% CI: −1.15 to −0.03, P = 0.040).

Conclusions

A staged telephone and SMS support intervention to mothers with children aged 2 years was associated with improved dietary and activity behaviors. The intervention was also associated with reduced children’s BMI at age 3 years only for those from lower income households.

Trial registration

The trial is registered with the Australian Clinical Trial Registry (ACTRN12618001571268)
Diosgenin restores memory function via SPARC-driven axonal growth from the hippocampus to the PFC in Alzheimer’s disease model mice
Authors: Yang Ximeng , Tohda Chihiro
Published: April 2023

Central nervous system axons have minimal capacity to regenerate in adult brains, hindering memory recovery in Alzheimer’s disease (AD). Although recent studies have shown that damaged axons sprouted in adult and AD mouse brains, long-distance axonal re-innervation to their targets has not been achieved. We selectively visualized axon-growing neurons in the neural circuit for memory formation, from the hippocampus to the prefrontal cortex, and showed that damaged axons successfully extended to their native projecting area in mouse models of AD (5XFAD) by administration of an axonal regenerative agent, diosgenin. In vivo transcriptome analysis detected the expression profile of axon-growing neurons directly isolated from the hippocampus of 5XFAD mice. Secreted protein acidic and rich in cysteine (SPARC) was the most expressed gene in axon-growing neurons. Neuron-specific overexpression of SPARC via adeno-associated virus serotype 9 delivery in the hippocampus recovered memory deficits and axonal projection to the prefrontal cortex in 5XFAD mice. DREADDs (Designer receptors exclusively activated by designer drugs) analyses revealed that SPARC overexpression-induced axonal growth in the 5XFAD mouse brain directly contributes to memory recovery. Elevated levels of SPARC on axonal membranes interact with extracellular rail-like collagen type I to promote axonal remodeling along their original tracings in primary cultured hippocampal neurons. These findings suggest that SPARC-driven axonal growth in the brain may be a promising therapeutic strategy for AD and other neurodegenerative diseases.
Marine picocyanobacterial PhnD1 shows specificity for various phosphorus sources but likely represents a constitutive inorganic phosphate transporter
Authors: Shah Bhumika S , Ford Benjamin A , Varkey Deepa , Mikolajek Halina , Orr Christian , Mykhaylyk Vitaliy , Owens Raymond J , Paulsen Ian T
Published: April 2023

Despite being fundamental to multiple biological processes, phosphorus (P) availability in marine environments is often growth-limiting, with generally low surface concentrations. Picocyanobacteria strains encode a putative ABC-type phosphite/phosphate/phosphonate transporter, phnDCE, thought to provide access to an alternative phosphorus pool. This, however, is paradoxical given most picocyanobacterial strains lack known phosphite degradation or carbon-phosphate lyase pathway to utilise alternate phosphorus pools. To understand the function of the PhnDCE transport system and its ecological consequences, we characterised the PhnD1 binding proteins from four distinct marine Synechococcus isolates (CC9311, CC9605, MITS9220, and WH8102). We show the Synechococcus PhnD1 proteins selectively bind phosphorus compounds with a stronger affinity for phosphite than for phosphate or methyl phosphonate. However, based on our comprehensive ligand screening and growth experiments showing Synechococcus strains WH8102 and MITS9220 cannot utilise phosphite or methylphosphonate as a sole phosphorus source, we hypothesise that the picocyanobacterial PhnDCE transporter is a constitutively expressed, medium-affinity phosphate transporter, and the measured affinity of PhnD1 to phosphite or methyl phosphonate is fortuitous. Our MITS9220_PhnD1 structure explains the comparatively lower affinity of picocyanobacterial PhnD1 for phosphate, resulting from a more limited H-bond network. We propose two possible physiological roles for PhnD1. First, it could function in phospholipid recycling, working together with the predicted phospholipase, TesA, and alkaline phosphatase. Second, by having multiple transporters for P (PhnDCE and Pst), picocyanobacteria could balance the need for rapid transport during transient episodes of higher P availability in the environment, with the need for efficient P utilisation in typical phosphate-deplete conditions.
Reduced inferior fronto-insular-thalamic activation during failed inhibition in young adults with combined ASD and ADHD compared to typically developing and pure disorder groups
Authors: Lukito Steve , O’Daly Owen G. , Lythgoe David J. , Hodsoll John , Maltezos Stefanos , Pitts Mark , Simonoff Emily , Rubia Katya
Published: April 2023

Autism spectrum disorder (ASD) often co-occurs with attention-deficit/hyperactivity disorder (ADHD) and people with these conditions have frontostriatal functional atypicality during motor inhibition. We compared the neural and neurocognitive correlates of motor inhibition and performance monitoring in young adult males with “pure” and combined presentations with age-and sex-matched typically developing controls, to explore shared or disorder-specific atypicality. Males aged 20–27 years with typical development (TD; n = 22), ASD (n = 21), combined diagnoses ASD + ADHD (n = 23), and ADHD (n = 25) were compared using a modified tracking fMRI stop-signal task that measures motor inhibition and performance monitoring while controlling for selective attention. In addition, they performed a behavioural go/no-go task outside the scanner. While groups did not differ behaviourally during successful stop trials, the ASD + ADHD group relative to other groups had underactivation in typical performance monitoring regions of bilateral anterior insula/inferior frontal gyrus, right posterior thalamus, and right middle temporal gyrus/hippocampus during failed inhibition, which was associated with increased stop-signal reaction time. In the behavioural go/no-go task, both ADHD groups, with and without ASD, had significantly lower motor inhibition performance compared to TD controls. In conclusion, only young adult males with ASD + ADHD had neurofunctional atypicality in brain regions associated with performance monitoring, while inhibition difficulties on go/no-go task performance was shared with ADHD. The suggests that young people with ASD + ADHD are most severely impaired during motor inhibition tasks compared to ASD and ADHD but do not reflect a combination of the difficulties associated with the pure disorders.
NGS-defined measurable residual disease (MRD) after initial chemotherapy as a prognostic biomarker for acute myeloid leukemia
Authors: Li Yonghong , Solis-Ruiz Jose , Yang Fei , Long Nicola , Tong Carmen H. , Lacbawan Felicitas L. , Racke Frederick K. , Press Richard D.
Published: April 2023

Treated AML patients often have measurable residual disease (MRD) due to persisting low-level clones. This study assessed whether residual post-treatment somatic mutations, detected by NGS, were significantly prognostic for subsequent clinical outcomes. AML patients (n = 128) underwent both pre-and post-treatment testing with the same 42-gene MRD-validated NGS assay. After induction, 59 (46%) patients were mutation-negative (0.0024 VAF detection limit) and 69 (54%) had ≥1 persisting NGS-detectable mutation. Compared with NGS-negative patients, NGS-positive patients had shorter overall survival (17 months versus median not reached; P = 0.004; hazard ratio = 2.2 [95% CI: 1.3–3.7]) and a shorter time to relapse (14 months versus median not reached; P = 0.014; HR = 1.9 [95% CI: 1.1–3.1]). Among 95 patients with a complete morphologic remission (CR), 43 (45%) were MRD-positive by NGS and 52 (55%) were MRD-negative. These MRD-positive CR patients had a shorter overall survival (16.8 months versus median not reached; P = 0.013; HR = 2.1 [95% CI: 1.2–3.9]) than did the MRD-negative CR patients. Post-treatment persisting MRD positivity, defined by the same NGS-based test used at diagnosis, is thus a more sensitive biomarker for low-level leukemic clones compared to traditional non-molecular methods and is prognostic of subsequent relapse and death.
Phase I/II sequencing study of azacitidine, epacadostat, and pembrolizumab in advanced solid tumors
Authors: Luke Jason J. , Fakih Marwan , Schneider Charles , Chiorean E. Gabriela , Bendell Johanna , Kristeleit Rebecca , Kurzrock Razelle , Blagden Sarah P. , Brana Irene , Goff Laura W. , O’Hayer Kevin , Geschwindt Ryan , Smith Michael , Zhou Feng , Naing Aung
Published: April 2023

Background

Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, contributes to tumor immune intolerance. Immune checkpoint inhibition may increase interferon levels; combining IDO1 inhibition with immune checkpoint blockade represents an attractive strategy. Epigenetic agents trigger interferon responses and may serve as an immunotherapy priming method. We evaluated whether epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers clinical benefit to patients with advanced solid tumors.

Methods

ECHO-206 was a Phase I/II study where treatment-experienced patients with advanced solid tumors (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary endpoints were safety/tolerability (Phase I), maximum tolerated dose (MTD) or pharmacologically active dose (PAD; Phase I), and investigator-assessed objective response rate (ORR; Phase II).

Results

In Phase I, no dose-limiting toxicities were reported, the MTD was not reached; a PAD was not determined. ORR was 5.7%, with four partial responses. The most common treatment-related adverse events (AEs) were fatigue (42.9%) and nausea (42.9%). Twelve (17.1%) patients experienced ≥1 fatal AE, one of which (asthenia) was treatment-related.

Conclusions

Although the azacitidine-epacadostat-pembrolizumab regimen was well tolerated, it was not associated with substantial clinical response in patients with advanced solid tumors previously exposed to immunotherapy.
The biophysical property of the limbal niche maintains stemness through YAP
Authors: Bhattacharya Swarnabh , Mukherjee Abhishek , Pisano Sabrina , Dimri Shalini , Knaane Eman , Altshuler Anna , Nasser Waseem , Dey Sunanda , Shi Lidan , Mizrahi Ido , Blum Noam , Jokel Ophir , Amitai-Lange Aya , Kaganovsky Anna , Mimouni Michael , Socea Sergiu , Midlij Mohamad , Tiosano Beatrice , Hasson Peleg , Feral Chloe , Wolfenson Haguy , Shalom-Feuerstein Ruby
Published: April 2023

The cell fate decisions of stem cells (SCs) largely depend on signals from their microenvironment (niche). However, very little is known about how biochemical niche cues control cell behavior in vivo. To address this question, we focused on the corneal epithelial SC model in which the SC niche, known as the limbus, is spatially segregated from the differentiation compartment. We report that the unique biomechanical property of the limbus supports the nuclear localization and function of Yes-associated protein (YAP), a putative mediator of the mechanotransduction pathway. Perturbation of tissue stiffness or YAP activity affects SC function as well as tissue integrity under homeostasis and significantly inhibited the regeneration of the SC population following SC depletion. In vitro experiments revealed that substrates with the rigidity of the corneal differentiation compartment inhibit nuclear YAP localization and induce differentiation, a mechanism that is mediated by the TGFβ−SMAD2/3 pathway. Taken together, these results indicate that SC sense biomechanical niche signals and that manipulation of mechano-sensory machinery or its downstream biochemical output may bear fruits in SC expansion for regenerative therapy.
Novel insight into the underlying dysregulation mechanisms of immune cell-to-cell communication by analyzing multitissue single-cell atlas of two COVID-19 patients
Authors: Qin Shijie , Yao Xiaohong , Li Weiwei , Wang Canbiao , Xu Weijun , Gan Zhenhua , Yang Yang , Zhong Aifang , Wang Bin , He Zhicheng , Wu Jian , Wu Qiuyue , Jiang Weijun , Han Ying , Wang Fan , Wang Zhihua , Ke Yuehua , Zhao Jun , Gao Junyin , Qu Liang , Jin Ping , Guan Miao , Xia Xinyi , Bian Xiuwu
Published: April 2023

How does SARS-CoV-2 cause lung microenvironment disturbance and inflammatory storm is still obscure. We here performed the single-cell transcriptome sequencing from lung, blood, and bone marrow of two dead COVID-19 patients and detected the cellular communication among them. Our results demonstrated that SARS-CoV-2 infection increase the frequency of cellular communication between alveolar type I cells (AT1) or alveolar type II cells (AT2) and myeloid cells triggering immune activation and inflammation microenvironment and then induce the disorder of fibroblasts, club, and ciliated cells, which may cause increased pulmonary fibrosis and mucus accumulation. Further study showed that the increase of T cells in the lungs may be mainly recruited by myeloid cells through ligands/receptors (e.g., ANXA1/FPR1, C5AR1/RPS19, and CCL5/CCR1). Interestingly, we also found that certain ligands/receptors (e.g., ANXA1/FPR1, CD74/COPA, CXCLs/CXCRs, ALOX5/ALOX5AP, CCL5/CCR1) are significantly activated and shared among lungs, blood and bone marrow of COVID-19 patients, implying that the dysregulation of ligands/receptors may lead to immune cell’s activation, migration, and the inflammatory storm in different tissues of COVID-19 patients. Collectively, our study revealed a possible mechanism by which the disorder of cell communication caused by SARS-CoV-2 infection results in the lung inflammatory microenvironment and systemic immune responses across tissues in COVID-19 patients.
PARP1 mediated PARylation contributes to myogenic progression and glucocorticoid transcriptional response
Authors: Tan Arnold , Younis Awais Z. , Evans Alexander , Creighton Jade V. , Coveny Clare , Boocock David J. , Sale Craig , Lavery Gareth G. , Coutts Amanda S. , Doig Craig L.
Published: April 2023

The ADP-ribosyltransferase, PARP1 enzymatically generates and applies the post-translational modification, ADP-Ribose (ADPR). PARP1 roles in genome maintenance are well described, but recent work highlights roles in many fundamental processes including cellular identity and energy homeostasis. Herein, we show in both mouse and human skeletal muscle cells that PARP1-mediated PARylation is a regulator of the myogenic program and the muscle transcriptional response to steroid hormones. Chemical PARP1 modulation impacts the expression of major myocellular proteins, including troponins, key in dictating muscle contractile force. Whilst PARP1 in absence of DNA damage is often assumed to be basally inactive, we show PARylation to be acutely sensitive to extracellular glucose concentrations and the steroid hormone class, glucocorticoids which exert considerable authority over muscle tissue mass. Specifically, we find during myogenesis, a transient and significant rise in PAR. This early-stage differentiation event, if blocked with PARP1 inhibition, reduced the abundance of important muscle proteins in the fully differentiated myotubes. This suggests that PAR targets during early-stage differentiation are central to the proper development of the muscle contractile unit. We also show that reduced PARP1 in myoblasts impacts a variety of metabolic pathways in line with the recorded actions of glucocorticoids. Currently, as both regulators of myogenesis and muscle mass loss, glucocorticoids represent a clinical conundrum. Our work goes on to identify that PARP1 influences transcriptional activation by glucocorticoids of a subset of genes critical to human skeletal muscle pathology. These genes may therefore signify a regulatory battery of targets through which selective glucocorticoid modulation could be achieved. Collectively, our data provide clear links between PARP1-mediated PARylation and skeletal muscle homeostatic mechanisms crucial to tissue mass maintenance and endocrine response.
Trends and variability in the Southern Annular Mode over the Common Era
Authors: King Jonathan , Anchukaitis Kevin J. , Allen Kathryn , Vance Tessa , Hessl Amy
Published: April 2023

The Southern Annular Mode (SAM) is the leading mode of atmospheric variability in the extratropical Southern Hemisphere and has wide ranging effects on ecosystems and societies. Despite the SAM’s importance, paleoclimate reconstructions disagree on its variability and trends over the Common Era, which may be linked to variability in SAM teleconnections and the influence of specific proxies. Here, we use data assimilation with a multi-model prior to reconstruct the SAM over the last 2000 years using temperature and drought-sensitive climate proxies. Our method does not assume a stationary relationship between the SAM and the proxy records and allows us to identify critical paleoclimate records and quantify reconstruction uncertainty through time. We find no evidence for a forced response in SAM variability prior to the 20th century. We do find the modern positive trend falls outside the 2σrange of the prior 2000 years at multidecadal time scales, supporting the inference that the SAM’s positive trend over the last several decades is a response to anthropogenic climate change.
Unlocking the general relationship between energy and entanglement spectra via the wormhole effect
Authors: Yan Zheng , Meng Zi Yang
Published: April 2023

Based on the path integral formulation of the reduced density matrix, we develop a scheme to overcome the exponential growth of computational complexity in reliably extracting low-lying entanglement spectrum from quantum Monte Carlo simulations. We test the method on the Heisenberg spin ladder with long entangled boundary between two chains and the results support the Li and Haldane’s conjecture on entanglement spectrum of topological phase. We then explain the conjecture via the wormhole effect in the path integral and show that it can be further generalized for systems beyond gapped topological phases. Our further simulation results on the bilayer antiferromagnetic Heisenberg model with 2D entangled boundary across the (2 + 1)D O(3) quantum phase transition clearly demonstrate the correctness of the wormhole picture. Finally, we state that since the wormhole effect amplifies the bulk energy gap by a factor of β, the relative strength of that with respect to the edge energy gap will determine the behavior of low-lying entanglement spectrum of the system.
In vivo bioluminescence imaging of natural bacteria within deep tissues via ATP-binding cassette sugar transporter
Authors: Zhang Qian , Song Bin , Xu Yanan , Yang Yunmin , Ji Jian , Cao Wenjun , Lu Jianping , Ding Jiali , Cao Haiting , Chu Binbin , Hong Jiaxu , Wang Houyu , He Yao
Published: April 2023

Most existing bioluminescence imaging methods can only visualize the location of engineered bacteria in vivo, generally precluding the imaging of natural bacteria. Herein, we leverage bacteria-specific ATP-binding cassette sugar transporters to internalize luciferase and luciferin by hitchhiking them on the unique carbon source of bacteria. Typically, the synthesized bioluminescent probes are made of glucose polymer (GP), luciferase, Cy5 and ICG-modified silicon nanoparticles and their substrates are made of GP and D-luciferin-modified silicon nanoparticles. Compared with bacteria with mutations in transporters, which hardly internalize the probes in vitro (i.e., ~2% of uptake rate), various bacteria could robustly engulf the probes with a high uptake rate of around 50%. Notably, the developed strategy enables ex vivo bioluminescence imaging of human vitreous containing ten species of pathogens collected from patients with bacterial endophthalmitis. By using this platform, we further differentiate bacterial and non-bacterial nephritis and colitis in mice, while their chemiluminescent counterparts are unable to distinguish them.