bluuebunny/crossref_metadata_2025 huggingface dataset:
A hybrid inductive learning-based and deductive reasoning-based 3-D path planning method in complex environments
Authors: Segato Alice , Calimeri Francesco , Testa Irene , Corbetta Valentina , Riva Marco , De Momi Elena
Published: May 2022

Traditional path planning methods, such as sampling-based and iterative approaches, allow for optimal path’s computation in complex environments. Nonetheless, environment exploration is subject to rules which can be obtained by domain experts and could be used for improving the search. The present work aims at integrating inductive techniques that generate path candidates with deductive techniques that choose the preferred ones. In particular, an inductive learning model is trained with expert demonstrations and with rules translated into a reward function, while logic programming is used to choose the starting point according to some domain expert’s suggestions. We discuss, as use case, 3-D path planning for neurosurgical steerable needles. Results show that the proposed method computes optimal paths in terms of obstacle clearance and kinematic constraints compliance, and is able to outperform state-of-the-art approaches in terms of safety distance-from-obstacles respect, smoothness, and computational time.
Littlewood-Paley-Stein Theory and Banach Spaces in the Inverse Gaussian Setting
Authors: Almeida Víctor , Betancor Jorge J. , Fariña Juan C. , Rodríguez-Mesa Lourdes
Published: May 2022

In this paper we consider Littlewood-Paley functions defined by the semigroups associated with the operator $\mathcal {A}=-\frac {1}{2}{\Delta }-x\nabla $
A
=
−

1

2

Δ
−
x
∇
in the inverse Gaussian setting for Banach valued functions. We characterize the uniformly convex and smooth Banach spaces by using $L^{p}(\mathbb R^{n},\gamma _{-1})$

L

p

(

ℝ

n

,

γ

−
1

)
- properties of the $\mathcal {A}$
A
-Littlewood-Paley functions. We also use Littlewood-Paley functions associated with $\mathcal {A}$
A
to characterize the Köthe function spaces with the UMD property.
Adverse childhood experiences and unhealthy lifestyles later in life: evidence from SHARE countries
Authors: Brugiavini A. , Buia R. E. , Kovacic M. , Orso C. E.
Published: May 2022

This paper investigates whether exposure to adverse experiences during childhood, such as physical and emotional abuse, affects the likelihood of unhealthy habits later in life. The novelty of our approach is twofold. First, we exploit the recently published data on adverse childhood experiences in 19 European countries from the Survey of Health, Ageing and Retirement (SHARE), which enables us to account for country-specific heterogeneity and investigate the long-term effects of exposure to adverse early-life circumstances (such as smoking, drinking, excess weight and obesity) on unhealthy lifestyles later in life. Second, we estimate the effect of childhood trauma on unhealthy lifestyles separately for European macro-regions using a clustering of countries emphasising cultural differences. Our results highlight the positive effect of exposure to adverse childhood experiences on the probability of unhealthy lifestyles in the long run. Harm from parents is associated with a higher probability of smoking in adulthood, while child neglect and a poor relationship with parents increase the probability of smoking later in life.
A concise review on the cultivation of microalgal biofilms for biofuel feedstock production
Authors: Patwardhan Sanchita Bipin , Pandit Soumya , Ghosh Dipankar , Dhar Dolly Wattal , Banerjee Srijoni , Joshi Sanket , Gupta Piyush Kumar , Lahiri Dibyajit , Nag Moupriya , Ruokolainen Janne , Ray Rina Rani , Kumar Kesari Kavindra
Published: May 2022

The enormous capability of microalgae for biomass production and co-products has recently been widely researched from a range of research approaches. Microalgae biomass has been discovered as a suitable feedstock for biofuel generation in the third generation. Although they may easily be cultivated in the laboratory, commercial cultivation involves several important considerations, including design, expense, contamination risk, and hygiene. This paper reviews some conventional microalgal cultivation methods along with some harvesting techniques. A short note on the disadvantages of conventional microalgal biofilm cultivation and the need for advanced cultivation techniques are also listed. Further, it highlights some of the modern techniques used for the cultivation of biofilm-based microalgae. It also gives brief information on the various factors affecting the formation of microalgal biofilm. A detailed description of the application of microalgal biofilm concerning biofuel generation is also reviewed.

Graphical abstract
Die Klimakrise als Lernanlass
Authors: Dinkelaker Jörg , Stimm Maria
Published: May 2022

Im vorliegenden Beitrag loten wir aus, inwiefern sich das Konzept der Lernanlässe dazu eignet, eine empirische Perspektive auf Konstellationen des Lernens Erwachsener im Horizont der Klimakrise zu eröffnen. Ausgehend von einer Kritik der einseitigen Orientierung von Konzepten der „Umweltbildung“ und der „Bildung für Nachhaltige Entwicklung“ an Lernnotwendigkeiten sichten wir Vorschläge zur theoretischen Bestimmung der Prozesse, in denen etwas zum Anlass von Lernen wird. Anhand exemplarischer Beobachtungen plädieren wir dafür, diese Bestimmungen aufzugreifen und um eine empirische Analyse der sozialen Kontexte zu erweitern, in denen die Klimafrage zum Gegenstand des Lernens Erwachsener wird.
Wellbeing and Social Network Characteristics in Rural Communities: Findings from a Cohort in Social Housing in Cornwall, United Kingdom
Authors: Long Emily , Stevens Sebastian , Topciu Raluca , Williams Andrew James , Taylor Timothy James , Morrissey Karyn
Published: May 2022

The mental wellbeing of those living in resource poor and rural localities is a public health priority. Despite evidence of a link between social networks and mental wellbeing, little is known about this relationship in the context of rural and resource poor environments. The current study uses novel social network methodology to investigate the extent to which social network size and composition is related to mental wellbeing in a social housing community in rural England. Data come from 88 individuals living in social housing in Cornwall. These participants are part of a larger study of 329 social housing households surveyed in 2017 and 2018. Mental wellbeing was measured by the Short Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS). A series of multivariable linear regression models were used to test associations between social network characteristics and mental wellbeing. Social network size was significantly associated with the SWEMWBS (b = 0.39, p < 0.01), such that individuals with larger networks reported better mental wellbeing, but after controlling for community social cohesion, this effect dissipated. Neither gender composition or talking with network members about health and wellbeing were significantly associated with the SWEMWBS. Findings suggest that both the quantity of social connections and perceptions of community cohesion are moderately associated with mental wellbeing in rural and resource poor localities. As such, efforts to improve mental wellbeing would benefit from targeting multiple aspects of social relationships, rather than focusing solely on increasing the size of individuals’ social networks.
Telemedicine for Patient Management in Remote Areas and Underserved Populations
Authors: Mohammadzadeh Niloofar , Rezayi Sorayya , Saeedi Soheila
Published: May 2022

Access to care services in remote areas is challenging. The use of telemedicine technology in these areas facilitates access to health care. This study aimed to summarize the current research on telemedicine in remote areas such as mountains and forests. A systematic search was conducted in databases including Medline (through PubMed), Scopus, IEEE Xplore Digital Library, and ISI Web of Science to identify relevant studies published until May 12, 2021. Screening of retrieved articles for selection and inclusion in the study was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes extension for Scoping Reviews (PRISMA-ScR) checklist. A total of 807 articles were identified after removing duplicates, from which 20 studies meeting our inclusion criteria were selected. Challenges, opportunities, and equipment required to use telemedicine in remote areas were extracted from the selected studies. The results revealed that telemedicine implementation in remote areas had many challenges, including harsh weather conditions, Internet connectivity problems, difficult equipment transportation, and ethical issues. Telemedicine also has many benefits, such as cost and time savings for patients, improving patients’ quality of life, and improving patient satisfaction. Telemedicine for inhabitants of forested and mountainous areas facilitates rapid access to health care and enhances patient satisfaction. Distinguishing advantages and barriers as well as reducing restrictions will have an essential role in accelerating the use of this technology.
Fluid–structure interactions of energy-harvesting membrane hydrofoils
Authors: Mathai Varghese , Tzezana Gali Alon , Das Asimanshu , Breuer Kenneth S.
Published: May 2022

We study the kinematics, dynamics and flow fields generated by an oscillating, compliant membrane hydrofoil extracting energy from a uniform water stream at a chord-based Reynolds number

$Re \approx 3 \times 10^4$

. Hydrodynamic forces during the foil's motion cause the membrane to dynamically morph its shape, effectively increasing the camber during the oscillation cycle. The membrane's deflection is modelled using the Young–Laplace equation, with pressure term approximated from thin-airfoil theory. Simultaneous tracking of the membrane deformation and the surrounding flow field using laser profiling and particle image velocimetry, respectively, reveals the role of dynamic cambering in stabilizing the leading-edge vortices on the membrane. In this regime of operation, we obtain up to 160 % higher power extraction when compared to a rigid, symmetric hydrofoil. The present work provides a demonstration of how passive compliance of soft materials interacting with fluids may be exploited in tidal and fluvial energy extraction.
A sensitive search for water masers associated with star formation regions in the Local Group Galaxy NGC 6822
Authors: Flanagan C. J. P. , Ellingsen S. P. , Cole A. A.
Published: May 2022

We report the results of a sensitive search for water maser emission in the Local Group Galaxy NGC 6822 with the Karl G. Jansky Very Large Array. The observations provide tentative single-epoch detections of four candidates, associated with two infrared-bright star formation regions (Hubble I/III and Hubble IV). The candidate maser detections are all offset from the velocity range where strong emission from Hi neutral gas is observed towards NGC 6822, with the closest offset by

$\sim\!40\, \mathrm{kms}^{-1}$

. Our observations include the location of NL1K, a previous tentative water maser detection in NGC 6822. We do not detect any emission from this location with a sensitivity limit approximately a factor of 5 better than the original Sardina Radio Telescope observations.
ON THE DIVISIBILITY AMONG POWER LCM MATRICES ON GCD-CLOSED SETS
Authors: ZHU GUANGYAN , LI MAO
Published: May 2022

Let
$a,b$
and n be positive integers and let
$S=\{x_1, \ldots , x_n\}$
be a set of n distinct positive integers. For
${x\in S}$
, define
$G_{S}(x)=\{d\in S: d<x, \,d\mid x \ \mathrm {and} \ (d\mid y\mid x, y\in S)\Rightarrow y\in \{d,x\}\}$
. Denote by
$[S^a]$
the
$n\times n$
matrix having the ath power of the least common multiple of
$x_i$
and
$x_j$
as its
$(i,j)$
-entry. We show that the bth power matrix
$[S^b]$
is divisible by the ath power matrix
$[S^a]$
if
$a\mid b$
and S is gcd closed (that is,
$\gcd (x_i, x_j)\in S$
for all integers i and j with
$1\le i, j\le n$
) and
$\max _{x\in S} \{|G_S (x)|\}=1$
. This confirms a conjecture of Shaofang Hong [‘Divisibility properties of power GCD matrices and power LCM matrices’, Linear Algebra Appl.428 (2008), 1001–1008].
Development and the art of nutritional maintenance
Authors: Gardner David S. , Gray Clint
Published: May 2022

Development from early conceptus to a complex, multi-cellular organism is a highly ordered process that is dependent on an adequate supply of nutrients. During this process, the pattern of organ growth is robust, driven by a genetic blueprint and matched to anticipated body mass with high precision and with built-in physiological reserve capacity. This apparent canalisation of the developmental process is particularly sensitive to variation in environmental stimuli, such as inappropriate drug or hormone exposure, or pattern of nutrient delivery. Significant variation in any of these factors can profoundly affect fetal and neonatal growth patterns, with later detriment for physiological function and/or reserve capacity of the resultant adult, with potential health impact. This paradigm shift in science has become known as the Developmental Origins of Health and Disease (DOHaD). Over the last 30 years, many animal and clinical studies have vastly expanded our fundamental knowledge of developmental biology, particularly in the context of later effects on health. In this horizons article, we discuss DOHaD through the lens of nutritional quality (e.g. micronutrient, amino acid, NSP intake). The concept of ‘Quality’ was considered undefinable by Robert Persig in his book, ‘Zen and the Art of Motorcycle Maintenance’. Here, development and the art of nutritional maintenance will define quality in terms of the pattern of nutrient intake, the quality of development and how each interact to influence later health outcomes.
Online harms? Suicide-related online experience: a UK-wide case series study of young people who die by suicide
Authors: Rodway C. , Tham S. G. , Richards N. , Ibrahim S. , Turnbull P. , Kapur N. , Appleby L.
Published: May 2022

Background

Few studies have examined online experience by young people who die by suicide.

Methods

A 3-year UK-wide consecutive case series of all young people aged 10–19 who died by suicide, based on national mortality data. We extracted information on the antecedents of suicide of 544 of these 595 deaths (91%) from official investigations, mainly inquests.

Results

Suicide-related online experience was reported in 24% (n = 128/544) of suicide deaths in young people between 2014 and 2016, equivalent to 43 deaths per year, and was more common in girls than boys (OR 1.87, 95% CI 1.23–2.85, p = 0.003) and those identifying as LGBT (OR 2.35, 95% CI 1.10–5.05, p = 0.028). Searching for information about method was most common (n = 68, 13%), followed by posting suicidal ideas online (n = 57, 10%). Self-harm, bereavement (especially by suicide), social isolation, and mental and physical ill-health were more likely in those known to have suicide-related online experience compared to those who did not. 29 (5%) were bullied online, more often girls (OR 2.84, 1.34–6.04, p = 0.007). Online bullying often accompanied face-to-face bullying (n = 16/29, 67%).

Conclusions

Suicide-related online experience is a common, but likely underestimated, antecedent to suicide in young people. Although its causal role is unclear, it may influence suicidality in this population. Mental health professionals should be aware that suicide-related online experience – not limited to social media – is a potential risk for young patients, and may be linked to experiences offline. For public health, wider action is required on internet regulation and support for children and their families.
Portraiture, Biography and Public Histories
Authors: Jordanova Ludmilla
Published: May 2022

Portraits and biographies play a central role in engaging non-specialists with the past, and hence invite careful scrutiny. Major enterprises, such as the National Portrait Gallery in London and the Dictionary of National Biography, in both its original and Oxford versions, provide rich examples for reflecting on public history and on the relationships between types of writing about past times. These issues relate to literature as well as to history, given the prominence of biographies of literary figures, and the role of literary scholars as authors of biographies. Using materials concerning the artist John Collier (1850–1934), the publisher George Smith (1824–1901) and the surgeon James Paget (1814–1899), this article examines the relationships between portraits and biographies and the types of insight they afford. Colin Matthew's innovation of including portraits in the Oxford Dictionary, together with his own scholarship on William Gladstone (1809–1898), including his portraits, provide the basis for suggestions about the role of work when representing lives, including those of historians. Public history can only benefit from research practices being discussed in an accessible manner, as attempted here.
Rainfall Generation Revisited: Introducing CoSMoS‐2s and Advancing Copula‐Based Intermittent Time Series Modeling
Authors: Papalexiou Simon Michael
Published: May 2022

What elements should a parsimonious model reproduce at a single scale to precisely simulate rainfall at many scales? We posit these elements are: (a) the probability of dry and linear correlation structure of the wet/dry sequence as a proxy reproducing the distribution of wet/dry spells, and (b) the marginal distribution of nonzero rainfall and its correlation structure. We build a two‐state rainfall model, the CoSMoS‐2s, that explicitly reproduces these elements and is easily applicable at any timescale. Additionally, the paper: (a) introduces the Generalized Exponential () distribution system comprising six flexible distributions with desired properties to describe nonzero rainfall and facilitate time series generation; (b) extends the CoSMoS framework to allow simulations with negative correlations; (c) simplifies the generation of binary sequences with any correlation structure by analytical approximations; (d) introduces the rank‐based CoSMoS‐2s that preserves Spearman's correlations, has an analytical formulation, and is also applicable for infinite variance time series, (e) introduces the copula‐based CoSMoS‐2s enabling intermittent times series generation with nonzero values having the dependence structure of any desired copula, and (f) offers conceptual generalizations for rainfall modeling and beyond, with specific ideas for future improvements and extensions. The CoSMoS‐2s is tested using four long hourly rainfall records; the simulations reproduce rainfall properties at multiple scales including the wet/dry spells, probability of dry, characteristics of nonzero rainfall, and the behavior of extremes.
Palmitoylated prolactin-releasing peptide treatment had neuroprotective but not anti-obesity effect in fa/fa rats with leptin signaling disturbances
Authors: Mráziková Lucia , Hojná Silvie , Pačesová Andrea , Hrubá Lucie , Strnadová Veronika , Neprašová Barbora , Železná Blanka , Kuneš Jaroslav , Maletínská Lenka
Published: May 2022

Background/Objective

Anorexigenic palmitoylated prolactin-releasing peptide (palm11-PrRP) is able to act centrally after peripheral administration in rat and mouse models of obesity, type 2 diabetes mellitus and/or neurodegeneration. Functional leptin and intact leptin signaling pathways are necessary for the body weight reducing and glucose tolerance improving effect of palm11-PrRP. We have previously shown that palm11-PrRP31 had glucose-lowering properties but not anti-obesity effect in Koletsky rats with leptin signaling disturbances, so improvements in glucose metabolism appear to be completely independent of leptin signaling. The purpose of this study was to describe relationship between metabolic and neurodegenerative pathologies and explore if palm11-PrRP31 could ameliorate them in obese fa/fa rat model with leptin signaling disruption.

Subject/Methods

The fa/fa rats and their age-matched lean controls at the age 32 weeks were used for this study. The rats were infused for 2 months with saline or palm11-PrRP31 (n = 7–8 per group) at a dose of 5 mg/kg per day using Alzet osmotic pumps. During the dosing period food intake and body weight were monitored. At the end of experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected and arterial blood pressure was measured. Then, markers of leptin and insulin signaling, Tau phosphorylation, neuroinflammation, and synaptogenesis were measured by western blotting and immunohistochemistry.

Results

Fa/fa rats developed obesity, mild glucose intolerance, and peripheral insulin resistance but not hypertension while palm11-PrRP31 treatment neither lowered body weight nor attenuated glucose tolerance but ameliorated leptin and insulin signaling and synaptogenesis in hippocampus.

Conclusion

We demonstrated that palm11-PrRP31 had neuroprotective features without anti-obesity and glucose lowering effects in fa/fa rats. This data suggest that this analog has the potential to exert neuroprotective effect despite of leptin signaling disturbances in this rat model.
Estradiol-mediated inhibition of DNMT1 decreases p53 expression to induce M2-macrophage polarization in lung cancer progression
Authors: Chen Yung-Ching , Young Ming-Jer , Chang Hui-Ping , Liu Chia-Yu , Lee Chia-Chi , Tseng Yau-Lin , Wang Yi-Ching , Chang Wen-Chang , Hung Jan-Jong
Published: May 2022

Previous studies indicate that estrogen positively regulates lung cancer progression. Understanding the reasons will be beneficial for treating women with lung cancer in the future. In this study, we found that tumor formation was more significant in female EGFRL858R mice than in male mice. P53 expression levels were downregulated in the estradiol (E2)-treated lung cancer cells, female mice with EGFRL858R-induced lung cancer mice, and premenopausal women with lung cancer. E2 increased DNA methyltransferase 1 (DNMT1) expression to enhance methylation in the TP53 promoter, which led to the downregulation of p53. Overexpression of GFP-p53 decreased DNMT1 expression in lung cancer cells. TP53 knockout in mice with EGFRL858R-induced lung cancer not only changed gene expression in cancer cells but also increased the polarization of M2 macrophages by increasing C–C motif chemokine ligand 5 (CCL5) expression and decreasing growth differentiation factor 15 (GDF15) expression. The TP53 mutation rate was increased in females with late-stage but not early-stage lung cancer compared to males with lung cancer. In conclusion, E2-induced DNMT1 and p53 expression were negatively regulated each other in females with lung cancer, which not only affected cancer cells but also modulated the tumor-associated microenvironment, ultimately leading to a poor prognosis.
Reversing insufficient photothermal therapy-induced tumor relapse and metastasis by regulating cancer-associated fibroblasts
Authors: Li Xin , Yong Tuying , Wei Zhaohan , Bie Nana , Zhang Xiaoqiong , Zhan Guiting , Li Jianye , Qin Jiaqi , Yu Jingjing , Zhang Bixiang , Gan Lu , Yang Xiangliang
Published: May 2022

Insufficient tumor accumulation and distribution of photosensitizers as well as low antitumor immunity severely restrict the therapeutic efficacy of photothermal therapy (PTT). Cancer-associated fibroblasts (CAFs) play a key role in tumor extracellular matrix (ECM) remodeling and immune evasion. Reshaping tumor microenvironment via CAF regulation might provide a potential approach for complete tumor elimination in combination with PTT. Here, tumor cell-derived microparticles co-delivering calcipotriol and Indocyanine green (Cal/ICG@MPs) are developed to modulate CAFs for improved PTT efficacy. Cal/ICG@MPs efficiently target tumor tissues and regulate CAFs to reduce tumor ECM, resulting in enhanced tumor accumulation and penetration of ICG to generate strong PTT efficacy and activate CD8+ T cell-mediated antitumor immunity. In addition, Cal/ICG@MPs-triggered CAF regulation enhances tumor infiltration of CD8+ T cells and ameliorates CAF-induced antigen-mediated activation-induced cell death of tumor-specific CD8+ T cells in response to PTT, eliciting long-term antitumor immune memory to inhibit tumor recurrence and metastasis. Our results support Cal/ICG@MPs as a promising drug to improve PTT efficacy in cancer treatment.
Elimination of human rabies in Goa, India through an integrated One Health approach
Authors: Gibson A. D. , Yale G. , Corfmat J. , Appupillai M. , Gigante C. M. , Lopes M. , Betodkar U. , Costa N. C. , Fernandes K. A. , Mathapati P. , Suryawanshi P. M. , Otter N. , Thomas G. , Ohal P. , Airikkala-Otter I. , Lohr F. , Rupprecht C. E. , King A. , Sutton D. , Deuzeman I. , Li Y. , Wallace R. M. , Mani R. S. , Gongal G. , Handel I. G. , Bronsvoort M. , Naik V. , Desai S. , Mazeri S. , Gamble L. , Mellanby R. J.
Published: May 2022

Dog-mediated rabies kills tens of thousands of people each year in India, representing one third of the estimated global rabies burden. Whilst the World Health Organization (WHO), World Organization for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO) have set a target for global dog-mediated human rabies elimination by 2030, examples of large-scale dog vaccination programs demonstrating elimination remain limited in Africa and Asia. We describe the development of a data-driven rabies elimination program from 2013 to 2019 in Goa State, India, culminating in human rabies elimination and a 92% reduction in monthly canine rabies cases. Smartphone technology enabled systematic spatial direction of remote teams to vaccinate over 95,000 dogs at 70% vaccination coverage, and rabies education teams to reach 150,000 children annually. An estimated 2249 disability-adjusted life years (DALYs) were averted over the program period at 526 USD per DALY, making the intervention ‘very cost-effective’ by WHO definitions. This One Health program demonstrates that human rabies elimination is achievable at the state level in India.
Noninvasive urinary protein signatures associated with colorectal cancer diagnosis and metastasis
Authors: Sun Yulin , Guo Zhengguang , Liu Xiaoyan , Yang Lijun , Jing Zongpan , Cai Meng , Zheng Zhaoxu , Shao Chen , Zhang Yefan , Sun Haidan , Wang Li , Wang Minjie , Li Jun , Tian Lusong , Han Yue , Zou Shuangmei , Gao Jiajia , Zhao Yan , Nan Peng , Xie Xiufeng , Liu Fang , Zhou Lanping , Sun Wei , Zhao Xiaohang
Published: May 2022

Currently, imaging, fecal immunochemical tests (FITs) and serum carcinoembryonic antigen (CEA) tests are not adequate for the early detection and evaluation of metastasis and recurrence in colorectal cancer (CRC). To comprehensively identify and validate more accurate noninvasive biomarkers in urine, we implement a staged discovery-verification-validation pipeline in 657 urine and 993 tissue samples from healthy controls and CRC patients with a distinct metastatic risk. The generated diagnostic signature combined with the FIT test reveals a significantly increased sensitivity (+21.2% in the training set, +43.7% in the validation set) compared to FIT alone. Moreover, the generated metastatic signature for risk stratification correctly predicts over 50% of CEA-negative metastatic patients. The tissue validation shows that elevated urinary protein biomarkers reflect their alterations in tissue. Here, we show promising urinary protein signatures and provide potential interventional targets to reliably detect CRC, although further multi-center external validation is needed to generalize the findings.
Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia
Authors: Baran Natalia , Lodi Alessia , Dhungana Yogesh , Herbrich Shelley , Collins Meghan , Sweeney Shannon , Pandey Renu , Skwarska Anna , Patel Shraddha , Tremblay Mathieu , Kuruvilla Vinitha Mary , Cavazos Antonio , Kaplan Mecit , Warmoes Marc O. , Veiga Diogo Troggian , Furudate Ken , Rojas-Sutterin Shanti , Haman Andre , Gareau Yves , Marinier Anne , Ma Helen , Harutyunyan Karine , Daher May , Garcia Luciana Melo , Al-Atrash Gheath , Piya Sujan , Ruvolo Vivian , Yang Wentao , Shanmugavelandy Sriram Saravanan , Feng Ningping , Gay Jason , Du Di , Yang Jun J. , Hoff Fieke W. , Kaminski Marcin , Tomczak Katarzyna , Eric Davis R. , Herranz Daniel , Ferrando Adolfo , Jabbour Elias J. , Emilia Di Francesco M. , Teachey David T. , Horton Terzah M. , Kornblau Steven , Rezvani Katayoun , Sauvageau Guy , Gagea Mihai , Andreeff Michael , Takahashi Koichi , Marszalek Joseph R. , Lorenzi Philip L. , Yu Jiyang , Tiziani Stefano , Hoang Trang , Konopleva Marina
Published: May 2022

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.
Structural insights into the mechanism of pancreatic KATP channel regulation by nucleotides
Authors: Wang Mengmeng , Wu Jing-Xiang , Ding Dian , Chen Lei
Published: May 2022

ATP-sensitive potassium channels (KATP) are metabolic sensors that convert the intracellular ATP/ADP ratio to the excitability of cells. They are involved in many physiological processes and implicated in several human diseases. Here we present the cryo-EM structures of the pancreatic KATP channel in both the closed state and the pre-open state, resolved in the same sample. We observe the binding of nucleotides at the inhibitory sites of the Kir6.2 channel in the closed but not in the pre-open state. Structural comparisons reveal the mechanism for ATP inhibition and Mg-ADP activation, two fundamental properties of KATP channels. Moreover, the structures also uncover the activation mechanism of diazoxide-type KATP openers.
The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation
Authors: Kumar Binod , Field Natania S. , Kim Dale D. , Dar Asif A. , Chen Yanqun , Suresh Aishwarya , Pastore Christopher F. , Hung Li-Yin , Porter Nadia , Sawada Keisuke , Shah Palak , Elbulok Omar , Moser Emily K. , Herbert De’Broski R. , Oliver Paula M.
Published: May 2022

Antigen encounter directs CD4+ T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4+ T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.
PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression
Authors: Lee Keun-Woo , Yeo So-Young , Gong Jeong-Ryeol , Koo Ok-Jae , Sohn Insuk , Lee Woo Yong , Kim Hee Cheol , Yun Seong Hyeon , Cho Yong Beom , Choi Mi-Ae , An Sugyun , Kim Juhee , Sung Chang Ohk , Cho Kwang-Hyun , Kim Seok-Hyung
Published: May 2022

Although stromal fibroblasts play a critical role in cancer progression, their identities remain unclear as they exhibit high heterogeneity and plasticity. Here, a master transcription factor (mTF) constructing core-regulatory circuitry, PRRX1, which determines the fibroblast lineage with a myofibroblastic phenotype, is identified for the fibroblast subgroup. PRRX1 orchestrates the functional drift of fibroblasts into myofibroblastic phenotype via TGF-β signaling by remodeling a super-enhancer landscape. Such reprogrammed fibroblasts have myofibroblastic functions resulting in markedly enhanced tumorigenicity and aggressiveness of cancer. PRRX1 expression in cancer-associated fibroblast (CAF) has an unfavorable prognosis in multiple cancer types. Fibroblast-specific PRRX1 depletion induces long-term and sustained complete remission of chemotherapy-resistant cancer in genetically engineered mice models. This study reveals CAF subpopulations based on super-enhancer profiles including PRRX1. Therefore, mTFs, including PRRX1, provide another opportunity for establishing a hierarchical classification system of fibroblasts and cancer treatment by targeting fibroblasts.
Anomalous size effect on yield strength enabled by compositional heterogeneity in high-entropy alloy nanoparticles
Authors: Yan Jingyuan , Yin Sheng , Asta Mark , Ritchie Robert O. , Ding Jun , Yu Qian
Published: May 2022

High-entropy alloys (HEAs), although often presumed to be random solid solutions, have recently been shown to display nanometer-scale variations in the arrangements of their multiple chemical elements. Here, we study the effects of this compositional heterogeneity in HEAs on their mechanical properties using in situ compression testing in the transmission electron microscope (TEM), combined with molecular dynamics simulations. We report an anomalous size effect on the yield strength in HEAs, arising from such compositional heterogeneity. By progressively reducing the sample size, HEAs initially display the classical “smaller-is-stronger” phenomenon, similar to pure metals and conventional alloys. However, as the sample size is decreased below a critical characteristic length (~180 nm), influenced by the size-scale of compositional heterogeneity, a transition from homogeneous deformation to a heterogeneous distribution of planar slip is observed, coupled with an anomalous “smaller-is-weaker” size effect. Atomic-scale computational modeling shows these observations arise due to compositional fluctuations over a few nanometers. These results demonstrate the efficacy of influencing mechanical properties in HEAs through control of local compositional variations at the nanoscale.
High-performance photocatalytic nonoxidative conversion of methane to ethane and hydrogen by heteroatoms-engineered TiO2
Authors: Zhang Wenqing , Fu Cenfeng , Low Jingxiang , Duan Delong , Ma Jun , Jiang Wenbin , Chen Yihong , Liu Hengjie , Qi Zeming , Long Ran , Yao Yingfang , Li Xiaobao , Zhang Hui , Liu Zhi , Yang Jinlong , Zou Zhigang , Xiong Yujie
Published: May 2022

Nonoxidative coupling of methane (NOCM) is a highly important process to simultaneously produce multicarbons and hydrogen. Although oxide-based photocatalysis opens opportunities for NOCM at mild condition, it suffers from unsatisfying selectivity and durability, due to overoxidation of CH4 with lattice oxygen. Here, we propose a heteroatom engineering strategy for highly active, selective and durable photocatalytic NOCM. Demonstrated by commonly used TiO2 photocatalyst, construction of Pd–O4 in surface reduces contribution of O sites to valence band, overcoming the limitations. In contrast to state of the art, 94.3% selectivity is achieved for C2H6 production at 0.91 mmol g–1 h–1 along with stoichiometric H2 production, approaching the level of thermocatalysis at relatively mild condition. As a benchmark, apparent quantum efficiency reaches 3.05% at 350 nm. Further elemental doping can elevate durability over 24 h by stabilizing lattice oxygen. This work provides new insights for high-performance photocatalytic NOCM by atomic engineering.
DVL1 and DVL3 require nuclear localisation to regulate proliferation in human myoblasts
Authors: Pruller Johanna , Figeac Nicolas , Zammit Peter S.
Published: May 2022

WNT signalling is essential for regulating a diverse range of cellular processes. In skeletal muscle, the WNT pathway plays crucial roles in maintenance of the stem cell pool and myogenic differentiation. Focus is usually directed at examining the function of central components of the WNT pathway, including β-CATENIN and the GSK3β complex and TCF/LEF transcription factors, in tissue homeostasis and cancer. Other core components of the WNT pathway though, are three dishevelled (DVL) proteins: membrane associated proteins that propagate WNT signalling from membrane to nucleus. Here we examined DVL function in human myogenesis and the muscle-related cancer alveolar rhabdomyosarcoma. We demonstrate that DVL1 and DVL3 are necessary for efficient proliferation in human myoblasts and are important for timely myogenic differentiation. DVL1 and DVL3 also contribute to regulation of proliferation in rhabdomyosarcoma. DVL1 or DVL3 must be present in the nucleus to regulate proliferation, but they operate through different protein domains: DVL3 requires the DIX and PDZ domains, while DVL1 does not. Importantly, DVL1 and DVL3 activity is independent of markedly increased translocation of β-CATENIN to the nucleus, normally a hallmark of active canonical WNT signalling.
Preprocess dependence of optical properties of ensembles and single siphonaxanthin-containing major antenna from the marine green alga Codium fragile
Authors: Brotosudarmo Tatas Hardo Panintingjati , Wittmann Bernd , Seki Soichiro , Fujii Ritsuko , Köhler Jürgen
Published: May 2022

The siphonaxanthin-siphonein-Chl-a/b-protein (SCP) is the light-harvesting complex of the marine alga Codium fragile. Its structure resembles that of the major light-harvesting complexes of higher plants, LHC II, yet it features a reversed Chl a:Chl b ratio and it accommodates other variants of carotenoids. We have recorded the fluorescence emission spectra and fluorescence lifetimes from ensembles and single SCP complexes for three different scenarios of handling the samples. While the data obtained from ensembles of SCP complexes yield equivalent results, those obtained from single SCP complexes featured significant differences as a function of the sample history. We ascribe this discrepancy to the different excitation intensities that have been used for ensemble and single complex spectroscopy, and conclude that the SCP complexes undergo an aging process during storage. This process is manifested as a lowering of energetic barriers within the protein, enabling thermal activation of conformational changes at room temperature. This in turn leads to the preferential population of a red-shifted state that features a significant decrease of the fluorescence lifetime.
Freshwater influx to the Eastern Mediterranean Sea from the melting of the Fennoscandian ice sheet during the last deglaciation
Authors: Vadsaria Tristan , Zaragosi Sébastien , Ramstein Gilles , Dutay Jean-Claude , Li Laurent , Siani Giuseppe , Revel Marie , Obase Takashi , Abe-Ouchi Ayako
Published: May 2022

Between the Last Glacial Maximum and the mid-Holocene, the Mediterranean Sea experienced major hydrological changes. The deposition of the last sapropel, S1, during the Early Holocene is a consequence of these changes. In order to cause anoxia in the Eastern Mediterranean Sea (EMS) bottom water, a long preconditioning period of a few thousand years would need to occur throughout the deglaciation prior to S1. It is generally believed that this freshwater was of North Atlantic origin, later supplemented by the African Humid period (AHP). Here, we investigate another potentially important source of freshwater to the EMS: the Fennoscandian ice sheet (FIS) meltwater, running into the Caspian and Black Seas. A few scenarios of continental hydrologic perturbation have been developed to drive a high-resolution Mediterranean Sea general circulation model. We demonstrate that, during the last deglaciation, FIS meltwater flowing into the Black Sea reduced surface salinity and ventilation over the main convection areas in the EMS. By including continental hydrological changes, a more consistent framework is produced to characterize the hydrology of the Mediterranean Sea during the last deglaciation and the Early Holocene.
Vibration velocity and frequency characteristics of surrounding rock of adjacent tunnel under blasting excavation
Authors: Luo Yi , Gong Hangli , Qu Dengxing , Zhang Xueping , Tao Yuhang , Li Xinping
Published: May 2022

The aim of this study is to improve the accuracy of response prediction and safety evaluation of blasting vibration of a deeply-buried tunnel group. For this purpose, the expression of frequency-domain and blasting vibration velocity spectra for the equivalent blasting load in multiple holes was derived through theoretical analysis, and propagation and attenuation of the primary frequency of blasting vibration of multiple cutting holes and caving holes in the infinite rock mass were explored. Response characteristics of vibration frequency spectra in rock surrounding of the adjacent tunnel induced by full-section blasting excavation of the tunnel under the high in situ stress were studied using the dynamic finite element method. The research indicates that blasting vibration waves have the greatest influences on the adjacent tunnel at the haunch in the side facing the blasting, where the vibration velocity is inversely proportional to the spacing between tunnels and directly proportional to the tunnel diameter. The centroid frequency increases with the increase of the spacing between tunnels and tunnel diameter. Furthermore, vibration velocity spectra at the most affected location (namely the haunch) in the side facing blasting of the adjacent tunnel under different conditions were derived. The coincidence of the theoretical formula was verified by comparing measured data of blasting of diversion tunnels in Pubugou Hydropower Station (Sichuan Province, China). The research results can provide theoretical guidance and reference for the prediction of blasting vibration response of similar projects in the future.
Structure-guided affinity maturation of a novel human antibody targeting the SARS-CoV-2 nucleocapsid protein
Authors: Wang Zhihong , Hu Naijing , Zhou Yangyihua , Shi Ning , Shen Beifen , Luo Longlong , Feng Jiannan
Published: May 2022

The continuous mutation of SARS-CoV-2 has presented enormous challenges to global pandemic prevention and control. Recent studies have shown evidence that the genome sequence of SARS-CoV-2 nucleocapsid proteins is relatively conserved, and their biological functions are being confirmed. There is increasing evidence that the N protein will not only provide a specific diagnostic marker but also become an effective treatment target. In this study, 2G4, which specifically recognizes the N protein, was identified by screening a human phage display library. Based on the computer-guided homology modelling and molecular docking method used, the 3-D structures for the 2G4 scFv fragment (VH-linker-VL structure, with (G4S)3 as the linker peptide in the model), SARS-CoV-2 N protein and its complex were modelled and optimized with a suitable force field. The binding mode and key residues of the 2G4 and N protein interaction were predicted, and three mutant antibodies (named 2G4-M1, 2G4-M2 and 2G4-M3) with higher affinity were designed theoretically. Using directed point mutant technology, the three mutant antibodies were prepared, and their affinity was tested. Their affinity constants of approximately 0.19 nM (2G4-M1), 0.019 nM (2G4-M2) and 0.075 nM (2G4-M3) were at least one order of magnitude lower than that of the parent antibody (3 nM; 2G4, parent antibody), as determined using a biolayer interferometry (BLI) assay. It is expected that high-affinity candidates will be used for diagnosis and even as potential therapeutic drugs for the SARS-CoV-2 pandemic.
Anxiety among pregnant women during the first wave of the COVID-19 pandemic in Poland
Authors: Ilska Michalina , Brandt-Salmeri Anna , Kołodziej-Zaleska Anna , Preis Heidi , Rehbein Emily , Lobel Marci
Published: May 2022

Although anxiety is common because of the transitional nature of the perinatal period, particularly high levels of anxiety have been observed in some studies of pregnant women during the pandemic. The purpose of this study was to evaluate the severity of anxiety among pregnant women during the first wave of the COVID-19 pandemic in Poland, and factors associated with it. Cross-sectional study with a total of 1050 pregnant women recruited via social media in Poland during the first wave of the COVID-19 pandemic, from March 1 until June 1, 2020. The survey included validated psychological measures: the GAD-7 (anxiety), the PREPS (pandemic stress), with two subscales: preparedness and infection stress, and obstetric, sociodemographic and COVID-19 related variables. T-tests, ANOVAs, and hierarchical binary logistic regression for dichotomized GAD-7 scores (minimal or mild vs. moderate or severe) were used. Over a third of respondents experienced moderate or severe levels of anxiety. Predictors of moderate or severe anxiety were non-pandemic related factors like unplanned pregnancy and emotional and psychiatric problems, as well as pandemic related pregnancy stress. Levels of anxiety among pregnant women during the first wave of the COVID-19 pandemic in Poland exceeded pre-pandemic norms. Findings suggest that prior psychiatric conditions, unplanned pregnancy, and elevated pandemic-related pregnancy stress due to concerns about infection or poor preparation for birth contributed to the risk of high anxiety in Polish pregnant women during the pandemic onset. Given the harmful effects of antenatal anxiety on the health and well-being of mothers and their children, psychotherapeutic interventions, efforts to alleviate pregnant women’s stress, and training in adaptive ways to cope with stress are vital to reduce the prevalence of maternal anxiety and its potential consequences during this global crisis.
In silico assessment of electrophysiological neuronal recordings mediated by magnetoelectric nanoparticles
Authors: Bok Ilhan , Haber Ido , Qu Xiaofei , Hai Aviad
Published: May 2022

Magnetoelectric materials hold untapped potential to revolutionize biomedical technologies. Sensing of biophysical processes in the brain is a particularly attractive application, with the prospect of using magnetoelectric nanoparticles (MENPs) as injectable agents for rapid brain-wide modulation and recording. Recent studies have demonstrated wireless brain stimulation in vivo using MENPs synthesized from cobalt ferrite (CFO) cores coated with piezoelectric barium titanate (BTO) shells. CFO–BTO core–shell MENPs have a relatively high magnetoelectric coefficient and have been proposed for direct magnetic particle imaging (MPI) of brain electrophysiology. However, the feasibility of acquiring such readouts has not been demonstrated or methodically quantified. Here we present the results of implementing a strain-based finite element magnetoelectric model of CFO–BTO core–shell MENPs and apply the model to quantify magnetization in response to neural electric fields. We use the model to determine optimal MENPs-mediated electrophysiological readouts both at the single neuron level and for MENPs diffusing in bulk neural tissue for in vivo scenarios. Our results lay the groundwork for MENP recording of electrophysiological signals and provide a broad analytical infrastructure to validate MENPs for biomedical applications.