bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-interventional Study Evaluating the Mobilization of Stem Cells by Plerixafor Before Salvage Autologous Stem Cell Transplant in Relapsed Multiple Myeloma (IFM-2015-03)
Authors: van de Wyngaert Zoe , Malard Florent , Hulin Cyrille , Caillot Denis , Mariette Clara , Facon Thierry , Touzeau Cyrille , Perrot Aurore , Moreau Philippe , Hebraud Benjamin , Kanouni Tarik , Heshmati Farhad , Lebon Delphine , Mohty Mohamad , Chabannon Christian
Published: February 2023

Introduction

Despite the implementation of new therapeutic agents, management of relapsed multiple myeloma (MM) remains a challenge. Salvage autologous hematopoietic cell transplant (AHCT) remains a valid therapeutic option for eligible patients who achieve prolonged response after a first AHCT. However, a second graft is not always available, and these patients may need a second mobilization.

Patients and Methods

This prospective, non-interventional, multicenter study aimed to collect data on the feasibility of salvage AHCT using a plerixafor-based hematopoietic cell mobilization in relapsed MM, according to the plerixafor label in France. Adult patients with relapsed MM eligible for a second AHCT and mobilized using granulocyte- colony stimulating factor (G-CSF) and plerixafor were included.

Results

Of the 23 patients, 17 achieved a successful hematopoietic cell mobilization and 13 were able to proceed to a second AHCT. Median age was 62.9 years (min–max 51–71). Ten patients (77%) were male. Eleven (85%) received AHCT as a third-line treatment or more. Median time between first and second AHCT was 5.4 years (range, 2.6–16.3). Among 18 evaluable patients, mobilization was successful for 17 (94%) of them [95% CI 84–100], with no reported side effects. Among the 13 patients who underwent salvage AHCT, the median time to engraftment was 14 days (min–max 11–29). One-year progression-free and overall survival were 88.9% [95% CI 43.3–98.4] and 100%, respectively.

Conclusion

This study demonstrated that plerixafor allows safe and efficient mobilization in relapsed MM patients who are candidates for a salvage AHCT.

Trial Registration

NCT02439476 Registered 8 May 2015, https://clinicaltrials.gov/ct2/show/NCT02439476.
Socioeconomic Determinants of Household Size in Bangladesh: Evidence from the Bangladesh Demographic and Health Survey Data
Authors: Islam Md. Akhtarul , Mahmud Md. Saleh , Das Shatabdi , Razu Shaharior Rahman
Published: February 2023

Background

Bangladesh is one of the most densely populated countries in the world. This large population predominantly affects the socioeconomic development of the people living in this country. Therefore, it is essential to identify the determinants of household size in the country and suggest implications for future interventions in similar contexts.

Objectives

The primary purpose of the present study was to explore the distribution of household size and its determinants based on the nationally representative Bangladesh Demographic and Health Survey (BDHS) data.

Material and Methods

The data were extracted from BDHS 2017–2018, a national survey. Individual responses from the adult women of each household were considered in this nationwide survey. We applied univariate and bivariate analyses (chi-squared test) to explore the distribution of household size and different selected determinants. The multinomial logistic regression was utilized to identify the association between household size and the selected independent determinants in our study.

Results

Findings of our multinomial logistic regression analysis showed that sex of the household head, division, decision about health, respondent’s age, residence, respondent’s education, husband’s education, wealth index, religion, husband’s occupation, and respondent’s working status were significantly associated with the household size (P ≤ 0.05). We observed that household size tended to be more prominent in rural areas, in the Sylhet division, in families where the head of the household was a male, and in families where others except the respondents and their husbands made health-related decisions. Besides, large household size was also common among respondents aged 25 years or less, respondents and their husbands with higher education, respondents from the rich and middle class, respondents who were Muslim, respondents whose husbands were businessmen and jobholders, and respondents who were workers.

Conclusions

The findings of our study suggest that household size in Bangladesh is associated with different socioeconomic factors. We recommend promoting awareness programs on family planning promotion and early marriage prevention, especially in rural areas, to prevent the rapid growth of the population. Expansion of education for both men and women and female involvement in income-generating activities should be encouraged to effectively control the household size in Bangladesh.
Power and Conviction
Authors: Wietzke Frank-Borge
Published: February 2023

This Element engages with recent attempts by economists and political scientists to rigorously estimate impacts of missionary work in sub-Saharan Africa. It argues that, although these efforts contribute to more accurate assessments of the 'true' effects of missionary presence, they also have a tendency to present Christian involvement in the region as a largely apolitical process, that was relatively unaffected by the rapidly evolving geopolitical and socio-cultural contexts of the colonial period. Countering this trend, this Element illustrates aspects of missionary behavior that were inherently more political and context-dependent, such as local struggles for religious hegemony between Protestants and Catholics and interactions between colonial regimes and the church-based provision of goods like education. The Element draws heavily on market-based theories of organized religious behavior. These perspectives are entirely compatible with the analytical language of economists and political scientists. Yet, they played surprisingly limited roles in recent literature on missionary impacts.
Emotional and intuitive eating: an emerging approach to eating behaviours related to obesity
Authors: Ayyıldız Feride , Akbulut Gamze , Karaçil Ermumcu Merve Şeyda , Acar Tek Nilüfer
Published: February 2023

Emotional and intuitive eating are associated with obesity. In the present study, it was aimed to evaluate the relationship between intuitive eating and emotional eating behaviours in adults with anthropometric measurements of obesity-related disease risk and gender. Body weight, body mass index (BMI), waist, hip and neck circumferences were taken. Emotional Eater Questionnaire and Intuitive Eating Scale-2 were used for the assessment of eating behaviour. A total of 3742 adult individuals (56⋅8 % (n 2125) female and (n 1617) male) were participated voluntarily. The total score and subscales of EEQ were higher in females than males (P < 0⋅001). The scores of the IES-2 subscales and the total score were higher in males than females (P < 0⋅05). In metabolic risk classification according to waist and neck circumference, EEQ scale scores (except type of food) were higher in the metabolic risk group, while IES-2 (except body-food congruence in neck circumference) scores were higher in the non-risk group (P < 0⋅05). While there was a positive correlation between EEQ and body weight, BMI, waist circumference, waist-height ratio, a negative correlation was found between age and waist-hip ratio. There was a negative correlation between IES-2 and body weight, BMI, waist-height ratio, waist-hip ratio. In addition, a negative correlation was found between IES-2 and EEQ. Intuitive eating and emotional eating differ by gender. Anthropometric measures and metabolic disease risk is associated with emotional eating and intuitive eating. Interventions to increase intuitive and decreasing emotional eating behaviour can be effective in preventing both obesity and obesity-related diseases.
Searching for coherence in a fragmented field: Temporal and keywords network analysis in political science
Authors: Zaytsev Dmitry G. , Kuskova Valentina V. , Khvatsky Gregory S. , Sokol Anna A.
Published: February 2023

In this paper, we answer the multiple calls for systematic analysis of paradigms and subdisciplines in political science—the search for coherence within a fragmented field. We collected a large dataset of over seven hundred thousand writings in political science from Web of Science since 1946. We found at least two waves of political science development, from behaviorism to new institutionalism. Political science appeared to be more fragmented than literature suggests—instead of ten subdisciplines, we found 66 islands. However, despite fragmentation, there is also a tendency for integration in contemporary political science, as revealed by co-existence of several paradigms and coherent and interconnected topics of the “canon of political science,” as revealed by the core-periphery structure of topic networks. This was the first large-scale investigation of the entire political science field, possibly due to newly developed methods of bibliometric network analysis: temporal bibliometric analysis and island methods of clustering. Methodological contribution of this work to network science is evaluation of islands method of network clustering against a hierarchical cluster analysis for its ability to remove misleading information, allowing for a more meaningful clustering of large weighted networks.
Voice mismatch and contrast in French Right-Node Raising
Authors: ABEILLÉ ANNE , SHIRAISHI AOI , HEMFORTH BARBARA
Published: February 2023

Right-Node Raising is generally considered to impose stricter identity conditions than other kinds of ellipsis, such as VP ellipsis, according to Hankamer & Sag 1976 and Hardt 1993. In this paper, we investigate voice mismatch in French Right-Node Raising (RNR) through a corpus study and two experiments. We show that RNR with voice mismatch can be found in a written corpus (frTenTen 2012) and that many examples involve coordination of a reflexive active and a short passive form. We suggest this is because semantic contrast (here, between self and external agent) plays a role according to Hartmann (2000) and Abeillé and Mouret (2010). We ran two acceptability judgement experiments to test voice mismatch and semantic contrast. We did not find any penalty for voice mismatch with VP ellipsis but an interaction with semantic contrast. We also found an effect of semantic contrast when coordinating an active and a passive VP without participle ellipsis. We conclude that voice mismatch is acceptable with RNR and propose a Head-driven Phrase-Structure Grammar (HPSG) analysis, following Chaves (2014) and Shiraïshi et al. (2019).
WARFARE, SACRIFICE, AND THE CAPTIVE BODY IN LATE CLASSIC MAYA SCULPTURE
Authors: Earley Caitlin C.
Published: February 2023

Traditional interpretations of Maya warfare have focused on the ritual aspects of war, including the necessity of taking captives for sacrifice. Captives are a common theme on carved stone monuments in the Late Classic period, and images like the murals at Bonampak suggest that captives taken in battle were ultimately sacrificed. Textual information from hieroglyphs and historical records, however, suggests a variety of fates for prisoners of war. Considering this information, the iconography of carved stone monuments is a poor indicator of historical outcomes for captives. What, then, was the function of captive imagery? In this article, I suggest that images of captives on carved stone monuments worked to prepare elite viewers for warfare by creating embodied social identities for warriors. Sculptures constructed a warrior identity that encompassed both victor and victim and emphasized the importance of elite bodies in the maintenance of political and ritual power. Understanding the ways in which images of captives were communicating allows a more robust view of how the practice of warfare differed from polity to polity and suggests that context is key to using art to learn about war.
UNLEASHING MAYA WARFARE: INQUIRY INTO THE PRACTICAL ASPECTS OF WAR-MAKING
Authors: Hernandez Christopher , Bracken Justin
Published: February 2023

Across many decades of Maya archaeology, the study of war has typically been focused on its geopolitical, systemic, evolutionary, and structural implications. We argue these approaches stand to benefit from deeper interrogations of practice. Such a perspective shifts scholarly attention toward the ways in which Maya peoples prepared for and engaged in combat, and how they administered the outcomes of war. Deploying this approach requires the study of tactics, strategy, fortifications, materiel, landscape, embodiment, and a host of other related factors. With the issue of practice at the forefront of our analysis, we demonstrate how the study of war has been “blackboxed” in Maya archaeology, then undertake a comparative analysis to highlight how digging into the details of past martial practice enriches debates in Mesoamerican studies regarding the role of war in the rise and disintegration of states.
Exploring changes in gamekeeper numbers in England (1851–1921)
Authors: Bailey Juliet
Published: February 2023

The gamekeeper played an important role in the development of modern gamebird shooting but has been peripheral in many analyses of the sport, which have tended to focus on the poacher, the landed elite, or the game laws. This study places the gamekeeper in a central position and, for a selection of counties, provides a detailed examination and comparison of changes in gamekeeper numbers between 1851 and 1921. The influence on gamekeeper numbers of population changes, estate area, landowner numbers and poaching prosecutions were also examined. Significant differences were found between the counties in gamekeeper numbers, and the magnitude and timing of changes in these. Average estate area varied greatly with no direct link to the area of the county, or to the number of gamekeepers on an estate. The type of quarry and interest of the landowner were important in determining the number of gamekeepers employed. In some counties, there may have been a link between the level of poaching and gamekeeper numbers, but there were significant differences between the counties. The results indicated a complex, regionally nuanced, picture in which factors such as the location, primary quarry and poaching pressure, as well as the interests of the landowner and the depth of his pockets, determined gamekeeper numbers.
Are older workers capable of working longer?
Authors: Quinby Laura D. , Wettstein Gal
Published: February 2023

Disability-free life expectancy had been rising continuously in the United States until 2010, suggesting working longer as a solution for those financially unprepared for retirement. However, recent developments suggest improvements in working life expectancy have stalled, especially for minorities and those with less education. This paper uses data from the National Vital Statistics System, the American Community Survey, and the National Health Interview Survey to assess how recent trends, up to 2018, in institutionalization, physical impediments to work, and mortality have affected working life expectancy for men and women age 50, by race and education.
End-of-life care for patients with cancer: Clinical, geographical, and sociocultural differences
Authors: Ostan Rita , Varani Silvia , Pannuti Francesco , Pannuti Raffaella , Biasco Guido , Bruera Eduardo
Published: February 2023

Objectives

Timely, effective and personalized identification of the multidimensional needs in patients with advanced cancer are major goals of appropriate palliative care (PC) delivery. However, there is considerable variation in structures, processes, and patient demographics that might influence the intensity of end-of-life care. This study aims to characterize patterns in clinical and demographic characteristics at the inception point and their association with the intensity of care during the last month of life in advanced cancer patients assisted at home.

Methods

Cancer patients entered in home PC during 2020 in Italy were considered. The association between home PC services during the last month of life (primary outcome) and demographic data, performance status (Karnofsky Performance Score [KPS]), symptoms, and therapies at the entry was explored in this retrospective study.

Results

Among 1,721 consecutive patients (919 in Centre-North and 802 in Centre-South Italy), patients from Centre-South were younger (p < 0.001), had worse KPS (p < 0.001), and shorter survival (p = 0.010). Patient age was inversely associated with the number of total/physician/nurses services during the last month of life (p < 0.001, p = 0.001, and p = 0.008, respectively). Patients with severe symptoms (asthenia, pain, and anxiety) at inception needed more PC services at the end of life (p = 0.026, p = 0.008, and p = 0.038, respectively). The distribution of workload differed according to the geographical area, with higher number of PC services provided by physicians (p < 0.001) in Centre-North and by nurses (p = 0.002) in Centre-South.

Significance of results

These findings highlight major disparity in access and nature of PC in a country with universal access to health services. Studies aimed at comparing PC models among different countries should pay attention to the local heterogeneity within each health-care system.
A Longitudinal Investigation of the Roles of Cognitive and Affective Job Insecurity Before and During the Pandemic
Authors: Shin Yuhyung , Hur Won-Moo , Rhee Seung-Yoon
Published: February 2023

Abstract: Background: While an increasing body of research has examined employees’ job insecurity during the COVID-19 pandemic, we know little about the role of cognitive and affective job insecurity in the pandemic context. Methods: We conducted a two-wave study on 211 service employees in South Korea to assess the indirect effect of their cognitive job insecurity that existed before the onset of the COVID-19 pandemic on their job performance after the onset of the pandemic, via affective job insecurity. Results: Mediation analysis revealed that pre-COVID cognitive job insecurity significantly indirectly affected mid-COVID job performance through mid-COVID affective job insecurity. Further, we found this indirect effect significant only among female employees. Discussion: These findings underscore the long-term effects of cognitive job insecurity on job performance in the context of the COVID-19 pandemic.
Heatwaves Similar to the Unprecedented One in Summer 2021 Over Western North America Are Projected to Become More Frequent in a Warmer World
Authors: Dong Zizhen , Wang Lin , Xu Peiqiang , Cao Jie , Yang Ruowen
Published: February 2023

Western North America (WNA) experienced an unprecedented heatwave from late June to early July 2021, which lies far outside the historical range. Based on the model outputs from Coupled Model Intercomparison Project Phase 6, we find that the likelihood of a heatwave over WNA similar to the 2021 one increases with global warming. Such a heatwave is projected to occur more frequently with increased extreme temperature and shortened return period. It means that a rare event in the current climate will be a more common event in a warmer climate, especially under a high‐emission scenario like the Shared Socioeconomic Pathways 585 (SSP5‐8.5). Moreover, we show a large expansion of areas over WNA that will break the 2021 record in the future with an increasing level of emission scenario. Nevertheless, some heatwave records west of the Rocky Mountains are still difficult to break, highlighting the specific extremity of the 2021 WNA heatwave.
Concentric Traveling Ionospheric Disturbances (CTIDs) Triggered by the 2022 Tonga Volcanic Eruption
Authors: Liu Lei , Morton Y. Jade , Cheng Pin‐Hsuan , Amores Angel , Wright Corwin J. , Hoffmann Lars
Published: February 2023

This paper investigates concentric traveling ionospheric disturbances (CTIDs) associated with the Tonga volcanic eruption. Results show that: (a) two types of CTIDs (CTID #1 and CTID #2) were identified that traveled radially from Tonga at the speed of 610–880 m/s (acoustic‐mode) and 300–380 m/s (Lamb‐mode), respectively. CTID #1 reached 3,800 and 5,000 km away from the eruption location toward the directions of New Zealand and Australia, respectively. CTID #2 propagated persistently for ∼9 hr over New Zealand and Australia. (b) The CTID #2 wavefront changed after 08:35 UT over New Zealand, possibly due to a combination of factors including the anisotropic propagation of CTID #2, the regional geomagnetic declination, and westward‐moving Lamb waves. (c) Topside total electron content (TEC) enhancement with a magnitude over two TECu was observed from COSMIC‐2 measurements. The enhancement agrees with CTID #1 peak from nearby ground‐based TEC observations and could be related to the upward propagation of the F layer’s CTID #1 signatures.
Effect of Fluid Salinity on Reaction Rate and Molecular Hydrogen (H2) Formation During Peridotite Serpentinization at 300°C
Authors: Huang Ruifang , Shang Xiuqi , Zhao Yusheng , Sun Weidong , Liu Xi
Published: February 2023

We conducted hydrothermal experiments at 300°C and at pressure varying from 2.2 to 3.4 kbar to study the effect of fluid salinity on the coupling between molecular hydrogen (H2) formation and olivine serpentinization, where peridotite and olivine with 25–50 μm of starting grain sizes were reacted with pure H2O and saline solutions (0.5, 1.5, and 3.3 M NaCl). Serpentine, the main hydrous mineral in most experiments, was quantified according to calibration curves based on Fourier‐transformed infrared spectroscopy and X‐ray diffraction analyses. Compared to pure H2O, saline solutions promote the hydrothermal alteration of olivine and peridotite. For experiments with peridotite and pure H2O, 67% of reaction extent was achieved after 14 days, which increased to 89% in experiments with medium‐salinity solutions (1.5 M NaCl) over the same period. Medium‐ and high‐salinity solutions inhibit H2 formation during serpentinization, which is associated with the serpentinization of pyroxene especially clinopyroxene. The redox conditions were constrained according to the equilibrium H2,aq = H2,g, and very reducing conditions were achieved during the serpentinization of olivine and peridotite. This study is the first to show iowaite formation directly from peridotite serpentinization, indicating alkaline solutions. Thermodynamic calculations suggest that the hydrolysis of NaCl (NaCl + H2O = HCl + NaOH) may yield alkaline solutions, due to higher dissociation constants of NaOH compared to HCl. This study suggests that chlorine greatly influences the serpentinization of olivine and peridotite in natural geological settings. It also indicates that iowaite formation may not require oxidizing conditions as previously thought.
Linkage of Spring Vegetation Dipole Pattern in Mid‐High Latitude Asia to Preceding Autumn Sea Ice Over the Barents‐Laptev Seas
Authors: Xin Ning , Zhou Botao , Chen Haishan , Sun Shanlei
Published: February 2023

Based on the normalized difference vegetation index (NDVI) and empirical orthogonal function analysis, a “northeast‐southwest” dipole pattern of spring vegetation in mid‐high latitude Asia was detected. This pattern was revealed to be associated with the autumn sea ice concentration (SIC) anomalies in the Barents‐Laptev Seas on the interannual variability. Increased autumn SIC over the Barents‐Laptev Seas tends to increase spring NDVI over the west of Lake Baikal and decrease spring NDVI in the Russian Far East. Further analyses indicated that the sea surface temperature (SST) anomalies persisting from winter to spring over the Northeast Atlantic and the Northwest Pacific play an important role in such a relationship. Increased autumn SIC over the Barents‐Laptev Seas is associated with a teleconnection pattern over the mid‐high latitudes in the following winter, accompanied by anomalous anticyclonic circulations over the Northeast Atlantic and the Northwest Pacific. Such changes in the large‐scale circulations induce downward net heat flux anomalies over the Northeast Atlantic and the Northwest Pacific, thereby contributing to the warming of SST which may persist to spring and in turn influence the atmospheric circulations. The Northeast Atlantic SST warming in spring may evoke a downstream wave train and cause positive geopotential height anomalies over the west of Lake Baikal, which increases local temperature and hence the vegetation. The Northwest Pacific SST warming in spring may lead to negative geopotential height anomalies over the Russian Far East through a meridional wave train, consequently resulting in a decrease in local temperature and hence vegetation.
Synthesis of Orbital Angular Momentum Antennas for Target Localization
Authors: Battaglia Giada M. , Isernia Tommaso , Palmeri Roberta , Morabito Andrea F.
Published: February 2023

The exploitation of Orbital Angular Momentum (OAM) is proposed to design circular‐support continuous aperture distributions and concentric‐ring arrays for target‐localization applications. The proposed approach allows generating a single isolated null of the field in the target direction, which is of interest with respect to common techniques leading to a line (or perpendicular lines) of power‐pattern zeroes in the spectral plane. In the presented design procedure, the optimal continuous aperture source is first identified by resorting to the most suitable OAM vortex and effective tools such as the Singular Value Decomposition of the involved operator and a smart Convex Programming optimization. Then, by exploiting fast deterministic algorithms, this continuous source is discretized into circular‐ring arrays emulating it at best. Relevant applications including equispaced arrays, sum‐difference reconfigurable arrays, and isophoric sparse arrays are presented. The proposed approach is also compared with the state‐of‐the‐art techniques and assessed through full‐wave electromagnetic simulations.
MiR146a-loaded engineered exosomes released from silk fibroin patch promote diabetic wound healing by targeting IRAK1
Authors: Li Qiankun , Hu Wenzhi , Huang Qilin , Yang Jie , Li Bingmin , Ma Kui , Wei Qian , Wang Yaxi , Su Jianlong , Sun Mengli , Cui Shengnan , Yang Rungong , Li Haihong , Fu Xiaobing , Zhang Cuiping
Published: February 2023

Unhealable diabetic wounds need to be addressed with the help of newer, more efficacious strategies. Exosomes combined with biomaterials for sustained delivery of therapeutic agents are expected to bring new hope for chronic wound treatment. Here, the engineered exosomes modified for efficiently loading miR146a and attaching to silk fibroin patch (SFP) were demonstrated to promote diabetic wound healing. Silk fibroin binding peptide (SFBP) was screened through phage display, and SFBP-Gluc-MS2 (SGM) and pac-miR146a-pac fusion protein were constructed. The designed exosomes (SGM-Exos, miR146a-Exos, and SGM-miR146a-Exos) were isolated from the engineered placental mesenchymal stem cells (PMSCs) transduced with SGM or/and pac-miR146a-pac protein. Gluc signals indicated SGM-Exo@SFP markedly increased the binding rate and the stability of SGM-Exo. Moreover, the loading efficiency of miR146a in SGM-miR146a-Exos was ten-fold higher than that in miR146a-Exos. Superior to untreated, SGM-miR146a-Exo-only treated, and SFP-only treated groups, SGM-miR146a-Exo@SFP drived wound healing associated with less inflammation, collagen deposition, and neovascularization. The transcriptomics analysis suggested anti-inflammatory and regenerative effects with SGM-miR146a-Exo@SFP treatment. Here, we show efficient exosome@biomaterial-based miRNA delivery systems for regenerative medicine and tissue engineering.
Methylation and expression of glucocorticoid receptor exon-1 variants and FKBP5 in teenage suicide-completers
Authors: Rizavi Hooriyah S. , Khan Omar S. , Zhang Hui , Bhaumik Runa , Grayson Dennis R. , Pandey Ghanshyam N.
Published: February 2023

A dysregulated hypothalamic-pituitary-adrenal (HPA) axis has repeatedly been demonstrated to play a fundamental role in psychiatric disorders and suicide, yet the mechanisms underlying this dysregulation are not clear. Decreased expression of the glucocorticoid receptor (GR) gene, which is also susceptible to epigenetic modulation, is a strong indicator of impaired HPA axis control. In the context of teenage suicide-completers, we have systematically analyzed the 5’UTR of the GR gene to determine the expression levels of all GR exon-1 transcript variants and their epigenetic state. We also measured the expression and the epigenetic state of the FK506-binding protein 51 (FKBP5/FKBP51), an important modulator of GR activity. Furthermore, steady-state DNA methylation levels depend upon the interplay between enzymes that promote DNA methylation and demethylation activities, thus we analyzed DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and growth arrest- and DNA-damage-inducible proteins (GADD45). Focusing on both the prefrontal cortex (PFC) and hippocampus, our results show decreased expression in specific GR exon-1 variants and a strong correlation of DNA methylation changes with gene expression in the PFC. FKBP5 expression is also increased in both areas suggesting a decreased GR sensitivity to cortisol binding. We also identified aberrant expression of DNA methylating and demethylating enzymes in both brain regions. These findings enhance our understanding of the complex transcriptional regulation of GR, providing evidence of epigenetically mediated reprogramming of the GR gene, which could lead to possible epigenetic influences that result in lasting modifications underlying an individual’s overall HPA axis response and resilience to stress.
Long range inter-chromosomal interaction of Oct4 distal enhancer loci regulates ESCs pluripotency
Authors: Moon Byoung-San , Huang David , Gao Fan , Cai Mingyang , Lyu Guochang , Zhang Lei , Chen Jun , Lu Wange
Published: February 2023

Nuclear architecture underlies the transcriptional programs within the cell to establish cell identity. As previously demonstrated, long-range chromatin interactions of the Oct4 distal enhancer (DE) are correlated with active transcription in naïve state embryonic stem cells. Here, we identify and characterize extreme long-range interactions of the Oct4 DE through a novel CRISPR labeling technique we developed and chromosome conformation capture to identify lethal giant larvae 2 (Llgl2) and growth factor receptor-bound protein 7 (Grb7) as putative functional interacting target genes in different chromosomes. We show that the Oct4 DE directly regulates expression of Llgl2 and Grb7 in addition to Oct4. Expression of Llgl2 and Grb7 closely correlates with the pluripotent state, where knock down of either result in loss of pluripotency, and overexpression enhances somatic cell reprogramming. We demonstrated that biologically important interactions of the Oct4 DE can occur at extreme distances that are necessary for the maintenance of the pluripotent state.
Human IFT-A complex structures provide molecular insights into ciliary transport
Authors: Jiang Meiqin , Palicharla Vivek Reddy , Miller Darcie , Hwang Sun-Hee , Zhu Hanwen , Hixson Patricia , Mukhopadhyay Saikat , Sun Ji
Published: February 2023

Intraflagellar transport (IFT) complexes, IFT-A and IFT-B, form bidirectional trains that move along the axonemal microtubules and are essential for assembling and maintaining cilia. Mutations in IFT subunits lead to numerous ciliopathies involving multiple tissues. However, how IFT complexes assemble and mediate cargo transport lacks mechanistic understanding due to missing high-resolution structural information of the holo-complexes. Here we report cryo-EM structures of human IFT-A complexes in the presence and absence of TULP3 at overall resolutions of 3.0–3.9 Å. IFT-A adopts a “lariat” shape with interconnected core and peripheral subunits linked by structurally vital zinc-binding domains. TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. We also determine the molecular impacts of disease mutations on complex formation and ciliary transport. Our work reveals IFT-A architecture, sheds light on ciliary transport and IFT train formation, and enables the rationalization of disease mutations in ciliopathies.
Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
Authors: Werba Gregor , Weissinger Daniel , Kawaler Emily A. , Zhao Ende , Kalfakakou Despoina , Dhara Surajit , Wang Lidong , Lim Heather B. , Oh Grace , Jing Xiaohong , Beri Nina , Khanna Lauren , Gonda Tamas , Oberstein Paul , Hajdu Cristina , Loomis Cynthia , Heguy Adriana , Sherman Mara H. , Lund Amanda W. , Welling Theodore H. , Dolgalev Igor , Tsirigos Aristotelis , Simeone Diane M.
Published: February 2023

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
A polymeric hydrogel electrocatalyst for direct water oxidation
Authors: Pei Zengxia , Tan Hao , Gu Jinxing , Lu Linguo , Zeng Xin , Zhang Tianqi , Wang Cheng , Ding Luyao , Cullen Patrick J. , Chen Zhongfang , Zhao Shenlong
Published: February 2023

Metal-free electrocatalysts represent a main branch of active materials for oxygen evolution reaction (OER), but they excessively rely on functionalized conjugated carbon materials, which substantially restricts the screening of potential efficient carbonaceous electrocatalysts. Herein, we demonstrate that a mesostructured polyacrylate hydrogel can afford an unexpected and exceptional OER activity – on par with that of benchmark IrO2 catalyst in alkaline electrolyte, together with a high durability and good adaptability in various pH environments. Combined theoretical and electrokinetic studies reveal that the positively charged carbon atoms within the carboxylate units are intrinsically active toward OER, and spectroscopic operando characterizations also identify the fingerprint superoxide intermediate generated on the polymeric hydrogel backbone. This work expands the scope of metal-free materials for OER by providing a new class of polymeric hydrogel electrocatalysts with huge extension potentials.
Immunotherapy in breast cancer: an overview of current strategies and perspectives
Authors: Debien Véronique , De Caluwé Alex , Wang Xiaoxiao , Piccart-Gebhart Martine , Tuohy Vincent K. , Romano Emanuela , Buisseret Laurence
Published: February 2023

Recent progress in immunobiology has led the way to successful host immunity enhancement against breast cancer. In triple-negative breast cancer, the combination of cancer immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors with chemotherapy was effective both in advanced and early setting phase 3 clinical trials. These encouraging results lead to the first approvals of immune checkpoint inhibitors in triple-negative breast cancer and thus offer new therapeutic possibilities in aggressive tumors and hard-to-treat populations. Furthermore, several ongoing trials are investigating combining immunotherapies involving immune checkpoint inhibitors with conventional therapies and as well as with other immunotherapeutic strategies such as cancer vaccines, CAR-T cells, bispecific antibodies, and oncolytic viruses in all breast cancer subtypes. This review provides an overview of immunotherapies currently under clinical development and updated key results from clinical trials. Finally, we discuss the challenges to the successful implementation of immune treatment in managing breast cancer and their implications for the design of future clinical trials.
pyGWBSE: a high throughput workflow package for GW-BSE calculations
Authors: Biswas Tathagata , Singh Arunima K.
Published: February 2023

We develop an open-source python workflow package, pyGWBSE to perform automated first-principles calculations within the GW-BSE (Bethe-Salpeter) framework. GW-BSE is a many body perturbation theory based approach to explore the quasiparticle (QP) and excitonic properties of materials. GW approximation accurately predicts bandgaps of materials by overcoming the bandgap underestimation issue of the more widely used density functional theory (DFT). BSE formalism produces absorption spectra directly comparable with experimental observations. pyGWBSE package achieves complete automation of the entire multi-step GW-BSE computation, including the convergence tests of several parameters that are crucial for the accuracy of these calculations. pyGWBSE is integrated with Wannier90, to generate QP bandstructures, interpolated using the maximally-localized wannier functions. pyGWBSE also enables the automated creation of databases of metadata and data, including QP and excitonic properties, which can be extremely useful for future material discovery studies in the field of ultra-wide bandgap semiconductors, electronics, photovoltaics, and photocatalysis.
Reinforcement learned adversarial agent (ReLAA) for active fault detection and prediction in space habitats
Authors: Overlin Matthew , Iannucci Steven , Wilkins Bradly , McBain Alexander , Provancher Jason
Published: February 2023

With growing interest for human space tourism in the twenty-first century, much attention has been directed to the robust engineering of Environmental Control and Life Support Systems in space habitats. The stable, reliable operation of such a habitat is partly achieved with an ability to recognize and predict faults. For these two purposes, a reinforcement learning adversarial agent (ReLAA) is utilized in this work. A ReLAA is trained with experimental data to actively recognize and predict faults. These capabilities are achieved by proposing actions that activate known faults in a system. Instead of issuing these harmful actions to the actual hardware, a digital twin of the mock space habitat is simulated to discover vulnerabilities that would lead to faulted operation. The methods developed in this work will allow for the discovery of damaging latent behavior, and the reduction of false positive and negative fault identification.
Transition from a polaronic condensate to a degenerate Fermi gas of heteronuclear molecules
Authors: Duda Marcel , Chen Xing-Yan , Schindewolf Andreas , Bause Roman , von Milczewski Jonas , Schmidt Richard , Bloch Immanuel , Luo Xin-Yu
Published: February 2023

The interplay of quantum statistics and interactions in atomic Bose–Fermi mixtures leads to a phase diagram markedly different from pure fermionic or bosonic systems. However, investigating this phase diagram remains challenging when bosons condense due to the resulting fast interspecies loss. Here we report observations consistent with a phase transition from a polaronic to a molecular phase in a density-matched degenerate Bose–Fermi mixture. The condensate fraction, representing the order parameter of the transition, is depleted by interactions, and the build-up of strong correlations results in the emergence of a molecular Fermi gas. The features of the underlying quantum phase transition represent a new phenomenon complementary to the paradigmatic Bose–Einstein condensate/Bardeen–Cooper–Schrieffer crossover observed in Fermi systems. By driving the system through the transition, we produce a sample of sodium–potassium molecules exhibiting a large molecule-frame dipole moment in the quantum-degenerate regime.
Structural basis of efficacy-driven ligand selectivity at GPCRs
Authors: Powers Alexander S. , Pham Vi , Burger Wessel A. C. , Thompson Geoff , Laloudakis Yianni , Barnes Nicholas W. , Sexton Patrick M. , Paul Steven M. , Christopoulos Arthur , Thal David M. , Felder Christian C. , Valant Celine , Dror Ron O.
Published: February 2023

A drug’s selectivity for target receptors is essential to its therapeutic utility, but achieving selectivity between similar receptors is challenging. The serendipitous discovery of ligands that stimulate target receptors more strongly than closely related receptors, despite binding with similar affinities, suggests a solution. The molecular mechanism of such ‘efficacy-driven selectivity’ has remained unclear, however, hindering design of such ligands. Here, using atomic-level simulations, we reveal the structural basis for the efficacy-driven selectivity of a long-studied clinical drug candidate, xanomeline, between closely related muscarinic acetylcholine receptors (mAChRs). Xanomeline’s binding mode is similar across mAChRs in their inactive states but differs between mAChRs in their active states, with divergent effects on active-state stability. We validate this mechanism experimentally and use it to design ligands with altered efficacy-driven selectivity. Our results suggest strategies for the rational design of ligands that achieve efficacy-driven selectivity for many pharmaceutically important G-protein-coupled receptors.
Ki67 increase after core needle biopsy associated with worse disease outcome in HER2-negative breast cancer patients
Authors: Tong Yiwei , Dai Jiangfeng , Huang Jiahui , Fei Xiaochun , Shen Kunwei , Liu Qingmeng , Chen Xiaosong
Published: February 2023

Ki67 would change after core needle biopsy (CNB) in invasive breast cancer. However, whether Ki67 alteration (ΔKi67) influences disease outcomes remains unclear. Here we aim to evaluate the prognostic value of ΔKi67. Patients with paired CNB and open excision biopsy (OEB) samples between January 2009 and June 2016 were retrospectively analyzed. ΔKi67 was calculated as the absolute difference between Ki67 level in CNB and OEB samples, and the median value of 5% was adopted to category patients into high- and low ΔKi67 groups. Disease-free survival (DFS) and overall survival (OS) were compared between different ΔKi67 groups. Overall, 2173 invasive breast cancer patients were included. Median Ki67 was higher in OEB than CNB samples: 25.00% versus 20.00% (P < 0.001). Axillary nodal status, STI, histological grading, and molecular subtype were independently associated with ΔKi67 (P < 0.05). In the whole population, patients with low ΔKi67 showed superior 5-year DFS (89.6% vs 87.0%, P = 0.026), but similar OS (95.8% vs 94.3%, P = 0.118) compared to those with high ΔKi67. HER2 status at surgery was the only significant factor interacting with ΔKi67 on both DFS (P = 0.026) and OS (P = 0.007). For patients with HER2-negative disease, high ΔKi67 was associated with worse 5-year DFS (87.2% vs 91.2%, P = 0.004) as well as impaired 5-year OS (93.9% vs 96.8%, P = 0.010). ΔKi67 had no significant impact on survival of HER2-positive patients. Ki67 increase after CNB was significantly associated with worse disease outcomes in HER2-negative, but not in HER2-positive patients, which warrants further study.
Analysis of C-reactive protein from finger stick dried blood spot to predict high risk of cardiovascular disease
Authors: Schakelaar Michael Y. , Kemperman Hans , Schoneveld Arjan H. , Hoefer Imo E. , Tiel Groenestege Wouter M.
Published: February 2023

C-reactive protein (CRP) is an acute-phase protein involved in inflammation. Furthermore, CRP is an important biomarker used in diagnostics to predict risk of cardiovascular disease (CVD) in addition to monitoring bacterial and viral infections. To measure plasma CRP, venipuncture is still necessitated and has to be performed by trained phlebotomists. As a solution, dried blood spots (DBS) are used for minimally invasive at-home sampling of blood and can be send to diagnostic laboratories by regular mail. In this study, we included 53 patients that presented to the outpatient clinic of the University Medical Center Utrecht. Capillary finger stick was used to spot blood on a filter paper card and allowed to dry. After extraction of DBS, CRP was analyzed on an automated high-throughput chemistry analyzer. Additional validation steps regarding stability, effect of hematocrit, precision, and limits of blank and quantitation were conducted according to corresponding Clinical and Laboratory Standards Institute standards. An excellent regression analysis of R2 (95% confidence interval) = 0.986 (0.982–0.989) was found. This enabled correct classification for high CVD risk of all 25 cases with sensitivity (95% CI) of 1.00 (1.00–1.00) and specificity (95% CI) of 0.96 (0.89–1.03) and correct diagnosis of inflammation of 12/13 cases with sensitivity (95% CI) of 0.92 (0.77–1.07) and specificity (95% CI) of 1.00 (1.00–1.00). Furthermore, CRP was found to be stable for 31 days and observed hematocrit variation amongst patients was clinically acceptable. CRP from DBS can be accurately measured on an automated high-throughput chemistry analyzer and used to diagnose inflammation and classify high CVD risk. This method enables individuals to engage in at-home sampling of blood on DBS for (tele)diagnostics, screening programs, patient follow-up, and medication management.
A validated LC–MS/MS method for clinical pharmacokinetics and presumptive phase II metabolic pathways following oral administration of Andrographis paniculata extract
Authors: Songvut Phanit , Pholphana Nanthanit , Suriyo Tawit , Rangkadilok Nuchanart , Panomvana Duangchit , Puranajoti Porranee , Satayavivad Jutamaad
Published: February 2023

Andrographis paniculata, a medicinal plant in Thailand national list of essential medicines, has been proposed for treatment of patients with mild to moderate coronavirus disease 2019. This study aims to develop a highly selective and sensitive liquid chromatography triple quadrupole tandem mass spectrometry method for quantitative determination of major diterpenoids in plasma and urine with application in pharmacokinetics. Chromatographic separation was performed on C18 column using a gradient mobile phase of water and acetonitrile. Mass spectrometry was analyzed using multiple reaction monitoring with negative ionization mode. This validated analytical method was very sensitive, less time consuming in analysis, and allowed the reliability and reproducibility on its application. The clinical pharmacokinetics was evaluated after single oral administration of A. paniculata extract (calculated as 60 mg of andrographolide). The disposition kinetics demonstrated that major diterpenoids could enter into systemic circulation, but they are mostly biotransformed (phase II) into conjugated glucuronide and sulfate metabolites. These metabolites are predominantly found in plasma and then extremely eliminated, in part through urinary excretion. The successful application of this analytical method supports its suitable uses in further clinical benefits after oral administration of A. paniculata.