bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatiotemporal analysis of the effect of global development indicators on child mortality
Authors: Amegbor Prince M. , Addae Angelina 
Published: May 2023

AbstractBackgroundChild mortality continue to be a major public health issue in most developing countries; albeit there has been a decline in global under-five deaths. The differences in child mortality can best be explained by socioeconomic and environmental inequalities among countries. In this study, we explore the effect of country-level development indicators on under-five mortality rates. Specifically, we examine potential spatio-temporal heterogeneity in the association between major world development indicators on under-five mortality, as well as, visualize the global differential time trend of under-five mortality rates.MethodsThe data from 195 countries were curated from the World Bank’s World Development Indicators (WDI) spanning from 2000 to 2017 and national estimates for under-five mortality from the UN Inter-agency Group for Child Mortality Estimation (UN IGME).We built parametric and non-parametric Bayesian space-time interaction models to examine the effect of development indicators on under-five mortality rates. We also used employed Bayesian spatio-temporal varying coefficient models to assess the spatial and temporal variations in the effect of development indicators on under-five mortality rates.ResultsIn both parametric and non-parametric models, the results show indicators of good socioeconomic development were associated with a reduction in under-five mortality rates while poor indicators were associated with an increase in under-five mortality rates. For instance, the parametric model shows that gross domestic product (GDP) (β = − 1.26, [CI − 1.51; − 1.01]), current healthcare expenditure (β = − 0.40, [CI − 0.55; − 0.26]) and access to basic sanitation (β = − 0.03, [CI − 0.05; − 0.01]) were associated with a reduction under-five mortality. An increase in the proportion practising open defecation (β = 0.14, [CI 0.08; 0.20]) an increase under-five mortality rate. The result of the spatial components spatial variation in the effect of the development indicators on under-five mortality rates. The spatial patterns of the effect also change over time for some indicators, such as PM2.5.ConclusionThe findings show that the burden of under-five mortality rates was considerably higher among sub-Saharan African countries and some southern Asian countries. The findings also reveal the trend in reduction in the sub-Saharan African region has been slower than the global trend.
Snail mediates GDF-8-stimulated human extravillous trophoblast cell invasion by upregulating MMP2 expression
Authors: Chen Jiaye , Song Tinglin , Yang Sizhu , Meng Qingxue , Han Xiaoyu , Wu Ze , Cheng Jung-Chien , Fang Lanlan 
Published: May 2023

Abstract
Background
Extravillous trophoblast (EVT) cell invasion is a tightly regulated process that requires for a normal pregnancy. The epithelial-mesenchymal transition (EMT) has been implicated in EVT cell invasion. Growth differentiation factor-8 (GDF-8), a member of the transforming growth factor-beta (TGF-β) superfamily, is expressed in the human placenta and promotes EVT cell invasion by upregulating the expression of matrix metalloproteinase 2 (MMP2). However, the underlying molecular mechanism of GDF-8-induced MMP2 expression remains undetermined. Therefore, the present study aims to examine the role of Snail and Slug, the EMT-related transcriptional regulators, in GDF-8-stimulated MMP2 expression and cell invasion in HTR-8/SVneo human EVT cell line and primary cultures of human EVT cells.

Methods
HTR-8/SVneo and primary cultures of human EVT cells were used to examine the effect of GDF-8 on MMP2 expression and explore the underlying mechanism. For gene silencing and overexpression, the HTR-8/SVneo cell line was used to make the experiments more technically feasible. The cell invasiveness was measured by Matrigel-coated transwell invasion assay.

Results
GDF-8 stimulated MMP2 expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effect of GDF-8 on MMP2 expression was blocked by the inhibitor of TGF-β type-I receptors, SB431542. Treatment with GDF-8 upregulated Snail and Slug expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effects of GDF-8 on Snail and Slug expression were blocked by pretreatment of SB431542 and siRNA-mediated knockdown of SMAD4. Interestingly, using the siRNA knockdown approach, our results showed that Snail but not Slug was required for the GDF-8-induced MMP2 expression and cell invasion in HTR-8/SVneo cells. The reduction of MMP2 expression in the placentas with preeclampsia (PE) was also observed.

Conclusions
These findings discover the physiological function of GDF-8 in the human placenta and provide important insights into the regulation of MMP2 expression in human EVT cells.
KLF4-mediated upregulation of the NKG2D ligand MICA in acute myeloid leukemia: a novel therapeutic target identified by enChIP
Authors: Alkhayer Reem , Ponath Viviane , Frech Miriam , Adhikary Till , Graumann Johannes , Neubauer Andreas , von Strandmann Elke Pogge 
Published: May 2023

AbstractThe immunoreceptor NKG2D, which is expressed on NK cells and T cell subsets is critically involved in tumor immune surveillance. This applies in particular to acute myeloid leukemia (AML), which evades immune detection by downregulation of NKG2D ligands (NKG2D-L), including MICA. The absence of NKG2D-L on AML cells is moreover associated with leukemia stem cell characteristics. The NKG2D/NKG2D-L system thus qualifies as an interesting and promising therapeutic target.Here we aimed to identify transcription factors susceptible to pharmacological stimulation resulting in the expression of the NKG2D-L MICA in AML cells to restore anti-tumor activity. Using a CRISPR-based engineered ChIP (enChIP) assay for the MICA promoter region and readout by mass spectrometry-based proteomics, we identified the transcription factor krüppel-like factor 4 (KLF4) as associated with the promoter. We demonstrated that the MICA promoter comprises functional binding sites for KLF4 and genetic as well as pharmacological gain- and loss-of-function experiments revealed inducible MICA expression to be mediated by KLF4.Furthermore, induction in AML cells was achieved with the small compound APTO253, a KLF4 activator, which also inhibits MYC expression and causes DNA damage. This induction in turn yielded increased expression and cell surface presentation of MICA, thus rendering AML cells more susceptible to NK cell-mediated killing. These data unravel a novel link between APTO253 and the innate anti-tumor immune response providing a rationale for targeting AML cells via APTO253-dependent KFL4/MICA induction to allow elimination by endogenous or transplanted NK and T cells in vivo.
Butyrate mitigates metabolic dysfunctions via the ERα-AMPK pathway in muscle in OVX mice with diet-induced obesity
Authors: Fu Qingsong , Li Tiantian , Zhang Chen , Ma Xiaotian , Meng Liying , Liu Limin , Shao Kai , Wu Guanzhao , Zhu Xing , Zhao Xiaoyun 
Published: May 2023

AbstractThe higher prevalence of metabolic syndrome (MetS) in women after menopause is associated with a decrease in circulating 17β-oestradiol. To explore novel treatments for MetS in women with oestrogen deficiency, we studied the effect of exogenous butyrate on diet-induced obesity and metabolic dysfunctions using ovariectomized (OVX) mice as a menopause model. Oral administration of sodium butyrate (NaB) reduced the body fat content and blood lipids, increased whole-body energy expenditure, and improved insulin sensitivity. Additionally, NaB induced oestrogen receptor alpha (ERα) expression, activated the phosphorylation of AMPK and PGC1α, and improved mitochondrial aerobic respiration in cultured skeletal muscle cells. In conclusion, oral NaB improves metabolic parameters in OVX mice with diet-induced obesity. Oral supplementation with NaB might provide a novel therapeutic approach to treating MetS in women with menopause.
Graphical Abstract
Effect of a relative pricing intervention and active merchandising on snack purchases: interrupted time series analysis of a hospital retailer-led strategy
Authors: Mah Catherine L. , Kennedy Laura , Taylor Nathan G. A. , Nicholson Taylor , Jago Emily , MacDonald Brenda 
Published: May 2023

Abstract
Background
Pricing policies have been shown to be an effective lever for promoting healthier dietary choices in consumer food environments. It is not yet well understood how pricing can be used to encourage healthier substitute purchases. The aim of the study was to assess the effect of a retailer-led relative pricing intervention on weekly purchases of targeted snack foods and beverages.

Methods
This was an ecological analysis in a real-world large tertiary hospital consumer food environment setting in urban Canada, comprised of four retail outlets: two large cafeterias, one smaller cafeteria, and one grab-and-go café. An interrupted time series analysis was designed to evaluate the effect of Snacking Made Simple, a retailer-led relative pricing intervention applied to 10 popular snack foods and beverages (n = 87 weeks, 66 weeks baseline and 21 weeks intervention, April 2018 to December 2019), on weekly purchase differences between healthier and less healthy targeted items, adjusted for weekly sales volume. Five healthier items were price discounted, alongside a price increase for five less healthy items. The intervention was actively merchandised in keeping with behaviour change theory.

Results
Weekly purchases of targeted snacks became healthier during the intervention period (β = 21.41, p = 0.0024). This followed a baseline period during which weekly purchases of less healthy targeted snacks had outpaced over time those of healthier targeted snacks (β = -11.02, p = 3.68E-14). We estimated that, all else being equal, a hypothetical 9.43 additional weeks of the intervention would be required to transition to net-healthier targeted snack purchases in this environment. The effects of the intervention varied by retail outlet, and the outcome appears driven by specific food items; further, examining merchandising implementation, we posited whether direct versus indirect substitution may have affected purchasing outcomes.

Conclusions
Relative pricing may be a promising way to incentivize healthier substitute purchasing in the consumer food environment. Added attention to merchandising strategy as well as value-add factors within food categories and their effects on price salience may be an important factor in effective intervention design.
A Pronectin™ AXL-targeted first-in-class bispecific T cell engager (pAXLxCD3ε) for ovarian cancer
Authors: Riillo Caterina , Polerà Nicoletta , Di Martino Maria Teresa , Juli Giada , Hokanson Craig A. , Odineca Tatjana , Signorelli Stefania , Grillone Katia , Ascrizzi Serena , Mancuso Antonia , Staropoli Nicoletta , Caparello Basilio , Cerra Maria , Nisticò Giuseppe , Tagliaferri Pierosandro , Crea Roberto , Caracciolo Daniele , Tassone Pierfrancesco 
Published: May 2023

AbstractBackgroundPronectins™ are a new class of fibronectin-3-domain 14th-derived (14Fn3) antibody mimics that can be engineered as bispecific T cell engager (BTCE) to redirect immune effector cells against cancer. We describe here the in vitro and in vivo activity of a Pronectin™ AXL-targeted first-in-class bispecific T cell engager (pAXLxCD3ε) against Epithelial Ovarian Cancer (EOC).MethodspAXLxCD3ε T-cell mediated cytotoxicity was evaluated by flow cytometry and bioluminescence. pAXLxCD3ε mediated T-cell infiltration, activation and proliferation were assessed by immunofluorescence microscopy and by flow cytometry. Activity of pAXLxCD3ε was also investigated in combination with poly-ADP ribose polymerase inhibitors (PARPi). In vivo antitumor activity of pAXLxCD3ε was evaluated in immunocompromised (NSG) mice bearing intraperitoneal or subcutaneous EOC xenografts and immunologically reconstituted with human peripheral blood mononuclear cells (PBMC).ResultspAXLxCD3ε induced dose-dependent cytotoxicity by activation of T lymphocytes against EOC cells, regardless of their histologic origin. The addition of PARPi to cell cultures enhanced pAXLxCD3ε cytotoxicity. Importantly, in vivo, pAXLxCD3ε was highly effective against EOC xenografts in two different NSG mouse models, by inhibiting the growth of tumor cells in ascites and subcutaneous xenografts. This effect translated into a significantly prolonged survival of treated animals.ConclusionpAXLxCD3ε is an active therapeutics against EOC cells providing a rational for its development as a novel agent in this still incurable disease. The preclinical validation of a first-in-class agent opens the way to the development of a new 14Fn3-based scaffold platform for the generation of innovative immune therapeutics against cancer.
EvoAug: improving generalization and interpretability of genomic deep neural networks with evolution-inspired data augmentations
Authors: Lee Nicholas Keone , Tang Ziqi , Toneyan Shushan , Koo Peter K. 
Published: May 2023

AbstractDeep neural networks (DNNs) hold promise for functional genomics prediction, but their generalization capability may be limited by the amount of available data. To address this, we propose EvoAug, a suite of evolution-inspired augmentations that enhance the training of genomic DNNs by increasing genetic variation. Random transformation of DNA sequences can potentially alter their function in unknown ways, so we employ a fine-tuning procedure using the original non-transformed data to preserve functional integrity. Our results demonstrate that EvoAug substantially improves the generalization and interpretability of established DNNs across prominent regulatory genomics prediction tasks, offering a robust solution for genomic DNNs.
Stereotactic Body radiotherapy and pedicLE screw fixatioN During one hospital visit for patients with symptomatic unstable spinal metastases: a randomized trial (BLEND RCT) using the Trials within Cohorts (TwiCs) design
Authors: Huele E. H. , van der Velden J. M. , Kasperts N. , Eppinga W. S. C. , Grutters J. P. C. , Suelmann B. B. M. , Weening A. A. , Delawi D. , Teunissen S. C. C. M. , Verkooijen H. M. , Verlaan J. J. , Gal R. 
Published: May 2023

Abstract
Background
Spinal metastases can lead to unremitting pain and neurological deficits, which substantially impair daily functioning and quality of life. Patients with unstable spinal metastases receive surgical stabilization followed by palliative radiotherapy as soon as wound healing allows. The time between surgery and radiotherapy delays improvement of mobility, radiotherapy-induced pain relief, local tumor control, and restart of systemic oncological therapy. Stereotactic body radiotherapy (SBRT) enables delivery of preoperative high-dose radiotherapy while dose-sparing the surgical field, allowing stabilizing surgery within only hours. Patients may experience earlier recovery of mobility, regression of pain, and return to systemic oncological therapy. The BLEND RCT evaluates the effectiveness of SBRT followed by surgery within 24 h for the treatment of symptomatic, unstable spinal metastases.

Methods
This phase III randomized controlled trial is embedded within the PRospective Evaluation of interventional StudiEs on boNe meTastases (PRESENT) cohort. Patients with symptomatic, unstable spinal metastases requiring stabilizing surgery and radiotherapy will be randomized (1:1). The intervention group (n = 50) will be offered same-day SBRT and surgery, which they can accept or refuse. According to the Trial within Cohorts (TwiCs) design, the control group (n = 50) will not be informed and receive standard treatment (surgery followed by conventional radiotherapy after 1–2 weeks when wound healing allows). Baseline characteristics and outcome measures will be captured within PRESENT. The primary outcome is physical functioning (EORTC-QLQ-C15-PAL) 4 weeks after start of treatment. Secondary endpoints include pain response, time until return to systemic oncological therapy, quality of life, local tumor control, and adverse events up to 3 months post-treatment.

Discussion
The BLEND RCT evaluates the effect of same-day SBRT and stabilizing surgery for the treatment of symptomatic, unstable spinal metastases compared with standard of care. We expect better functional outcomes, faster pain relief, and continuation of systemic oncological therapy. The TwiCs design enables efficient recruitment within an ongoing cohort, as well as prevention of disappointment bias and drop-out as control patients will not be informed about the trial.

Trial registration
ClinicalTrials.gov NCT05575323. Registered on October 11, 2022.
A Study of Individualized Diagnosis and Treatment for Depression with Atypical Features (iDoT-AFD): study protocol for a randomized clinical trial and prognosis study
Authors: Zhou Rubai , Zhang Huifeng , He Shen , Li Yi , Xu Guiyun , Huang Jinsong , Wang Huaning , Wang Qian , Li Biao , Wang Xuemei , Chen Ningning , Li Fang , Li Xiaosa , Liu Mengjun , Peng Daihui 
Published: May 2023

Abstract
Background
Major depressive disorder (MDD) with atypical features, namely depression with atypical features (AFD), is one of the most common clinical specifiers of MDD, closely associated with bipolar disorder (BD). However, there is still a lack of clinical guidelines for the diagnosis, treatment, and prognosis of AFD. Our study mainly focuses on three issues about how to identify AFD, what is the appropriate individualized treatment for AFD, and what are the predictive biomarkers of conversion to BD.

Methods
The Study of Individualized Diagnosis and Treatment for Depression with Atypical Features (iDoT-AFD) is a multicenter, prospective, open-label study consisting of a 12-week randomized controlled trial (RCT) and a continued follow-up until 4 years or reaching the study endpoint. It is enrolling 480 patients with AFD (120 per treatment arm), 100 patients with BD, and 100 healthy controls (HC). Multivariate dimension information is collected including clinical features, cognitive function, kynurenine pathway metabolomics, and multimodal magnetic resonance imaging (MRI) data. Firstly, multivariate informatics analyses are performed to recognize patients with AFD from participants including the first-episode and recurrent atypical depression, patients with BD, and patients with HC. Secondly, patients with atypical depression are randomly allocated to one of the four treatment groups including “single application of selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI)”, “SSRI/SNRI combined with mood stabilizer,” “SSRI/SNRI combined with quetiapine (≥ 150 mg/day),” or “treatment as usual (TAU)” and then followed up 12 weeks to find out the optimized treatment strategies. Thirdly, patients with atypical depression are followed up until 4 years or switching to BD, to explore the risk factors of conversion from atypical depression to BD and eventually build the risk warning model of conversion to BD.

Discussion
The first enrolment was in August 2019. The iDoT-AFD study explores the clinical and biological markers for the diagnosis, treatment, and prognosis of AFD and further provides evidence for clinical guidelines of AFD.

Trial registration
ClinicalTrials.gov NCT04209166. Registered on December 19, 2019.
Engineering Corynebacterium glutamicum for de novo production of 2-phenylethanol from lignocellulosic biomass hydrolysate
Authors: Zhu Nianqing , Xia Wenjing , Wang Guanglu , Song Yuhe , Gao Xinxing , Liang Jilei , Wang Yan 
Published: May 2023

Abstract
Background
2-Phenylethanol is a specific aromatic alcohol with a rose-like smell, which has been widely used in the cosmetic and food industries. At present, 2-phenylethanol is mainly produced by chemical synthesis. The preference of consumers for “natural” products and the demand for environmental-friendly processes have promoted biotechnological processes for 2-phenylethanol production. Yet, high 2-phenylethanol cytotoxicity remains an issue during the bioproduction process.

Results
Corynebacterium glutamicum with inherent tolerance to aromatic compounds was modified for the production of 2-phenylethanol from glucose and xylose. The sensitivity of C. glutamicum to 2-phenylethanol toxicity revealed that this host was more tolerant than Escherichia coli. Introduction of a heterologous Ehrlich pathway into the evolved phenylalanine-producing C. glutamicum CALE1 achieved 2-phenylethanol production, while combined expression of the aro10. Encoding 2-ketoisovalerate decarboxylase originating from Saccharomyces cerevisiae and the yahK encoding alcohol dehydrogenase originating from E. coli was shown to be the most efficient. Furthermore, overexpression of key genes (aroGfbr, pheAfbr, aroA, ppsA and tkt) involved in the phenylpyruvate pathway increased 2-phenylethanol titer to 3.23 g/L with a yield of 0.05 g/g glucose. After introducing a xylose assimilation pathway from Xanthomonas campestris and a xylose transporter from E. coli, 3.55 g/L 2-phenylethanol was produced by the engineered strain CGPE15 with a yield of 0.06 g/g xylose, which was 10% higher than that with glucose. This engineered strain CGPE15 also accumulated 3.28 g/L 2-phenylethanol from stalk hydrolysate.

Conclusions
In this study, we established and validated an efficient C. glutamicum strain for the de novo production of 2-phenylethanol from corn stalk hydrolysate. This work supplied a promising route for commodity 2-phenylethanol bioproduction from nonfood lignocellulosic feedstock.

Graphical Abstract
Assessment of symptom induction via artificial inoculation of the obligate biotrophic fungus Phyllachora maydis (Maubl.) on corn leaves
Authors: Góngora-Canul Carlos , Jiménez-Beitia Fidel E. , Puerto-Hernández Carlos , Avellaneda C. Mavir Carolina , Kleczewski Nathan , Telenko Darcy E. P. , Shim Sujoung , Solórzano José E. , Goodwin Stephen B. , Scofield Steven R. , Cruz C. D. 
Published: May 2023

Abstract
Objective
Tar spot is a foliar disease of corn caused by Phyllachora maydis, which produces signs in the form of stromata that bear conidia and ascospores. Phyllachora maydis cannot be cultured in media; therefore, the inoculum source for studying tar spot comprises leaves with stromata collected from naturally infected plants. Currently, there is no effective protocol to induce infection under controlled conditions. In this study, an inoculation method was assessed under greenhouse and growth chamber conditions to test whether stromata of P. maydis could be induced on corn leaves.

Results
Experiments resulted in incubation periods ranging between 18 and 20 days and stromata development at the beginning of corn growth stage VT-R1 (silk). The induced stromata of P. maydis were confirmed by microscopy, PCR, or both. From thirteen experiments conducted, four (31%) resulted in the successful production of stromata. Statistical analyses indicate that if an experiment is conducted, there are equal chances of obtaining successful or unsuccessful infections. The information from this study will be valuable for developing more reliable P. maydis inoculation methods in the future.