bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress-Induced Phenoptosis: Mechanistic Insights and Evolutionary Implications
Authors: Pandey Taruna , Ma Dengke K.
Published: January 2023

Evolution by natural selection results in biological traits that enable organismic adaptation and survival under various stressful environments. External stresses can be sometimes too severe to overcome, leading to organismic death either because of failure in adapting to such stress, or alternatively, through a regulated form of organismic death (phenoptosis). While regulated cell deaths, including apoptosis, have been extensively studied, little is known about the molecular and cellular mechanisms underlying phenoptosis and its evolutionary significance for multicellular organisms. In this article, we review documented phenomena and mechanistic evidence emerging from studies of stress-induced phenoptosis in the multicellular organism C. elegans and stress-induced deaths at cellular levels in organisms ranging from bacteria to mammals, focusing on abiotic and pathogen stresses. Genes and signaling pathways involved in phenoptosis appear to promote organismic death during severe stress and aging, while conferring fitness and immune defense during mild stress and early life, consistent with their antagonistic pleiotropy actions. As cell apoptosis during development can shape tissues and organs, stress-induced phenoptosis may also contribute to possible benefits at the population level, through mechanisms including kin selection, abortive infection, and soma-to-germline resource allocation. Current models can generate experimentally testable predictions and conceptual frameworks with implications for understanding both stress-induced phenoptosis and natural aging.
Pharmacokinetic interaction between verapamil and ritonavir-boosted nirmatrelvir: implications for the management of COVID-19 in patients with hypertension
Authors: Haque Obaid Imtiyazul , Mahar Samantha , Hussain Shahzad , Sloane Peter
Published: January 2023

A woman in her 80s was brought to the emergency department for acute onset of generalised weakness, lethargy and altered mental state. The emergency medical service found her to have symptomatic bradycardia, and transcutaneous pacing was done. Medical history was notable for hypertension, hyperlipidaemia, type 2 diabetes, and a recently diagnosed SARS-CoV-2 (COVID-19) infection for which she was prescribed ritonavir-boosted nirmatrelvir (Paxlovid) two days before the presentation. On arrival at the hospital, she was found to have marked bradycardia with widened QRS, hyperglycaemia and metabolic acidosis. Transvenous pacing along with pressor support and insulin were initiated, and she was admitted to the intensive care unit. Drug interaction between ritonavir-boosted nirmatrelvir and verapamil leading to verapamil toxicity was suspected of causing her symptoms, and both drugs were withheld. She reverted to sinus rhythm on the fourth day, and the pacemaker was discontinued.
Differential age-associated brain atrophy and white matter changes among homeless and precariously housed individuals compared with the general population
Authors: Stubbs Jacob L , Jones Andrea A , Wolfman Daniel , Chan Ryan C Y , Vila-Rodriguez Fidel , Vertinsky Alexandra T , Heran Manraj K , Su Wayne , Lang Donna J , Field Thalia S , Gicas Kristina M , Woodward Melissa L , Thornton Allen E , Barr Alasdair M , Leonova Olga , MacEwan William , Rauscher Alexander , Honer William G , Panenka William J
Published: January 2023

Background

Homeless or precariously housed individuals live with poor health and experience premature mortality compared with the general population, yet little is known about age-related brain changes among these individuals. We evaluated whether MRI measures of brain structure are differentially associated with age and selected risk factors among individuals who are homeless or precariously housed compared with a general population sample.

Methods

We compared T1-weighted and diffusion tensor imaging measures of brain macrostructure and white matter microstructure in a well-characterised sample of 312 precariously housed participants with a publicly available dataset of 382 participants recruited from the general population. We used piecewise and multiple linear regression to examine differential associations between MRI measures and between the samples, and to explore associations with risk factors in the precariously housed sample.

Results

Compared with the general population sample, older age in the precariously housed sample was associated with more whole-brain atrophy (β=−0.20, p=0.0029), lower whole-brain fractional anisotropy (β=−0.32, p<0.0001) and higher whole-brain mean diffusivity (β=0.69, p<0.0001). Several MRI measures had non-linear associations with age, with further adverse changes after age 35–40 in the precariously housed sample. History of traumatic brain injury, stimulant dependence and heroin dependence was associated with more atrophy or alterations in white matter diffusivity in the precariously housed sample.

Conclusions

Older age is associated with adverse MRI measures of brain structure among homeless and precariously housed individuals compared with the general population. Education, improvements in care provision and policy may help to reduce the health disparities experienced by these individuals.
Codesigning an intervention to strengthen COVID-19 vaccine uptake in Congolese migrants in the UK (LISOLO MALAMU): a participatory qualitative study protocol
Authors: Crawshaw Alison F , Hickey Caroline , Lutumba Laura Muzinga , Kitoko Lusau Mimi , Nkembi Sarah , Knights Felicity , Ciftci Yusuf , Goldsmith Lucy Pollyanna , Vandrevala Tushna , Forster Alice S , Hargreaves Sally
Published: January 2023

Introduction

Migrants positively contribute to host societies yet experience barriers to health and vaccination services and systems and are considered to be an underimmunised group in many European countries. The COVID-19 pandemic has highlighted stark inequities in vaccine uptake, with migrants facing access and informational barriers and lower vaccine confidence. A key challenge, therefore, is developing tailored vaccination interventions, services and systems which account for and respond to the unique drivers of vaccine uptake in different migrant populations. Participatory research approaches, which meaningfully involve communities in co-constructing knowledge and solutions, have generated considerable interest in recent years for those tasked with designing and delivering public health interventions. How such approaches can be used to strengthen initiatives for COVID-19 and routine vaccination merits greater consideration.

Methods and analysis

LISOLO MALAMU (‘Good Talk’) is a community-based participatory research study which uses qualitative and coproduction methodologies to involve adult Congolese migrants in developing a tailored intervention to increase COVID-19 vaccine uptake. Led by a community–academic coalition, the study will involve (1) semistructured in-depth interviews with adult Congolese migrants (born in Democratic Republic of Congo, >18 years), (2) interviews with professional stakeholders and (3) codesign workshops with adult Congolese migrants. Qualitative data will be analysed collaboratively using reflexive thematic analysis, and behaviour change theory will be used in parallel to support the coproduction of interventions and make recommendations across socioecological levels. The study will run from approximately November 2021 to November 2022.

Ethics and dissemination

Ethics approval was granted by the St George’s University Research Ethics Committee (REC reference: 2021.0128). Study findings will be disseminated to a range of local, national and international audiences, and a community celebration event will be held to show impact and recognise contributions. Recommendations for implementation and evaluation of prototyped interventions will be made.
Radiation to all macroscopic sites of tumor permits greater systemic antitumor response to in situ vaccination
Authors: Carlson Peter M , Patel Ravi B , Birstler Jen , Rodriquez Matthew , Sun Claire , Erbe Amy K , Bates Amber M , Marsh Ian , Grudzinski Joseph , Hernandez Reinier , Pieper Alexander A , Feils Arika S , Rakhmilevich Alexander L , Weichert Jamey P , Bednarz Bryan P , Sondel Paul M , Morris Zachary S
Published: January 2023

Background

The antitumor effects of external beam radiation therapy (EBRT) are mediated, in part, by an immune response. We have reported that a single fraction of 12 Gy EBRT combined with intratumoral anti-GD2 hu14.18-IL2 immunocytokine (IC) generates an effective in situ vaccine (ISV) against GD2-positive murine tumors. This ISV is effective in eradicating single tumors with sustained immune memory; however, it does not generate an adequate abscopal response against macroscopic distant tumors. Given the immune-stimulatory capacity of radiation therapy (RT), we hypothesized that delivering RT toallsites of disease would augment systemic antitumor responses to ISV.

Methods

We used a syngeneic B78 murine melanoma model consisting of a ‘primary’ flank tumor and a contralateral smaller ‘secondary’ flank tumor, treated with 12 Gy EBRT and intratumoral IC immunotherapy to the primary and additional EBRT to the secondary tumor. As a means of delivering RT to all sites of disease, both known and occult, we also used a novel alkylphosphocholine analog, NM600, conjugated to90Y as a targeted radionuclide therapy (TRT). Tumor growth, overall survival, and cause of death were measured. Flow cytometry was used to evaluate immune population changes in both tumors.

Results

Abscopal effects of local ISV were amplified by delivering as little as 2–6 Gy of EBRT to the secondary tumor. When the primary tumor ISV regimen was delivered in mice receiving 12 Gy EBRT to the secondary tumor, we observed improved overall survival and more disease-free mice with immune memory compared with either ISV or 12 Gy EBRT alone. Similarly, TRT combined with ISV resulted in improved overall survival and a trend towards reduced tumor growth rates when compared with either treatment alone. Using flow cytometry, we identified an influx of CD8+T cells with a less exhausted phenotype in both the ISV-targeted primary and the distant secondary tumor following the combination of secondary tumor EBRT or TRT with primary tumor ISV.

Conclusions

We report a novel use for low-dose RT, not as a direct antitumor modality but as an immunomodulator capable of driving and expanding antitumor immunity against metastatic tumor sites following ISV.
Decrease of natalizumab drug levels after switching from intravenous to subcutaneous administration in patients with multiple sclerosis
Authors: Toorop Alyssa A , van Kempen Zoé L E , Steenhuis Maurice , Nielsen Jessica , Sinnige L G F , van Dijk Gert , Roosendaal Christiaan M , Arnoldus Edo P J , Hoitsma Elske , Lissenberg-Witte Birgit I , de Jong Brigit A , Oosten Bob W van , Strijbis Eva M M , Uitdehaag Bernard M J , Rispens Theo , Killestein Joep
Published: January 2023

Background

Natalizumab is effective in the treatment of multiple sclerosis (MS). In 2021, the European Medicines Agency approved the subcutaneous (SC) variant of natalizumab which can be used instead of intravenous administration. However, the course of drug levels varies between administration routes, and the Food and Drug Administration rejected the request for approval of natalizumab SC for reasons that were not disclosed. Our objective was to evaluate the course of natalizumab trough drug levels in patients who switched from natalizumab intravenous to SC on various treatment intervals.

Methods

The NEXT-MS trial (N=382) investigates personalised treatment of natalizumab, in which infusion intervals are prolonged based on individual natalizumab trough drug levels. In 2021, an amendment was approved allowing participants to switch from intravenous to SC administration with frequent measurements of natalizumab drug levels and antidrug antibodies (ADAs). Results were compared with linear mixed model analyses.

Results

Until December 2022, 15 participants switched to SC natalizumab. Natalizumab drug levels with SC administration were on average 55% lower compared with intravenous administration (Exp (estimate) 0.45, 95% CI 0.39 to 0.53, p<0.001), leading to very low trough drug levels in three patients on extended treatment intervals. No natalizumab ADAs were detected during intravenous or SC treatment. None of the participants on natalizumab SC showed evidence of MS disease activity.

Conclusions

Natalizumab trough drug levels can decrease after switching from natalizumab intravenous to SC administration. We advise to monitor trough drug levels in patients with low natalizumab drug levels during intravenous treatment, patients with higher body mass index or patients on extended treatment intervals who switch to SC administration of natalizumab.
Development and validation of prediction models for incident atrial fibrillation in heart failure
Authors: Vinter Nicklas , Gerds Thomas Alexander , Cordsen Pia , Valentin Jan Brink , Lip Gregory Y H , Benjamin Emelia J J , Johnsen Søren Paaske , Frost Lars
Published: January 2023

Objectives

Accurate prediction of heart failure (HF) patients at high risk of atrial fibrillation (AF) represents a potentially valuable tool to inform shared decision making. No validated prediction model for AF in HF is currently available. The objective was to develop clinical prediction models for 1-year risk of AF.

Methods

Using the Danish Heart Failure Registry, we conducted a nationwide registry-based cohort study of all incident HF patients diagnosed from 2008 to 2018 and without history of AF. Administrative data sources provided the predictors. We used a cause-specific Cox regression model framework to predict 1-year risk of AF. Internal validity was examined using temporal validation.

Results

The population included 27 947 HF patients (mean age 69 years; 34% female). Clinical experts preselected sex, age at HF, NewYork Heart Association (NYHA) class, hypertension, diabetes mellitus, chronic kidney disease, obstructive sleep apnoea, chronic obstructive pulmonary disease and myocardial infarction. Among patients aged 70 years at HF, the predicted 1-year risk was 9.3% (95% CI 7.1% to 11.8%) for males and 6.4% (95% CI 4.9% to 8.3%) for females given all risk factors and NYHA III/IV, and 7.5% (95% CI 6.7% to 8.4%) and 5.1% (95% CI 4.5% to 5.8%), respectively, given absence of risk factors and NYHA class I. The area under the curve was 65.7% (95% CI 63.9% to 67.5%) and Brier score 7.0% (95% CI 5.2% to 8.9%).

Conclusion

We developed a prediction model for the 1-year risk of AF. Application of the model in routine clinical settings is necessary to determine the possibility of predicting AF risk among patients with HF more accurately and if so, to quantify the clinical effects of implementing the model in practice.
Detection of the pathogenic fungus Cordyceps farinosa in the Thitarodes armoricanus soil-rearing environment based on nucleic acid targets
Authors: Tong Chaoqun , Li Tian , Luo Shisui , Chen Ruoni , Chen Shijiang , Wei Junhong , Qing Yuling , Qin Shaorong , Pan Guoqing , Li Chunfeng , Zhou Zeyang
Published: January 2023

Cordyceps farinosa, an entomopathogenic fungus, infects and leads to high mortality of Thitarodes armoricanus larvae, which die soon after the infection of C. farinose, usually before the colonization of Ophiocordyceps sinensis owing to competitive inhibition and fruiting body formation. Therefore, monitoring C. farinosa in the O. sinensis cultivation environment is critical for minimizing the C. farinosa infection-induced losses. In this study, we initially designed a PCR primer pair (Tar-1F/Tar-1R) through open reading frame prediction and homology comparison of the C. farinosa genome sequence. This primer pair can detect both C. farinosa and Samsoniella hepiali. To further distinguish, primers (ITS5-172/ITS4-95) were then designed to selectively amplify the large ribosomal subunit sequences in the C. farinosa genome. All these primers were applied in combination for detection of C. farinosa in soil samples. The sensitivity reached a detection limit of 1 × 106 spores/g soil. In addition, these primers can detect the presence of C. farinosa in dead T. armoricanus larval samples. This newly established rapid detection method provides important information for C. farinosa control during O. sinensis cultivation.
Predicting the masses of exotic hadrons with data augmentation using multilayer perceptron
Authors: Bahtiyar Huseyin
Published: January 2023

Recently, there have been significant developments in neural networks, which led to the frequent use of neural networks in the physics literature. This work focuses on predicting the masses of exotic hadrons, doubly charmed and bottomed baryons using neural networks trained on meson and baryon masses that are determined by experiments. The original dataset has been extended using the recently proposed artificial data augmentation methods. We have observed that the neural network’s predictive ability will increase with the use of augmented data. The results indicated that data augmentation techniques play an essential role in improving neural network predictions; moreover, neural networks can make reasonable predictions for exotic hadrons, doubly charmed, and doubly bottomed baryons. The results are also comparable to Gaussian Process and Constituent Quark Model.
Leader-Following Formation Tracking for Multiple Quadrotor Helicopters Over Switching Networks
Authors: He Changran , Huang Jie
Published: January 2023

In this paper, we study the leader-following formation tracking problem for multiple quadrotor helicopters via the distributed observer approach. In contrast with existing results in the literature, our approach offers the following features. First, our results apply to jointly connected switching communication networks, which are more general than static communication networks. Second, our control law is fully distributed in the sense that we do not assume that every vehicle can access the information of the desired formation trajectory. Third, with the virtual leader system being modeled by an exosystem, our control law can accomplish the formation tracking for a large class of leader’s trajectories. Two numerical examples are used to illustrate our design.
Ordovician geology of the Sibumasu Block, SE Asia
Authors: Agematsu Sachiko , Oo Thura
Published: January 2023

This paper describes the Ordovician stratigraphy of the Sibumasu Block, which formed part of equatorial peri-Gondwana during the early Paleozoic, and summarizes the palaeoenvironmental conditions that prevailed during that time. Upper Cambrian sequences are commonly dominated by coarse-grained clastic rocks of shallow-marine origin. The lithology of the Lower Ordovician varies from region to region, with fine-grained clastic rocks in the Shan Plateau, shallow-marine clastic rocks in northern to western Thailand and shallow-marine carbonate rocks in southern Thailand to northwestern Malaysia. Middle Ordovician strata consist entirely of shallow- to deeper-water carbonate rocks, with the exception of turbidites in midwestern Malaysia. Upper Ordovician rocks show an overall deeper environment, and the uppermost Ordovician consists of pelagic and deeper, fine-grained clastic rocks. On the basis of palaeobiogeographical data, the Sibumasu Block was adjacent to Western Australia throughout the early Paleozoic. Upper Cambrian rhyolitic rocks in the Shan Plateau and Lower–Middle Ordovician volcanics in midwestern Malaysia may have formed as a result of tectonomagmatism associated with the subduction of the Proto-Tethys Ocean plate into the northern Gondwanan margin. The close similarity of Late Ordovician fossil assemblages from Sibumasu and South China may be due to a sea-level rise during this time.
Trace element release from Bowland Shale into spring water in Lancashire
Authors: Armstrong Joseph Graham Trevor , Parnell John , Boyce Adrian Joseph , Perez Magali
Published: January 2023

A sulfurous spring emerges at an outcrop of Bowland Shale Formation on Crimpton Brook, Lancashire. The spring is marked by the precipitation of white and yellow jarosite. Comparable light sulfur isotope compositions suggest that the jarosite was derived from surface oxidation of pyritic shale. The shale contains anomalous concentrations of selenium and other trace elements, in common with other exposures of the Bowland Shale Formation in the north of England. The selenium is resident in the pyrite, and was released during oxidation and incorporated into the jarosite in Crimpton Brook. The small scale of the water flow at the site and the remote situation pose no environmental problem, but the data exemplify the potential danger of pyrite weathering into groundwater on a larger scale.
How Textiles Open Up Data as a Material in and on the Body
Authors: Nachtigall Troy
Published: January 2023

A designerly journey into textiles and HCI leads to thinking about data as a material for a cybernetic future.
What Makes Wearable Technologies Socially Acceptable?
Authors: Koelle Marion
Published: January 2023

Novel wearable computing devices challenge our perception of what is socially acceptable. Research in human-computer interaction asks, "What makes a wearable socially acceptable?" and provides insights that may help designers and developers design for social acceptability.
Optimized Heat Transfer Rate in Cu/CNT Nano Composite Prepared by Electrodeposition Technique
Authors: Bharathi K. Divya , Rahman M. R. , Yadav Ajay Kumar , Rudra Murthy B. V. , Devadas Bhat P.
Published: January 2023

The Cu/CNT nanocomposites are prepared by reinforcing Carbon Nanotubes (CNT) in a copper matrix through the electrodeposition technique. These nanocomposites are prepared by varying the diameter and concentrations of the CNT and are characterized by heat transfer rate. This study describes the overall heat transfer phenomena of Cu/CNT nanocomposite due to the preferential deposition of CNTs in the Cu matrix. The heat transfer rate is optimized and increased by 41.08% and 46.91% in natural and forced convection respectively compared to pure Cu coating. The reason is attributed to the better alignment, the optimum concentration of CNT in the composite, and the homogenously placed CNTs network in the composite.
Prediction of Remaining Useful Life of Packing Sets in a Plunger-Type High-Pressure Compressor Based on the PCA/SVD Analysis and NN Model
Authors: Liang Jin-Wei , Huang Shyh-Chin , Lin Chun-Ling
Published: January 2023

A machine learning-based prognostic strategy is developed in this paper for predicting the remaining useful life (RUL) of high-pressure packing in plunger-type hypercompressors. The proposed strategy applies principal component analysis (PCA) to identify the three most important sensors out of 33 possible options which seem relevant to the subject of high-pressure packing. Singular-value decomposition (SVD) is then performed with respect to chronological Hankel matrices reconstructed from one of these three pieces of sensor data, namely, leakage flow. The normalised correlation coefficient between SVD eigenvalue vectors of chronological data is defined with a view to formulate health state assessment measurement. In order to enhance the prediction accuracy of the RUL of high-pressure packing, a linear regression algorithm and a two-term power series regression algorithm are both integrated into the NN (neural network) model. The effectiveness of the method is examined using the averaged difference (over 13 data sets) between predicted and real failure events. The results showed that the maximum prediction RUL error of the model is less than 15 days, and an averaged prediction RUL error is 7.23 days for 13 run-to-failure events. Additionally, a more recent test was performed using online data to examine the health states of four identical types of packing.
Operative versus Nonoperative Treatment in Patients with Advanced Non-Small-Cell Lung Cancer: Recommended for Surgery
Authors: Wang Hui , Yang Di , Lv Yan , Lin Jing , Wang Haibin
Published: January 2023

Background. There is currently limited evidence for a correlation between the recommended operation and overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC). Methods. NSCLC patients with stages III and IV, recommended for operation, were identified in the US National Cancer Institute Surveillance, Epidemiology, and End Results database (SEER).We used propensity score matching (PSM) and multivariable Cox proportional hazards regression to ensure the robustness of our findings. The cumulative rates of death were compared between patients with and without recommended operations using the Kaplan−Meier curves. Results. Operation was recommended for 3331 patients but was not performed in 912 (27.4%) patients (then on-operative group). After PSM, 553 pairs matched. Compared to the nonoperative group, the hazard ratios (HRs) in the operative group were 0.46 (95% CI 0.23–0.95 and

p
=
0.037

) in stage IIIA and 0.54 (95% CI 0.42–0.68 and

p
<
0.001

) in stage IVA. However, in stages IIIB, IIIC, and IVB, the recommended operative group was not associated with better OS. The OS was not different in stage IIIA-N2, stage IVA-N1, and stage IVA-N3 patients between groups (

p
=
0.28

,

p
=
0.14

, and

p
=
0.79

, respectively). Moreover, the recommended operative group had better OS than the nonoperative group in stage IIIA-N0 (

p
=
0.00085

), stage IIIA-N1 (

p
=
0.009

), stage IVA-N0 (

p
<
0.001

), and stage IVA-N2 (

p
=
0.034

). Conclusion. Compared to the nonoperative group, recommended operation improved survival in NSCLC patients with stage IIIA-N0, stage IIIA-N1, stage IVA-N0, and stage IVA-N2. However, in stages IIIA-N2, IIIB, IIIC, IVA-N1, IVA-N3, and IVB, recommended operation did not lead to significantly improved survival time.
A Simulation‐Based Optimization Method for Truck‐Prohibit Ramp Placement along Freeways
Authors: Chen Dawei , Cheng Shiwei , Liu Jinyang , Zhang Jun , You Xinyu
Published: January 2023

The increasing number of trucks has a negative impact pertinent to efficiency and safety concerns on the operation of mixed traffic flow along freeways, especially at freeway entrance and exit ramps. To address such issue, this study proposes a simulation‐based method for truck‐prohibit ramp placement along freeways. The method framework contains two parts: the first part is to generate a set of new truck restriction schemes using simulation experiments, and the second part is to evaluate the generated schemes and find out the current optimal location of truck‐prohibit ramps based upon the AHP‐TOPSIS method. Three patterns of evaluation indicators are utilized to estimate the performance of freeway service in terms of traffic efficiency, road safety, and accessibility. A case study of the Beijing‐Hong Kong‐Macao freeway within Henan Province, China, is conducted to verify the effectiveness of the proposed method. Results could provide beneficial insights on the optimal location setting of truck‐prohibit ramps to enhance the entire performance of mixed traffic flow along freeways.
Pesticide Residues and Unauthorized Dyes as Adulteration Markers in Chilli Pepper and Tomato
Authors: Essuman Edward Ken , Teye Ernest , Dadzie Rosemond Godbless , Sam-Amoah Livingstone K.
Published: January 2023

To assess the contamination of processed chilli pepper and tomatoes, a report over the past four decades since the establishment of the Rapid Alert System for Food and Feed (RASFF) was retrieved and analysed. Out of the 887 notification reports assessed for eligibility, 446 were found regarding chilli pepper and tomato contamination. This study identified India as the country of origin with the highest number of reported cases relating to chilli pepper contamination. Italy and Türkiye were the countries with the highest number of reported cases regarding the exportation of adulterated tomatoes to other countries according to the RASFF report. Unauthorized dyes such as Sudan I, III, IV, orange II, rhodamine B, and para red were reported to have been detected in either chilli pepper or tomato in the supply chain. Almost all unauthorized dyes in this study were found to be more than the range (0.5 to 1 mg/kg) of the detection limit of Sudan dye and other related dyes using analytical methods set by the European Union. Unapproved pesticides by the European Union (EU) found in this study were acetamiprid, chlorothalonil, chlorpyrifos, dimethoate, methomyl, monocrotophos, omethoate, oxamyl, and thiophanate methyl. The present study indicates the persistence of chilli pepper and tomato contamination with harmful dyes and pesticide residues despite the ban on the use of certain chemicals in the food chain.
Comprehensive Analysis Identified Glycosyltransferase Signature to Predict Glioma Prognosis and TAM Phenotype
Authors: Qi Yiwei , Lv Wenchang , Liu Xiaojin , Wang Quanji , Xing Biao , Jiang Qian , Wang Zihan , Huang Yimin , Shu Kai , Lei Ting
Published: January 2023

Glycosylation is the most common posttranslational modification of proteins. Glycosyltransferase gene differential expression dictates the glycosylation model and is epigenetically regulating glioma progression and immunity. This study is aimed at identifying the glycosyltransferase gene signature to predict the prognosis and immune characteristics of glioma. The glycosyltransferase gene signature of glioma was identified in the TCGA database and validated in the CGGA database. Glioma patients were then divided into high‐ and low‐risk groups based on risk scores to compare survival differences and predictive capacity. Subsequently, validation of glycosyltransferase gene signature merits by comparing with other signatures and utility in clinical judgment. The immune cell infiltration, immune pathways, and immune checkpoint expression level were also analyzed and compared in the high‐ and low‐risk groups. Finally, the signature and its gene function were tested in our cohort and in vitro experiments. Eight glycosyltransferase genes were identified to establish the glycosyltransferase signature to predict the prognosis of glioma patients. The survival time was shorter in the high‐risk group compared to the low‐risk group based on glycosyltransferase signature and was confirmed in an independent external cohort. The glycosyltransferase signature displayed outstanding predictive capacity than other signatures in the TCGA and CGGA database cohorts. Furthermore, patients in the high‐risk group were positively correlated with TAM infiltration, immune checkpoint expression level, and protumor immune pathways in TCGA cohorts. Validation of clinical tissue specimens revealed that the high‐risk group was closely associated with infiltration of M2 TAMs. High‐risk genes in the signature promote glioma proliferation, invasion, and macrophage recruitment in an in vitro validation of U87 and U251 cell lines. This carefully constructed that glycosyltransferase signature can predict the prognosis and immune profile of gliomas and help us evaluate subsequent macrophage‐targeted therapies as well as other immune microenvironment modulation therapeutic strategies.
Characterization of Primary Cilia Formation in Human ESC-Derived Retinal Organoids
Authors: Ning Ke , Luo Ziming , Kowal Tia J. , Tran Matthew , Majumder Rishab , Jarin Trent M. , Wu Albert Y. , Goldberg Jeffrey L. , Sun Yang
Published: January 2023

Objectives. Primary cilia are conserved organelles found in polarized mammalian cells that regulate neuronal growth, migration, and differentiation. Proper cilia formation is essential during eye development. Our previous reports found that both amacrine and retinal ganglion cells (RGCs) contain primary cilia in primate and rodent retinas. However, whether primary cilia are present in the inner retina of human retinal organoids remains unknown. The purpose of this study is to characterize the primary cilia distribution in human embryonic stem cell (hESC-derived retinal organoid development. Materials and Methods. Retinal organoids were differentiated from a hESC line, harvested at various developmental timepoints (day 44-day 266), and immunostained with antibodies for primary cilia, including Arl13b (for the axoneme), AC3, and Centrin3 (for the basal body). AP2α, Prox1, GAD67, Calretinin, GFAP, PKCα, and Chx10 antibodies as well as Brn3b-promoted tdTomato expression were used to visualize retinal cell types. Results. A group of ciliated cells were present in the inner aspects of retinal organoids from day 44 to day 266 in culture. Ciliated Chx10-positive retinal progenitor cells, GFAP-positive astrocytes, and PKCα-positive rod-bipolar cells were detected later during development (day 176 to day 266). Ciliation persisted during all stages of retinal developmental in AP2α-positive amacrine cells, but it was decreased in Brn3b-positive retinal ganglion cells (RGCs) at later time points. Additionally, AC3-positive astrocytes significantly decreased during the later stages of organoid formation. Conclusions. Amacrine cells in retinal organoids retain cilia throughout development, whereas RGC ciliation gradually and progressively decreases with organoid maturation.
EVL Promotes Osteo-/Odontogenic Differentiation of Dental Pulp Stem Cells via Activating JNK Signaling Pathway
Authors: Zeng Kangrui , Kang Qiongyi , Li Yutong , Li Weiping , Cheng Qing , Xia Wenwei
Published: January 2023

Objective. Human dental pulp stem cells (hDPSCs) were recognized as a suitable and promising source of stem cells in dental pulp regeneration. However, the mechanism by which hDPSCs differentiation into osteo-/odontogenic lineage remains unclear. Ena/VASP-like protein (EVL) has been found to be involved in diverse biological processes. In this study, we explored the role and underlying mechanism of EVL in osteo-/odontogenic differentiation of hDPSCs. Methods. Expression of EVL was detected in hDPSCs by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB) analyses during osteo-/odontogenic differentiation. The function of EVL in osteo-/odontogenic differentiation and involvement of MAPK signaling pathways were evaluated by alkaline phosphatase (ALP) staining and activity, alizarin red staining (ARS), and qRT-PCR and western blot analyses. Results. The expression of EVL was upregulated during osteo-/odontogenic differentiation of hDPSCs. Overexpression of EVL significantly increased osteo-/odontogenic capacity of hDPSCs, which was reflected in increased alkaline phosphatase (ALP) staining, ALP activity, mineralized nodule formation, and the expressions of genes related to osteo-/odontogenic differentiation, while downregulation of EVL inhibited it. In addition, EVL activated the JNK pathway and phosphorylation of p38 MAPK during differentiation procedure of hDPSCs. The EVL-enhanced differentiation of DPSCs was suppressed by blocking the JNK pathway, rather than the p38 MAPK pathway. Conclusion. EVL promotes the osteo-/odontogenic differentiation of hDPSCs by activating the JNK pathway, providing a future target for osteo-/odontogenic differentiation and dental pulp regeneration.
Oral Administration of Spirulina platensis at Early Gestation Modulates Litter Size and the Expression of Inhibin, Insulin, IGF‐I, CO Q10, and BMP‐15 in Ewes Induced for Twinning
Authors: Zeitoun Moustafa , Ali Mohamed , Almundarij Tariq , Mousa Emad , Alghonaim Ahmed
Published: January 2023

Gestation in sheep necessitates the support of nutrients to avoid early embryonic mortalities. Therefore, this study investigates the effects of supplementing either L‐arginine or Spirulina alga in the first trimester on the pregnancy rate, litter size, inhibin, insulin, IGF‐I, CO Q10, and bone morphogenetic peptide 15 (BMP15) in maternal circulation. Animals were offered barley (500 g/head/day, 14% CP), alfalfa hay (1 kg/head/day, 12% CP), clean water, and balanced salt block licks as free choices. Forty Noemi and Najdi ewes were randomly allotted into three groups: control (C, n = 8), L‐arginine (ARG, n = 16), and Spirulina (SP, n = 16). All females were implanted with CIDR for ten days. On days 8, 9, and 10, treated ewes were given a protocol comprised of human recombinant FSH at descending doses (50, 50, 40, 40, and 30, 30 IU, A.M, and P.M, respectively). At the fifth dose, animals were given an equivalent dose of hCG (240 IU). After CIDR withdrawal, ewes were exposed to fertile rams for mating. SP‐ewes were orally given 50 ml (2%) Spirulina, and ARG‐ewes were given 50 ml (35 mg/kg BW) L‐arginine daily for 50 days postbreeding. Blood inhibin, insulin, IGF‐I, CO Q10, and BMP15 were determined throughout gestation until parturition. The findings indicated that the conception rates were 25, 75, and 87.5% in C, ARG, and SP, respectively (P < 0.05). The percent of ewes giving birth to twins was 0, 25, and 50% in C, ARG, and SP, respectively (P < 0.05). The survival rates were 100, 81.8, and 83.3%, respectively. Birth weight was 5.6, 3.2, and 3.4 kg in C, ARG, and SP, respectively. Weaning weights were 28.3, 25.6, and 27.2 kg in C, ARG, and SP, respectively. BMP‐15 was reduced (P < 0.05) in ARG than in C and SP. However, SP decreased (P < 0.05) inhibin more than in C and ARG. ARG and SP increased (P < 0.05) insulin than in C, whereas SP decreased (P < 0.05) IGF‐I. SP increased CO Q10 compared with ARG. Ewes bearing twins revealed higher (P < 0.05) IGF‐I (8.57 ng/ml) than those bearing singles (4.63 ng/ml); however, BMP‐15 was higher in single (796.6 pg/ml) than in twin‐bearing (387.5 pg/ml) ewes. In conclusion, providing early‐gestating ewes with Spirulina enhances maternal health, productivity, and reproductive outcomes.
Interaction Solutions of the (2+1)-Dimensional Sawada-Kotera Equation
Authors: Meng Yong
Published: January 2023

The N-soliton solution of the (2+1)-dimensional Sawada-Kotera equation is given by using the Hirota bilinear method, and then, the conjugate parameter method and the long-wave limit method are used to get the breather solution and the lump solution, as well as the interaction solution of the elastic collision properties between them. In addition, according to the expression of the lump-type soliton solution and the striped soliton solution, the completely inelastic collision, rebound, absorption, splitting, and other particle characteristics of the two solitons in the interaction process are directly studied with the simulation method, which reveals the laws of physics reflected behind the phenomenon.
A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition inBRAFV600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study
Authors: Tan Lavinia , Tran Ben , Tie Jeanne , Markman Ben , Ananda Sumi , Tebbutt Niall C. , Michael Michael , Link Emma , Wong Stephen Q. , Chandrashekar Sushma , Guinto Jerick , Ritchie David , Koldej Rachel , Solomon Benjamin J. , McArthur Grant A. , Hicks Rodney J. , Gibbs Peter , Dawson Sarah-Jane , Desai Jayesh
Published: January 2023

Purpose:

BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies.

Patients and Methods:

We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib.

Results:

Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification.

Conclusions:

The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.
On the Choice of Longitudinal Models for the Analysis of Antitumor Efficacy in Mouse Clinical Trials of Patient-derived Xenograft Models
Authors: Savel Hélène , Barbier Sandrine , Proust-Lima Cécile , Rondeau Virginie , Thiébaut Rodolphe , Meyer-Losic Florence , Richert Laura
Published: January 2023

In translational oncology research, the patient-derived xenograft (PDX) model and its use in mouse clinical trials (MCT) are increasingly described. This involves transplanting a human tumor into a mouse and studying its evolution during follow-up or until death. A MCT contains several PDXs in which several mice are randomized to different treatment arms. Our aim was to compare longitudinal modeling of tumor growth using mixed and joint models.

Mixed and joint models were compared in a real MCT (N = 225 mice) to estimate the effect of a chemotherapy and a simulation study. Mixed models assume that death is predictable by observed tumor volumes (data missing at random, MAR) while the joint models assume that death depends on nonobserved tumor volumes (data missing not at random, MNAR).

In the real dataset, of 103 deaths, 97 mice were sacrificed when reaching a predetermined tumor size (MAR data). Joint and mixed model estimates of tumor growth slopes differed significantly [0.24 (0.13;0.36)log(mm3)/week for mixed model vs. −0.02 [−0.16;0.11] for joint model]. By disrupting the MAR process of mice deaths (inducing MNAR process), the estimate of the joint model was 0.24 [0.04;0.45], close to mixed model estimation for the original dataset. The simulation results confirmed the bias in the slope estimate from the joint model.

Using a MCT example, we show that joint model can provide biased estimates under MAR mechanisms of dropout. We thus recommend to carefully choose the statistical model according to nature of mice deaths.

Significance:

This work brings new arguments to a controversy on the correct choice of statistical modeling methods for the analysis of MCTs. We conclude that mixed models are more robust than joint models.
Segmental Abnormalities of White Matter Microstructure in Primary Hypothyroidism Identified by Automated Fiber Quantification
Authors: Cao Jiancang , Chen Chen , Zhang Taotao , Han Yalan , Qin Rui , Su Wenxiu , Tian Jing , Liang Fengli , Shi Qian , Zhang Huiyan , Huang Gang , Tian Limin , Wang Ying , Zhao Lianping
Published: January 2023

Introduction: Hypothyroidism leads to impaired white matter (WM) integrity, associated with cognitive/neuropsychiatric dysfunction. However, the specific segmental abnormalities of the fibers remain unexplored. Therefore, this study aimed to investigate whether the damage of the WM is limited to a specific segment or the entire bundle via diffusion metrics using automated fiber quantification. Methods: A cross-sectional study was conducted on 31 hypothyroid patients and 28 healthy controls. Thyroid-related hormone levels, cognitive/neuropsychiatric function, and diffusion tensor image data were collected and analyzed. Correlation and random forest analyses were also performed. Results: The mean fractional anisotropy (FA) values were reduced at the fiber tract level. The mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were increased in several fiber tracts, i.e., cingulum cingulate (CC), anterior forceps of corpus callosum (CCF_A). Significant correlations were found between cognitive function and diffusion indicators such as the FA value of the left corticospinal tract and arcuate fasciculus (AF), the MD value of left CC, the RD value of left AF, the AD value of left CC, and CCF_A. The widespread microstructure disruption was spread on multiple specific segments of different tracts at the point-wise level. The random forest revealed that the accuracy of recognizing hypothyroid patients was 82.5%, with the anterior component of CCF_A having the most significant contribution. Conclusion: WM microstructural integrity impairments were found in multi-segments of the multiple fiber bundles in hypothyroidism, which might be a potential mechanism of the underlying neurocognitive decline and cerebral impairment. The CCF_A might serve as a neuro biomarker for early warning of cerebral impairment in hypothyroidism.
Frequency of Thrombectomy in Early and Late Postonset Time Windows Among Emergency Medical Services Patients With Acute Ischemic Stroke
Authors: Bosson Nichole , Saver Jeffrey L. , Lyden Patrick D. , Gausche‐Hill Marianne
Published: January 2023

Background

With recent trials demonstrating benefit of endovascular thrombectomy (EVT) up to 24 hours from last known well time (LKWT), emergency medical services systems must consider stroke center routing for patients with LKWT ≤24 hours. We sought to determine the frequency of thrombectomy by prehospital‐determined LKWT using retrospective data from a tiered regional stroke care system.

Methods

During the July 2018 to March 2019 study period, patients with potential large‐vessel occlusion, based on a Los Angeles Motor Scale of 4 or 5, were routed directly to a designated EVT center if within 30 minutes. We determined the frequency of thrombectomy by time intervals from prehospital‐determined LKWT to first medical contact.

Results

Emergency medical services transported 830 patients with acute ischemic stroke with documented prehospital‐determined LKWT ≤24 hours to EVT centers. The ≤6 hours, >6 to ≤16 hours, and >16 to ≤24 hours epochs accounted for 75%, 20%, and 5% of transports to EVT centers, respectively. Men accounted for 47% of the study population, with a median age of 77 years (interquartile range, 64–86 years) and National Institutes of Health Stroke Scale median of 11 (interquartile range, 4–20). Overall, 28.2% (234/830) received EVT. Time window–specific EVT frequencies were: ≤6 hours (29.8% of patients [187/627]); >6 to ≤16 hours (24.1% of patients [39/162]); and >16 to ≤24 hours (19.5% of [8/41]).

Conclusion

In this regional stroke system with 2‐tiered routing, patients in the >6‐ to 24‐hour postonset window accounted for nearly one fourth of transports to EVT centers and 23% received thrombectomy.
Rule and Exemplar-based Transfer in Category Learning
Authors: Liu Zhiya , Liao Siyao , Seger Carol A.
Published: January 2023

We compared the neural systems involved in transfer to novel stimuli via rule application versus exemplar processing. Participants learned a categorization task involving abstraction of a complex rule and then categorized different types of transfer stimuli without feedback. Rule stimuli used new features and therefore could only be categorized using the rule. Exemplar stimuli included only one of the features necessary to apply the rule and therefore required participants to categorize based on similarity to individual previously learned category members. Consistent and inconsistent stimuli were formed so that both the rule and feature similarity indicated the same category (consistent) or opposite categories (inconsistent). We found that all conditions eliciting rule-based transfer recruited a medial prefrontal–anterior hippocampal network associated with schematic memory. In contrast, exemplar-based transfer recruited areas of the intraparietal sulcus associated with learning and executing stimulus-category mappings along with the posterior hippocampus. These results support theories of categorization that postulate complementary learning and generalization strategies based on schematic and exemplar mechanisms.