bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and application of a rapid all-in-one plasmid CRISPR-Cas9 system for iterative genome editing in Bacillus subtilis
Authors: Zou Yu , Qiu Lu , Xie Aowen , Han Wenyuan , Zhang Shangbo , Li Jinshan , Zhao Shumiao , Li Yingjun , Liang Yunxiang , Hu Yongmei
Published: August 2022

Background

Bacillus subtilis, an important industrial microorganism, is commonly used in the production of industrial enzymes. Genome modification is often necessary to improve the production performance of cell. The dual-plasmid CRISPR-Cas9 system suitable for iterative genome editing has been applied in Bacillus subtilis. However, it is limited by the selection of knockout genes, long editing cycle and instability.

Results

To address these problems, we constructed an all-in-one plasmid CRISPR-Cas9 system, which was suitable for iterative genome editing of B. subtilis. The PEG4000-assisted monomer plasmid ligation (PAMPL) method greatly improved the transformation efficiency of B. subtilis SCK6. Self-targeting sgRNArep transcription was tightly controlled by rigorous promoter PacoR, which could induce the elimination of plasmids after genome editing and prepare for next round of genome editing. Our system achieved 100% efficiency for single gene deletions and point mutations, 96% efficiency for gene insertions, and at least 90% efficiency for plasmid curing. As a proof of concept, two extracellular protease genes epr and bpr were continuously knocked out using this system, and it only took 2.5 days to complete one round of genome editing. The engineering strain was used to express Douchi fibrinolytic enzyme DFE27, and its extracellular enzyme activity reached 159.5 FU/mL.

Conclusions

We developed and applied a rapid all-in-one plasmid CRISPR-Cas9 system for iterative genome editing in B. subtilis, which required only one plasmid transformation and curing, and accelerated the cycle of genome editing. To the best of our knowledge, this is the rapidest iterative genome editing system for B. subtilis. We hope that the system can be used to reconstruct the B. subtilis cell factory for the production of various biological molecules.
Circular RNA circWWC3 augments breast cancer progression through promoting M2 macrophage polarization and tumor immune escape via regulating the expression and secretion of IL-4
Authors: Zheng Yang , Ren Shuguang , Zhang Yu , Liu Sihua , Meng Lingjiao , Liu Fei , Gu Lina , Ai Ning , Sang Meixiang
Published: August 2022

Interaction between tumor cells and tumor microenvironment (TME) is critical to promote tumor progression and metastasis. As the most abundant immune cells in TME, macrophages can be polarized into M2-like tumor-associated macrophages (TAMs) which further promote tumor progression. However, to date, the molecular mechanisms of TAM polarization in TME are still largely unknown. In the present study, we revealed that circular RNA circWWC3 could up-regulate the expression and secretion of IL-4 in breast cancer cells. Enhanced secretion of IL-4 from breast cancer cells could augment the M2-like polarization of macrophages in TME, which further promotes the migration of breast cancer cells. In addition, increased secretion of IL-4 from breast cancer cells could induce the expression PD-L1 in M2 macrophages. Moreover, up-regulated IL-4 also enhanced the expression of PD-L1 in breast cancer cells, which further facilitates breast cancer immune evasion. Though analyzing the expression of circWWC3, IL-4, PD-L1, and CD163 in 140 cases of breast cancer tissues, we found that high expression of circWWC3 was associated with poor overall survival and disease-free survival of breast cancer patients. Breast cancer patients with circWWC3high/PD-L1high breast cancer cells and CD163high macrophages had a poorer overall survival and disease-free survival. Conclusively, circWWC3 might augment breast cancer progression through promoting M2 macrophage polarization and tumor immune escape via regulating the expression and secretion of IL-4. CircWWC3 might be a potential therapeutic target in breast cancer.
Multimodal targeting of glioma with functionalized nanoparticles
Authors: Marei Hany E.
Published: August 2022

The most common and aggressive primitive intracranial tumor of the central nervous system is the glioma. The blood–brain barrier (BBB) has proven to be a significant obstacle to the effective treatment of glioma. To effectively treat glioma, different ways have been used to cross the BBB to deliver drugs to the brain. Drug delivery through nanocarriers proves to be an effective and non-invasive technique for the treatment of glioma and has great potential in the treatment of glioma. In this review, we will provide an overview of nanocarrier-mediated drug delivery and related glioma therapy. Nanocarrier-mediated drug delivery techniques to cross the BBB (liposomes, micelles, inorganic systems, polymeric nanoparticles, nanogel system, and biomimetic nanoparticles) are explored. Finally, the use of nanotherapeutic approaches in the treatment of glioblastoma including chemotherapy, radiotherapy, photothermal therapy, gene therapy, glioma genome editing, immunotherapy, chimeric antigen receptor (CAR) T-cells, immune checkpoint modulators, immune photothermal therapy, vaccine-based immunotherapy, and combination therapy is summarized. Furthermore, this article offers various views on the clinical applicability of nanomedicine.
Tumor-derived small extracellular vesicles: potential roles and mechanism in glioma
Authors: Guo Xu , Sui Rui , Piao Haozhe
Published: August 2022

Small extracellular vesicles (SEVs) are extracellular vesicles containing DNA, RNA, and proteins and are involved in intercellular communication and function, playing an essential role in the growth and metastasis of tumors. SEVs are present in various body fluids and can be isolated and extracted from blood, urine, and cerebrospinal fluid. Under both physiological and pathological conditions, SEVs can be released by some cells, such as immune, stem, and tumor cells, in a cytosolic manner. SEVs secreted by tumor cells are called tumor-derived exosomes (TEXs) because of their origin in the corresponding parent cells. Glioma is the most common intracranial tumor, accounting for approximately half of the primary intracranial tumors, and is characterized by insidious onset, high morbidity, and high mortality rate. Complete removal of tumor tissues by surgery is difficult. Chemotherapy can improve the survival quality of patients to a certain extent; however, gliomas are prone to chemoresistance, which seriously affects the prognosis of patients. In recent years, TEXs have played a vital role in the occurrence, development, associated immune response, chemotherapy resistance, radiation therapy resistance, and metastasis of glioma. This article reviews the role of TEXs in glioma progression, drug resistance, and clinical diagnosis.
High-density lipoproteins may play a crucial role in COVID-19
Authors: Nain Minu , Gupta Apoorv , Malhotra Sumit , Sharma Amit
Published: August 2022

Background

Lipids play a central role in the virus life cycle and are a crucial target to develop antiviral therapeutics. Importantly, among the other lipoproteins, the ‘good cholesterol’ high-density lipoprotein (HDL) has been widely studied for its role in not only cardiovascular but several infectious diseases as well. Studies have suggested a role of serum lipids and lipoproteins including HDL, total cholesterol (TC), triglycerides (TG), and low-density lipoproteins (LDL) in several viral infections including COVID-19. This disease is currently a major public health problem and there is a need to explore the role of these host lipids/lipoproteins in virus pathogenesis.

Methodology

A total of 75 retrospective COVID-19 positive serum samples and 10 COVID-19 negative controls were studied for their lipid profiles including TC, HDL, LDL, and very-low-density lipoproteins (VLDL), and TG.

Results

Systematic literature search on dyslipidemia status in India shows that low HDL is the most common dyslipidemia. In this cohort, 65% (49) of COVID-19 patients had severely low HDL levels whereas 35% (26) had moderately low HDL and none had normal HDL levels. On the other hand, ~ 96% of samples had normal TC (72) and LDL (72) levels. VLDL and TG levels were also variable. In the controls, 100% of samples had moderately low HDL but none severely low HDL levels.

Conclusion

HDL likely plays a crucial role in COVID-19 infection and outcomes. The causal relationships between HDL levels and COVID-19 need to be studied extensively for an understanding of disease pathogenesis and management.
An interpretable radiomics model to select patients for radiotherapy after surgery for WHO grade 2 meningiomas
Authors: Park Chae Jung , Choi Seo Hee , Eom Jihwan , Byun Hwa Kyung , Ahn Sung Soo , Chang Jong Hee , Kim Se Hoon , Lee Seung-Koo , Park Yae Won , Yoon Hong In
Published: August 2022

Objectives

This study investigated whether radiomic features can improve the prediction accuracy for tumor recurrence over clinicopathological features and if these features can be used to identify high-risk patients requiring adjuvant radiotherapy (ART) in WHO grade 2 meningiomas.

Methods

Preoperative magnetic resonance imaging (MRI) of 155 grade 2 meningioma patients with a median follow-up of 63.8 months were included and allocated to training (n = 92) and test sets (n = 63). After radiomic feature extraction (n = 200), least absolute shrinkage and selection operator feature selection with logistic regression classifier was performed to develop two models: (1) a clinicopathological model and (2) a combined clinicopathological and radiomic model. The probability of recurrence using the combined model was analyzed to identify candidates for ART.

Results

The combined clinicopathological and radiomics model exhibited superior performance for the prediction of recurrence compared with the clinicopathological model in the training set (area under the curve [AUC] 0.78 vs. 0.67, P = 0.042), which was also validated in the test set (AUC 0.77 vs. 0.61, P = 0.192). In patients with a high probability of recurrence by the combined model, the 5-year progression-free survival was significantly improved with ART (92% vs. 57%, P = 0.024), and the median time to recurrence was longer (54 vs. 17 months after surgery).

Conclusions

Radiomics significantly contributes added value in predicting recurrence when integrated with the clinicopathological features in patients with grade 2 meningiomas. Furthermore, the combined model can be applied to identify high-risk patients who require ART.
First evidence of vertical Hepatozoon canis transmission in dogs in Europe
Authors: Schäfer Ingo , Müller Elisabeth , Nijhof Ard M. , Aupperle-Lellbach Heike , Loesenbeck Gerhard , Cramer Sybille , Naucke Torsten J.
Published: August 2022

Background

Hepatozoon canis is a protozoal agent that is known to be transmitted by oral uptake of H. canis-infected Rhipicephalus sanguineus sensu lato ticks in dogs. Vertical transmission of H. canis has only been described once in a study evaluating dogs from Japan. The aim of this study was to investigate the parasitological status of puppies from a bitch that had tested positive for Hepatozoon spp. prior to giving birth.

Findings

A 4-year-old, female, pregnant dog imported from Italy (Sardinia) to Germany showed clinical signs of lethargy and tachypnoea and tested positive for H. canis by PCR. The dog gave birth to eight puppies, one of which was stillborn and another that had to be reanimated. Haematology, buffy coat analysis and a biochemistry profile were performed for each dog. EDTA-blood of the surviving seven puppies and bone marrow, liver, spleen, amniotic fluid, and umbilical cord of the stillborn puppy was tested for the presence of Hepatozoon spp. by PCR.

The mother and the seven surviving puppies tested positive for H. canis by PCR at day 62 post-partum. Gamonts were detected in all dogs by buffy coat evaluation. Haematological and biochemistry results revealed mild abnormalities. In the stillborn puppy, spleen, umbilical cord, and amniotic fluid were positive for H. canis.

Conclusion

The results confirm that vertical transmission is a possible route of H. canis infection in dogs, demonstrated by molecular detection of the pathogen in the stillborn puppy. In the seven surviving puppies, vertical transmission was the most likely transmission route. A potential impact of the level of parasitaemia on the health of puppies, as well as its pathogenesis, should be investigated further.

Graphical Abstract
Novel Ehrlichia canis genogroup in dogs with canine ehrlichiosis in Cuba
Authors: Navarrete Maylin González , Hodžić Adnan , Corona-González Belkis , Cordeiro Matheus Dias , da Silva Claudia Bezerra , Báez Liani Coronado , Obregón Dasiel , de Aguiar Daniel Moura , da Silva Campos Amanda Noeli , Taques Ísis Indaiara Gonçalves Granjeiro , Wu-Chuang Alejandra , López Eugenio Roque , Piloto-Sardiñas Elianne , Abuin-Denis Lianet , da Fonseca Adivaldo Henrique , Cabezas-Cruz Alejandro
Published: August 2022

Background

Canine monocytic ehrlichiosis (CME) is caused by the tick-borne pathogen Ehrlichia canis, an obligate intracellular Gram-negative bacterium of the family Anaplasmataceae with tropism for canine monocytes and macrophages. The trp36 gene, which encodes for the major immunoreactive protein TRP36 in E. canis, has been successfully used to characterize the genetic diversity of this pathogen in different regions of the world. Based on trp36 sequence analysis, four E. canis genogroups, United States (US), Taiwan (TWN), Brazil (BR) and Costa Rica (CR), have been identified. The aim of this study was to characterize the genetic diversity of E. canis in Cuba based on the trp36 gene.

Methods

Whole blood samples (n = 8) were collected from dogs found to be infested with the tick vector Rhipicephalus sanguineus sensu lato (s.l.) and/or presenting clinical signs and symptoms of CME. Total DNA was extracted from the blood samples and trp36 fragments were amplified by PCR. Nucleotide and protein sequences were compared using alignments and phylogenetic analysis.

Results

Four of the trp36 sequences obtained (n = 8) fall within the phylogenetic cluster grouping the US genogroup E. canis strains. The other E. canis trp36 sequences formed a separate and well-supported clade (94% bootstrap value) that is phylogenetically distant from the other major groups and thus represents a new genogroup, herein designated as the ‘Cuba (CUB) genogroup’. Notably, dogs infected with the CUB genogroup presented frequent hemorrhagic lesions.

Conclusions

The results of this study suggest that genetic diversification of E. canis in Cuba is associated with the emergence of E. canis strains with increased virulence.
Encephalomyelitis associated with coronavirus disease 2019: a case report
Authors: Estiasari Riwanti , Maharani Kartika , Octaviana Fitri , Putri Anyelir Nielya Mutiara , Ramadhan Syifa Laila , Rozaliani Anna , Imran Darma
Published: August 2022

Background

Despite a considerable number of articles regarding neurological manifestations associated with severe acute respiratory syndrome coronavirus 2 infection, reports on transverse myelitis and encephalitis are scarce.

Case presentation

We report a 35-year-old Asian Arab female presenting with longitudinally extensive transverse myelitis within 3 weeks after being diagnosed with mild coronavirus disease 2019 infection. Administration of high-dose methylprednisolone led to significant clinical improvement. However, 2 days after discharge, the patient was readmitted with encephalitis manifestations, consisting of fever and loss of consciousness, along with deterioration in myelitis symptoms. Severe acute respiratory syndrome coronavirus 2 antibody was detected in cerebrospinal fluid, but DNA of severe acute respiratory syndrome coronavirus 2 was not found. Clinical recovery was achieved after the administration of intravenous immunoglobulin.

Conclusion

Longitudinally extensive transverse myelitis can be a neurological manifestation of coronavirus disease 2019 and can be followed by encephalomyelitis episodes. High-dose steroids and intravenous immunoglobulin as an immunomodulator are possible effective treatment options.
Changes in thrombosis-related parameters after AstraZeneca COVID-19 vaccination in a male volunteer: a case report
Authors: Hong Sae-Yong , Jun Sang-Sin , Seo Sang-Wook , Park Jeong-Rae , Im Joung-Il
Published: August 2022

Background

We speculated that subclinical thrombosis may occur frequently through crosstalk between immune/inflammatory reactions and hemostasis after corona virus disease-2019 (COVID-19) vaccination. To test this hypothesis, we measured thrombosis-related parameters after COVID-19 vaccination in a volunteer for 21 days.

Case presentation

The following parameters were measured in a 72-year-old Korean man at 1 day before vaccination and on days 1, 3, 7, 14, and 21 post vaccination (AstraZeneca COVID-19 vaccine: ChAdOx1-S/nCoV-19, CTMAV563): complete blood count, platelet indices, thrombin receptor-activating peptide-induced platelet aggregation, prothrombin time, activated partial thromboplastin time, D-dimer, thrombin–antithrombin III complex (TAT), plasmin-α2 antiplasmin complex (PAP), von Willebrand factor (vWF) antigen and activity, plasminogen activator inhibitor-1 (PAI-1), protein C and protein S antigen and activity, lupus anticoagulant, fibrinogen degradation product, and plasminogen. We found that the TAT had significantly increased from 0.7 ng/mL (baseline) to 21.7 ng/mL (day 1). There was a transient increase in the PAI-1 level from 7.2 ng/mL (baseline) to 10.9 ng/mL (day 3), followed by a decrease in PAP level from 0.9 ng/mL (baseline) to 0.3 μg/mL (day 7), suggesting that plasmin generation is suppressed by PAI-1.

Conclusions

Increased thrombotic factors (such as decreased protein S) and decreased fibrinolytic activity due to increased PAI-1 were potential factors causing thrombogenesis after COVID-19 vaccination. Sequential measurement of platelet indices, TAT, PAP, protein C, protein S, vWF, D-dimer, and PAI-1 following COVID-19 vaccination was informative.
Impact of industry sponsorship on the quality of systematic reviews of vaccines: a cross-sectional analysis of studies published from 2016 to 2019
Authors: Pieper Dawid , Hellbrecht Irma , Zhao Linlu , Baur Clemens , Pick Georgia , Schneider Sarah , Harder Thomas , Young Kelsey , Tricco Andrea C. , Westhaver Ella , Tunis Matthew
Published: August 2022

Background

Systematic reviews (SRs) provide the highest level of evidence and inform evidence-based decision making in health care. Earlier studies found association with industry to be negatively associated with methodological quality of SRs. However, this has not been investigated in SRs on vaccines.

Methods

We performed a systematic literature search using MEDLINE and EMBASE in March 2020. The results were restricted to those published between 2016 and 2019 with no language restrictions. Study characteristics were extracted by one person and checked by an experienced reviewer. The methodological quality of the SRs was assessed with the AMSTAR 2 tool by multiple reviewers after a calibration exercise was performed. A summary score for each SR was calculated. The Mann-Whitney U test and Fisher’s exact test were performed to compare both groups.

Results

Out of 185 SRs that met all inclusion criteria, 27 SRs were industry funded. Those were matched with 30 non-industry funded SRs resulting in a total sample size of 57. The mean AMSTAR 2 summary score across all SRs was 0.49. Overall, the median AMSTAR 2 summary score was higher for the non-industry funded SRs than for the industry-funded SRs (0.62 vs. 0.36; p < .00001). Lower ratings for industry funded SRs were consistent across all but one AMSTAR 2 item, though significantly lower only for three specific items.

Conclusion

The methodological quality of SRs in vaccination is comparable to SRs in other fields, while it is still suboptimal. We are not able to provide a satisfactory explanation why industry funded SRs had a lower methodological quality than non-industry funded SRs over recent years. Industry funding is an important indicator of methodological quality for vaccine SRs and should be carefully considered when appraising SR quality.
Negative emotions and creativity among Chinese college students during the COVID-19 pandemic: the mediating role of psychological resilience and the moderating role of posttraumatic growth
Authors: Zeng Wei , Huang Dongtao , Li Qian , Xu Yanhua , Xu Ziying , Wu Chujin , Chen Zhihao , Yang Yuhao , Shao Jinlian , Wu Xingrou , Zhu Ziqi , Wu Jiamin , Zeng Yuqing
Published: August 2022

Background

The aim of the study was to use a moderated mediation model to understand and examine the relationship between negative emotions and creativity among college students during the COVID-19 pandemic, using psychological resilience as a mediator and posttraumatic growth as a moderator.

Methods

A sample of 881 college students in mainland China completed a self-report questionnaire that included four scales: the Depression-Anxiety-Stress Scale, Psychological Resilience Scale, Runco Ideational Behavior Scale and Posttraumatic Growth Inventory.

Results

Findings indicated that:(1) negative emotions were a strong predictor of creativity; (2) psychological resilience partially mediated the association between negative emotions and creativity; and (3) posttraumatic growth moderated the positive effect of psychological resilience, such that the indirect effect between negative emotions and creativity via psychological resilience was stronger for someone with a low level of resilience.

Conclusion

The findings further clarify the mechanisms that affect the relationship between negative emotions and creativity among college students.
Analysis of gene expression profiles in two spinal cord injury models
Authors: Yuan Haifeng , Zhang Bi , Ma Junchi , Zhang Yufei , Tuo Yifan , Li Xusheng
Published: August 2022

Objectives

To analyze the changes of gene expression at different timepoints after spinal cord injury (SCI) with tenth segment thoracic injury.

Methods

Two SCI models, the complete paraplegia (H) and Allen’s strike (D) methods were applied to induce SCI in rats, and transcriptome sequencing was performed 1, 3, 7, 14, 56, and 70 days after SCI, respectively. Principal component analysis, differentially expressed gene analysis, and hierarchical clustering analysis were applied to analyze the differentially expressed genes (DEGs). Gene Ontology GO enrichment analysis, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and Gene Set Enrichment Analysis revealed the pathway of gene enrichment.

Results

There were 1,907, 3,120, 3,728, 978, 2,319, and 3,798 DEGs in the complete paraplegia group and 2,380, 878, 1,543, 6,040, 1,945, and 3,850 DEGs in the Allen’s strike method group and after SCI at 1, 3, 7, 14, 56, and 70 days, respectively. The transcriptome contours of D1, H1, D3, and H14 were clustered with C; the H56, D56, H70, and D70 transcriptome contours were similar and clustered together. H3, D7, and H7 were clustered together, and D14 was clustered separately. The transcriptome differences of the two SCI models were mainly concentrated during the first 2 weeks after SCI. The DEGs after SCI in the complete paraplegia group were more concentrated. Most of the early transcriptional regulation stabilized within 2 weeks after injury.

Conclusions

There were DEGs between the two SCI models. Through the gene changes and pathway enrichment of the entire time period after SCI, the molecular mechanism of SCI repair was revealed in depth, which provided a reference for SCI treatment in the future.
Methods to derive the magnetopause from soft X-ray images by the SMILE mission
Authors: Wang Chi , Sun Tianran
Published: August 2022

Solar wind Magnetosphere Ionosphere Link Explorer (SMILE) is a novel self-standing mission dedicated to observing the solar wind–magnetosphere coupling via simultaneous in situ solar wind/magnetosheath plasma and magnetic field measurements, soft X-ray images of the magnetosheath and polar cusps, and UV images of global auroral distributions. While analyzing the observed images after the launch of SMILE, it will be a challenging task to reconstruct the 3-dimensional surface of the magnetopause from 2-dimensional images. Therefore, one of the most important key issues about SMILE is the reconstruction of magnetopause from X-ray images. This paper will review four main approaches have been developed so far, namely, the boundary fitting approach (BFA), the tangent fitting approach (TFA), the tangential direction approach (TDA), and the computed tomography approach (CTA). We will discuss their scope of application and pros and cons, and hopefully inspire future efforts.
Mendel paved the path toward understanding genetic diseases
Authors: Das Sreejon Sundar
Published: August 2022

Background

July 20th, 2022, marks the 200th anniversary of the “Father of Genetics,” Gregor Mendel’s birth. His experiments with pea plants established the fundamental principles of genetic inheritance.

Main text

In this article, a succinct review of literature is hereby done to answer two key questions: (1) How Mendel’s principles of genetic inheritance helped us understand Mendelian disorders? and (2) How the study of Mendelian disorders can help us understand complex diseases?

Conclusion

This literature review concludes that continued effort to understand the genetic basis of Mendelian disorders will improve our understanding and treatment strategies for complex diseases.
Narrative Analysis of a Woman’s Experience Transferring from a TYC Reveals Impact of Supporting Characters
Authors: Wood Laura A. H. , Sawtelle Vashti
Published: August 2022

Narrative analysis of a transfer student’s story highlights differences in her sense of community at the two institutions. Instructors and programmatic staff at 4-year colleges (FYCs) who aim to better support transfer students in their transition can learn from the kinds of scenes this student cited as helpful in her time at the 2-year college (TYC) as well as the FYC.
Why Students Struggle in Undergraduate Biology: Sources and Solutions
Authors: Tracy Claire B. , Driessen Emily P. , Beatty Abby E. , Lamb Todd , Pruett Jenna E. , Botello Jake D. , Brittain Cara , Ford Ísada Claudio , Josefson Chloe C. , Klabacka Randy L. , Smith Tyler , Steele Ariel , Zhong Min , Bowling Scott , Dixon Lucinda , Ballen Cissy J.
Published: August 2022

Student struggle in undergraduate biology is largely correlated with incoming preparation, instructor, and course performance. In this study, students often attributed their struggle to external sources (i.e., classroom factors, external resources, etc.); however, they were more likely to overcome internal sources of struggle.
Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma
Authors: Chesney Jason A. , Ribas Antoni , Long Georgina V. , Kirkwood John M. , Dummer Reinhard , Puzanov Igor , Hoeller Christoph , Gajewski Thomas F. , Gutzmer Ralf , Rutkowski Piotr , Demidov Lev , Arenberger Petr , Shin Sang Joon , Ferrucci Pier Francesco , Haydon Andrew , Hyngstrom John , van Thienen Johannes V. , Haferkamp Sebastian , Guilera Josep Malvehy , Rapoport Bernardo Leon , VanderWalde Ari , Diede Scott J. , Anderson James R. , Treichel Sheryl , Chan Edward L. , Bhatta Sumita , Gansert Jennifer , Hodi Frank Stephen , Gogas Helen
Published: August 2022

PURPOSE

The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma.

METHODS

Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis.

RESULTS

Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm.

CONCLUSION

T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.
2D F(R) gravity and AdS2/CFT1correspondence
Authors: Nojiri S. , Odintsov S. D.
Published: August 2022

We studied the canonical structure of 2D F(R) gravity. Its equivalence with Jackiw-Teitelboim gravity is demonstrated when no matter is present. Then, due to AdS2/CFT1 correspondence, such F(R) gravity is equivalent to the Sachdev-Ye-Kitaev models. The singular

limit of F(R) gravity is also studied. It is shown that in such a limit AdS2/CFT1 correspondence is not realized.
The role of syntax in the formation of scale-free language networks
Authors: Yang Mu , Liu Haitao
Published: August 2022

The overall structure of a network is determined by its micro features, which are different in both syntactic and non-syntactic networks. However, the fact that most language networks are small-world and scale-free raises the question: does syntax play a role in forming the scale-free feature? To answer this question, we build syntactic networks and co-occurrence networks to compare the generation mechanisms of nodes, and to investigate whether syntactic and non-syntactic factors have distinct roles. The results show that frequency is the foundation of the scale-free feature, while syntax is beneficial to enhance this feature. This research introduces a microscopic approach, which may shed light on the scale-free feature of language networks.
The Androgen Metabolome of Preterm Infants Reflects Fetal Adrenal Gland Involution
Authors: Flück Christa E , Kuiri-Hänninen Tanja , Silvennoinen Sanna , Sankilampi Ulla , Groessl Michael
Published: August 2022

Context

The human adrenal cortex changes with fetal-neonatal transition from the fetal to the adult organ, accompanied by changes in the steroid metabolome.

Objective

As it is unclear how the observed developmental changes differ between preterm and full-term neonates, we investigated whether the involution of the fetal adrenals is following a fixed time course related to postmenstrual age or whether it is triggered by birth. Furthermore, the fetal and postnatal androgen metabolome of preterm infants was characterized in comparison to term babies.

Methods

This was a prospective, longitudinal, 2-center study collecting spot urines of preterm and term infants during the first 12 to 18 months of life. Steroid metabolites were measured from spot urines by gas chromatography–mass spectrometry. Data relating were modeled according to established pre- and postnatal pathways.

Results

Fetal adrenal involution occurs around term-equivalent age in preterm infants and is not triggered by premature birth. Testosterone levels are higher in preterm infants at birth and decline slower until term compared to full-term babies. Dihydrotestosterone levels and the activity of the classic androgen biosynthesis pathway are lower in premature infants as is 5α-reductase activity. No difference was found in the activity of the alternate backdoor pathway for androgen synthesis.

Conclusion

Human adrenal involution follows a strict timing that is not affected by premature birth. By contrast, prematurity is associated with an altered androgen metabolome after birth. Whether this reflects altered androgen biosynthesis in utero remains to be investigated.
Feeling Media
Authors: Sas Miryam
Published: August 2022

In Feeling Media Miryam Sas explores the potentialities and limitations of media theory and media art in Japan. Opening media studies and affect theory up to a deeper engagement with works and theorists outside Euro-America, Sas offers a framework of analysis she calls the affective scale—the space where artists and theorists work between the level of the individual and larger global and historical shifts. She examines intermedia, experimental animation, and Marxist theories of the culture industries of the 1960s and 1970s in the work of artists and thinkers ranging from filmmaker Matsumoto Toshio, photographer Nakahira Takuma, and the Three Animators' Group to art critic Hanada Kiyoteru and landscape theorist Matsuda Masao. She also outlines how twenty-first-century Japanese artists—especially those responding to the Fukushima disaster—adopt and adapt this earlier work to reframe ideas about collectivity, community, and connectivity in the space between the individual and the system.
Breasi-CRISPR: an efficient genome-editing method to interrogate protein localization and protein–protein interactions in the embryonic mouse cortex
Authors: Meyerink Brandon L. , KC Pratiksha , Tiwari Neeraj K. , Kittock Claire M. , Klein Abigail , Evans Claire M. , Pilaz Louis-Jan
Published: August 2022

In developing tissues, knowing the localization and interactors of proteins of interest is key to understanding their function. Here, we describe the Breasi-CRISPR approach (Brain Easi-CRISPR), combining Easi-CRISPR with in utero electroporation to tag endogenous proteins within embryonic mouse brains. Breasi-CRISPR enables knock-in of both short and long epitope tag sequences with high efficiency. We visualized epitope-tagged proteins with varied expression levels, such as ACTB, LMNB1, EMD, FMRP, NOTCH1 and RPL22. Detection was possible by immunohistochemistry as soon as 1 day after electroporation and we observed efficient gene editing in up to 50% of electroporated cells. Moreover, tagged proteins could be detected by immunoblotting in lysates from individual cortices. Next, we demonstrated that Breasi-CRISPR enables the tagging of proteins with fluorophores, allowing visualization of endogenous proteins by live imaging in organotypic brain slices. Finally, we used Breasi-CRISPR to perform co-immunoprecipitation mass-spectrometry analyses of the autism-related protein FMRP to discover its interactome in the embryonic cortex. Together, these data demonstrate that Breasi-CRISPR is a powerful tool with diverse applications that will propel the understanding of protein function in neurodevelopment.
Biomechanics of the jaws of spotted ratfish
Authors: Herbert Amanda M. , Dean Mason N. , Summers Adam P. , Wilga Cheryl D.
Published: August 2022

Elasmobranch fishes (sharks, skates and rays) consume prey of a variety of sizes and properties, and the feeding mechanism typically reflects diet. Spotted ratfish, Hydrolagus colliei (Holocephali, sister group of elasmobranchs), consume both hard and soft prey; however, the morphology of the jaws does not reflect the characteristics typical of durophagous elasmobranchs. This study investigated the mechanical properties and morphological characteristics of the jaws of spotted ratfish over ontogeny, including strain, stiffness and second moment of area, to evaluate the biomechanical function of the feeding structures. Compressive stiffness of the jaws (E=13.51–21.48 MPa) is similar to that of silicone rubber, a very flexible material. In Holocephali, the upper jaw is fused to the cranium; we show that this fusion reduces deformation experienced by the upper jaw during feeding. The lower jaw resists bending primarily in the posterior half of the jaw, which occludes with the region of the upper jaw that is wider and flatter, thus potentially providing an ideal location for the lower jaw to crush or crack prey. The mechanical properties and morphology of the feeding apparatus of spotted ratfish suggest that while the low compressive stiffness is a material limit of the jaw cartilage, spotted ratfish, and perhaps all holocephalans, evolved structural solutions (i.e. fused upper jaw, shape variation along lower jaw) to meet the demands of a durophagous diet.
Ηθικά Παιχνίδια για την Διδασκαλία της Βιοηθικής
Authors: Κλεισούρας Αχιλλέας
Published: August 2022

Τα συμμετοχικά παιχνίδια που διερευνώνται σε αυτό το βιβλίο έχουν ως στόχο να καθοδηγήσουν την λήψη ηθικών αποφάσεων. Το βιβλίο τιτλοφορείται Ηθικά Παιχνίδια για την Διδασκαλία της Βιοηθικής, αλλά τα παιχνίδια μπορούν να χρησιμοποιηθούν για πολλά θέματα και να προσαρμοστούν ώστε να κάνουν τη μάθηση ευχάριστη για όλους τους εμπλεκόμενους. Η ιδέα της χρήσης ηθικών παιχνιδιών συνδέεται με κινήματα όπως η μαθητοκεντρική μάθηση, η συμμετοχική μάθηση και η δράση. Υπάρχει ένας αριθμός προσεγγίσεων, εργαλείων, στάσεων και συμπεριφορών που επιτρέπουν στους ανθρώπους να παρουσιάζουν, να μοιράζονται, να αναλύουν και να εμπλουτίζουν τις γνώσεις τους. Τα παιχνίδια που παρουσιάζονται σε αυτό το βιβλίο μπορούν να μας βοηθήσουν να σχεδιάζουμε, να δρούμε, να παρακολουθούμε, να αξιολογούμε και να προβληματιζόμαστε σχετικά με τις ηθικές μας επιλογές. Το βιβλίο παρέχει ορισμένα παραδείγματα συμμετοχικών παιχνιδιών που μπορούν να χρησιμοποιηθούν κατά την διδασκαλία λήψης ηθικών αποφάσεων. Τα Ηθικά Παιχνίδια για την Διδασκαλία της Βιοηθικής ενθαρρύνουν την συμμετοχή των μαθητών, με μια σειρά ηθικών παιχνιδιών και ασκήσεων. Όσο μεγαλύτερη είναι η συμμετοχή και η πνευματική εμπλοκή, τόσο μεγαλύτερη αναμένεται να είναι η επίδραση των παιχνιδιών.
Research on fatigue life of all-terrain vehicle control arm based on measured load spectrum
Authors: Zou Xihong , Zhou Yuting , Zhou Yuhang , Xiao Yukai , Yuan Dongmei , Xiang Gang
Published: August 2022

Background: All-terrain vehicles are mostly used in poor driving environments. A key part of the suspension mechanism of all-terrain vehicles, the lower control arm, bears various loads when the vehicle is driving. This component is prone to be fatigue and failure, which affects the performance of the entire vehicle. Therefore, in order to improve the performance of all-terrain vehicles, the fatigue life of the lower control arm was studied based on the measured force load spectrum.

Methods: Firstly, the finite element model of the lower control arm is established, the free modal simulation analysis is carried out, and the experimental research is carried out by building a modal test system. Then combining the calculated modal and experimental modal results, the finite element model is verified. Next, through the road load spectrum acquisition test in the automobile proving ground, the force time history of the lower control arm is obtained, and the signal is processed and analyzed to verify the reliability of the force load signal. On this basis, the boundary constraints of the lower control arm are established based on the actual working conditions of the all-terrain vehicle, and the dynamics simulation analysis is carried out with the measured force as input. Finally, according to stress-strain signal in dynamic analysis results, combining the modified local stress-strain method and the Landgrave damage criterion, the fatigue life of the lower control arm is calculated.

Results: The minimum fatigue cycle life of the lower control arm on the test roads is 3.56×105 km, and its fatigue life meets the design and use requirements.

Conclusions: The result shows that based on the actual driving load spectrum, the actual driving fatigue life can be calculated and forecasted more accurately.
Developing an African medical and health professions student regional elective exchange program: approaches and lessons learned
Authors: Nawagi Faith , Iacone Anna , Seeling Justin , Mukherjee Snigdha
Published: August 2022

Background:Given the significant gap in International Medical Elective (IME) opportunities for African health professions students, the Educational Commission for Foreign Medical Graduates and the Foundation for Advancement of International Medical Education and Research (ECFMG|FAIMER) launched an African regional elective exchange program through the Global Educational Exchange in Medicine and the Health Professions (GEMx) in 2016. This paper provides an overview of the development of the GEMx program, the pillars of successful implementation, and lessons learned.

Methods:The authors conducted a longitudinal qualitative study utilizing in-depth interviews with institutional leaders, Program leaders, and faculty, participant observation through symposia, strategic planning meetings, staff meetings, and document review of the annual progress reports, strategic plans, and newsletter articles, abstracts and concept notes. Common categories were identified and incorporated into a matrix to create themes. Data were analyzed using the manifest content approach guided by a literature review.

Results:The key pillars for the successful implementation of the GEMx Africa regional elective exchange program included: the commitment from African training institutional networks and their member institutions that enabled electives to happen, the GEMx Charter (multilateral agreement) that enabled reciprocity and diversity of elective opportunities, GEMx web-based application system that enabled the centralization of the application process and real-time feedback on acceptance, GEMx Africa Regional Coordination Center in Kampala, Uganda that lead the development and implementation in Africa, and ECFMG mini-grants that help defray the biggest part of the elective costs.

Conclusions:Through the development of successful partnerships across the continent, the GEMx regional elective exchange program contributed towards bridging a long-existing gap of inadequate opportunities for African health professions students to enhance their global exposure and strengthen their knowledge and skills.
METAPHOR AS A LINGUISTIC CATEGORY
Authors: ROMANYUK M , KHACHATUROVA M
Published: August 2022

The issue of studying the metaphor features is still relevant nowadays. This article deals with various approaches to the study of metaphor as a linguistic category. The article is especially focused on modern linguistic research in which the metaphor is studied within the close connection of language, culture and human consciousness.
Similarity effects of two types of adaptogens (transcutaneous electrical stimulation with the device “VEB” ® and using of bioactive Naftussya water) on the human body
Authors: Popovych Igor
Published: August 2022

Background. The studies of the Truskavetsian Scientific School of Balneology have shown that both the Naftussya bioactive water and the standard balneotherapy complex (Naftussya drink, ozokerite applications, mineral baths) exhibit the properties of adaptogens, similar to such ginseng and phytocompositions. At the same time, in the process of researching the influence of devices for transcutaneous electrical stimulation on the human body, we found that changes in the parameters of the neuro-endocrine-immune complex and metabolism also have an adaptogenic character. The purpose of this study is to find effects common to adaptogens of chemical and physical nature. Materials and Methods. The object of observation were 29 women 30-76 (50±13) y and 28 men 25-69 (48±13) y without a clinical diagnosis, but with the deviations from the norm in a number of parameters of the neuro-endocrine-immune complex as a manifestation of dysadaptation. Parameters of biophotonics, acupuncture points, EEG, HRV, immunity, metabolism, blood pressure and hormones levels before and after a four-day transcutaneous electrical stimulation session or one-week course of drinking of Naftussya water registered. Results. Screening revealed that 43 variables respond to the action of adaptogens according to the law of the initial level, at the same time, 4 initially elevated and 9 normal variables show further growth. Caused by adaptogens changes in 7 EEG and 7 HRV parameters determine favorable changes in 2 endocrine, 10 immune, 3 metabolic, 2 hemodynamic and 3 biophotonics parameters by 83,5%. Conclusion. The adaptogens both of chemical and physical nature, activating the receptors of the gut mucosa or the skin, respectively, have similar favorable effects on the parameters of the neuroendocrine-immune complex, metabolism, hemodynamics and biophotonics.
Unintentional overdose of paracetamol as a problem of modern times - a case report
Authors: Pożarowska Kinga , Brzuszkiewicz Kinga , Rudziński Gracjan , Orczykowski Maciej , Rosińska Agata , Tchórz Michał
Published: August 2022

INTRODUCTION

Paracetamol is one of the most widely used analgesics and antipyretics in the world. An overdose of this drug can occur after a single ingestion of a large amount of paracetamol or after repeated ingestion of smaller amounts that eventually exceed the recommended total dose and can result in liver damage.  It is believed that the maximum daily dose of paracetamol for an adult is 4g.

MATERIALS AND METHOD

Patient information was collected from hospital records available in the clinical toxicology department. In addition, we conducted a literature review on paracetamol using PubMed.

CASE REPORT

A patient, 16 years old, was admitted from a district hospital to the Clinical Toxicology and Cardiology Department in Lublin for paracetamol intoxication and suspected intoxication with a psychoactive substance. The patient's history revealed that he had taken a total of 20 paracetamol 500mg (10g) tablets in short intervals of 2 h for abdominal pain. The patient was treated with a full dose of antidote (ACC), and the drug infusion was continued at a maintenance dose. Despite the treatment administered, increasing features of liver damage were observed (INR 2.78, AST 6273 U/l, ALT 8854 U/l, bilirubin 3.83 mg/dl).The patient was consulted to qualify for a possible liver transplant. With intensive treatment maintained, a downward trend in liver damage parameters was achieved. The patient was discharged from the Department in good general condition, without complaints.

CONCLUSION

Due to the increasing number of paracetamol overdoses (intentional or accidental), strategies should be implemented to raise awareness and prevent this-educating patients, encouraging label/leaflet reading, reducing the amount of paracetamol in packages, more visible warnings on packages.
30 lat minęło... : historia powstania oraz działalności Sekcji Historycznej Polskiego Towarzystwa Anestezjologii i Intensywnej Terapii w latach 1986-2020
Authors: Macheta Alicja
Published: August 2022

Z wielką przyjemnością zapoznałem się z pracą dr n. med. Alicji Machety 30 lat minęło..., stanowiącą historię Sekcji Historycznej PTAiIT. W większości przedstawianych zdarzeń brałem udział osobiście. Autorka bardzo skrupulatnie zestawiła wszystkie działania Sekcji Historycznej, grupując je w kilku rozdziałach (...). Bardzo miłym akcentem jest (...) rozdział poświęcony sylwetce prof. dr. hab. n. med. Mariana Kusia, który został wybrany pierwszym przewodniczącym Sekcji Historycznej PTAiIT. Praca jest napisana bardzo przejrzyście i podaje fakty, w których w większości osobiście brała udział Autorka. Dr n. med. Alicja Macheta jest jedyną osobą, która mogła taką pracę napisać, stąd tak duża wartość merytoryczna tej publikacji. Z recenzji prof. dr. hab. n. med.