bluuebunny/crossref_metadata_2025 huggingface dataset:
The Development of Kinemaster Animation Video as a Media to Improve Science Literacy in Elementary Schools
Authors: Amrullah Abdul Rochman , Suryanti Suryanti , Suprapto Nadi
Published: December 2021

The research was conducted to develop kinemaster animation video media using the four D development model to improve students' scientific literacy on magnetism. The aim of this study was the Kinemaster animated video media that tried out to 27 six-grade students of SDN Bulusidokare Sidoarjo with Control Group Pretest-Posttest Design. Data collection techniques were validation, observation, tests, and questionnaire. The analysis of research result revealed that the feasibility included: 1) valid, the media and instructional tools that were developed by the researchers were feasible to be experimented; 2) practical, the feasibility of learning went very well with the percentage of 88% to 100%, best practice that was found were students’ enthusiasm increased, the media could be played many times and able to motivate students in doing experiments. The obstacles that happened during the learning process were students’ readiness, insubstantial facilities and infrastructure, and nonoptimal online learning supervision; 3) effective, the science-literacy-test result of experimental-class students passed with N-gain 0,5 to 1,0. Whereas on the control-class, some students faced failure with N-gain 0,17 to 0,57. Data from N-gain results (%) both classes got normal and homogenous distribution, thus independent sample t-test was conducted with significance result 0,00 < 0,05. It can be affirmed that there was effectivity difference in improving science literacy on experimental-class and control-class. Good responses that students gave reached 89% to 100%. The conclusion of this study is Kinemaster animated video media was feasible and effective to be used in improving science literacy on primary school students.
Kajian Risiko Bencana Berdasarkan Jumlah Kejadian dan Dampak Bencana di Indonesia Periode Tahun 2010 – 2020
Authors: Azizah Mir'atul , Khoirudin Apriadi Rio , Tri Januarti Riskina , Winugroho Tri , Yulianto Sugeng , Kurniawan Wahyu , Dewa Ketut Kerta Widana I
Published: December 2021

“Ring of fire” yang mengelilingi wilayah Indonesia, bonus demografi dan beberapa faktor lainnya membuat Indonesia menjadi wilayah yang rawan terhadap bencana. Hal tersebut seperti yang terekam pada DIBI pada periode tahun 2010 – 2020 terdapat 24.969 kejadian bencana. Penelitian ini merupakan kajian  risiko bahaya bencana berdasarkan jumlah kejadian dan dampak bencana di Indonesia pada periode tersebut. Tujuan dari penelitian ini sendiri adalah untuk menilai risiko bahaya akibat bencana yang terjadi dan kedepannya bisa dijadikan sebagai bahan pembelajaran serta acuan dalam mitigasi, pencegahan, kesiagaan, kesiapsiagaan bencana di Indonesia. Metode yang digunakan dalam penelitian ini berupa kuantitatif dengan pendekatan deskriptif berdasarkan data sekunder. Hasil dari penelitian ini menunjukkan bahwa bencana yang paling berisiko tinggi adalah banjir. Hal tersebut sesuai dengan data yang terekam oleh Data dan Informasi Bencana Indonesia (DIBI) frekuensi kejadian banjir merupakan bencana yang paling sering terjadi di Indonesia. Dan wilayah Indonesia yang mempunyai risiko bahaya paling tinggi terhadap bencana adalah Provinsi Jawa Barat. Kesimpulan dari penelitian ini adalah semua Provinsi di Indonesia mempunyai risiko bahaya terhadap bencana. Sehingga perlu adanya perhatian lebih terhadap mitigasi, pencegahan, kesiagaan dan kesiapsiagaan sesuai dengan tingkat risiko khususnya bencana banjir dan Jawa Barat. Bencana banjir merupakan bencana yang mempunyai risiko paling tinggi dan Provinsi Jawa Barat merupakan wilayah yang mempunyai risiko bahaya paling tinggi terhadap bencana.
Management of Multiple Myeloma in Older Patients
Authors: Li Jian , Chan Henry
Published: December 2021

Multiple myeloma is a condition that affects predominantly the older population. There are now various approved chemotherapy regimens as a result of advances in treatment. Choosing the optimal regimen for older patients with myeloma remains a challenge because of frailty and a lack of head-to-head comparisons between backbone regimens. The purpose of this literature review is to summarise the recent literature on frailty assessment, disease biology, and treatment efficacy in the frontline and relapsed settings to aid the decision-making process.
Digit-all: Rare Diseases
Authors: Baynam Gareth , Chediak Lynsey , Bilkey Gemma , Gration Dylan , Wiafe Samuel Agyei
Published: December 2021

Rare diseases are increasingly recognised as a global public health priority and contribute to significant and disproportionately high health system impacts. Accordingly, they present clinical and public health challenges, as well as opportunities for digital health solutions across the lifespan, including improved diagnosis, treatment, navigation and care coordination, and integration and coordination for broader societal and patient wellbeing. People living with rare diseases, individually and cumulatively, are digital disruptors. In this manuscript the authors describe some of the unique dynamics of the rare disease domain as they currently, or have the potential to in the future, apply to digital health; highlight some recent international rare diseases digital health initiatives; and touch upon implications for those with more common disorders.
Rapid Reconfiguration of Paediatric Services in a District General Hospital During COVID-19, Addressing Challenges, and Seeing Opportunities
Authors: Khan Ahmed Faraz , McConville Julie , Barr Suzanne
Published: December 2021

The scale, speed, and impact of the coronavirus disease (COVID-19) pandemic disruption to healthcare services has been unprecedented, placing significant additional pressures on the National Health Service (NHS). COVID-19 presented exceptional challenges to vulnerable families and is placing increasing pressure on children’s services. The child population does not seem to have been severely impacted by COVID-19; however, some will require hospital care in addition to the current caseload. It is imperative that steps are taken to ensure continued delivery of urgent and emergency paediatric services and the associated maternity and neonatal services at local levels throughout the pandemic. A rapid reconfiguration of services was necessary when the pandemic reached the NHS. Healthcare services had to rethink how to deliver care in the short and medium term, better preparing them for future demands and ensuring that safe and effective care was maintained.
Starch and triacylglycerol accumulation in the cells of the stain Chlorella sp. IPPAS C-1210
Authors: Bobrovnikova Lidia A. , Pakholkova Maria S. , Sidorov Roman A. , Sinetova Maria A.
Published: December 2021

Strain Сhlorella sp. IPPAS C-1210 is an effective lipid and triacilglycerols (TAG) producer. The strain could be used eventually in such industries as bioenergetics, food industry and agriculture. The objective of this work was investigation of conditions in which the strain Сhlorella sp. IPPAS C-1210 accumulates the most starch and TAG in cells with a view to optimise its growth and productivity. The following cultivation parameters were investigated in order to figure out their influence on accumulation of starch and TAG: nitrogen- and phosphorous-starvation and cultivation on media with different nitrogen (nitrate, urea) and carbon (carbon dioxide, bicarbonate) sources. Pigments, starch, protein and lipid content in cells were measured. The exclusion of nitrogen or phosphorus source from medium decreased the biomass productivity significantly, caused chlorosis and reduction of protein content. Total lipid content increased slightly after phosphorous starvation and stayed almost constant under nitrogen starvation, however a greater TAG increase was observed during nitrogen starvation. Both nitrogen and phosphorous starvations caused the increase of the amount of reserve carbohydrates: during phosphorous starvation increase was insignificant, whereas the latter almost doubled the amount of reserve carbohydrates. The highest biomass and lipid productivity was observed in cells grown in bicarbonate supplement medium and the highest starch productivity was observed in cells grown in standard BBM-3N medium.
Classification of Bird Based on Face Types Using Gray Level Co-Occurrence Matrix (GLCM) Feature Extraction Based on the k-Nearest Neighbor (K-NN) Algorithm
Authors: Sinaga Daurat , Agustina Feri , Setiyanto Noor Ageng , Suprayogi Suprayogi , Jatmoko Cahaya
Published: December 2021

Indonesia is one of the countries with a large number of fauna wealth. Various types of fauna that exist are scattered throughout Indonesia. One type of fauna that is owned is a type of bird animal. Birds are often bred as pets because of their characteristic facial voice and body features. In this study, using the Gray Level Co-Occurrence Matrix (GLCM) based on the k-Nearest Neighbor (K-NN) algorithm. The data used in this study were 66 images which were divided into two, namely 55 training data and 11 testing data. The calculation of the feature value used in this study is based on the value of the GLCM feature extraction such as: contrast, correlation, energy, homogeneity and entropy which will later be calculated using the k-Nearest Neighbor (K-NN) algorithm and Eucliden Distance. From the results of the classification process using k-Nearest Neighbor (K-NN), it is found that the highest accuracy results lie at the value of K = 1 and at an degree of 0 ° of 54.54%.
Dies Process Performance Improvement Maintenance With e-DMIS Based on Iot Technology
Authors: Widya Adi Rusdi , Romli Ikhsan
Published: December 2021

Improvement between departments within the company requires a mutually supportive system so that cooperation occurs between interrelated departments. This requires effort and commitment that needs to be supported by related share holders so that the occurrence of lost time during the production process can be minimized so that the planned time runs effectively and efficiently in increasing productivity. The difficulty in supervising and controlling the production process is the reason for knowing the abnormality in the process of replacing the dies and controlling the process of replacing printing equipment or dies for the Stamping process still using a manual system and the process recording system still using paper that is prone to loss and is engineered irresponsibly . The method used to create an electronic Dies replacement monitoring system by collecting problem data, comparing manual systems with several experiments and testing tools, using IoT in the form of PLC, HDMI as a tool for online communication. The DIMS monitoring system can be used to monitor and provide initial information when there is a request for the Dies replacement process so that replacement requests and needs in the process can be carried out immediately because they can be detected early.
‘the most beautifully bound book in the University Library’: The Seventeenth-Century Embroidered Wardlaw Bible in the Special Collections of the University of St Andrews
Authors: Harding Briony
Published: December 2021

In 2001 Wardlaw family descendants gifted to the University of St Andrews a pair of embroidered seventeenth-century gauntlet gloves and an embroidered seventeenth-century Geneva Bible bound with The CL. Psalmes of David in Meeter. Family tradition purports that the bible and gloves were given by Charles I to Sir Henry and Lady Wardlaw. Although it is feasible that the gloves were gifted to the first Sir Henry by Charles I, the bible was published after 1640—its 1599 date of imprint is false—and it, therefore, cannot have been given to Sir Henry, who died in 1637. It is also questionable if Charles I would have gifted a Geneva Bible, rather than the King James Version. Following a detailed description of the binding and the conservation it has undergone, the Wardlaw family legend is re-examined through comparing the embroidered binding to others of the seventeenth century, examining the provenance within the bible, and discussing the Geneva version of the bible.
Who Made the Turreted Brooches of Argyll? Nacken and Elite Silver Craftwork
Authors: Ramsay Rhona
Published: December 2021

During the 1500s the distinctive turreted brooches of Lochbuie, Lorn and Ugadale were produced for the Argyll families Maclaine, MacDougall and Mackay. Unusual in style by comparison with other brooches of the time, they are stylistically similar as a group. Around 1730 an inscription was added to the Lochbuie brooch stating that it was made by a ‘Tinker’. This paper examines the style, skills, materials and techniques involved in itinerant silversmithing in order to evaluate the claim that the three brooches were made by ‘Tinkers’, otherwise known as Nacken. Drawing on elements of art historical, ethnographic and archaeological research, the paper challenges existing assumptions about itinerant silversmithing.
Comprehensive Analysis of the Effects of Genetic Ancestry and Genetic Characteristics on the Clinical Evolution of Oral Squamous Cell Carcinoma
Authors: Guo Junfeng , Liu Xiaoping , Zeng Yi , Liang Taotao , Tang Kanglai , Guo Junfeng , Zheng Weiwei
Published: December 2021

Oral squamous cell carcinoma (OSCC), a kind of malignant cancer, is associated with increasing morbidity and mortality. Patients with different genetic ancestries may respond differently to clinical treatment. The limited understanding of the influence of genetic ancestry and genetic characteristics on OSCC impedes the development of precision medicine. To provide a reference for clinical treatment, this study comprehensively analyzed multigenomic differences in OSCC patients with different genetic ancestries and their impact on prognosis. An analysis of data from OSCC patients with different genetic ancestries in The Cancer Genome Atlas (TCGA) showed that the overall survival (OS) of African (AFR) patients was lower than that of primarily European (EUR) patients, and differences were also observed in the tumor–stroma ratio (TSR) and tumor-infiltrating lymphocytes (TILs), which are associated with prognosis. FAT1 is a key mutant gene in OSCC, and it has inconsistent effects on clinical evolution for patients with diverse genetic characteristics. PIKfyve and CAPN9 showed a significant difference in mutation frequency between EUR and AFR; PIKfyve was related to Ki-67 expression, suggesting that it could promote tumor proliferation, and CAPN9 was related to the expression of Bcl-2, promoting tumor cell apoptosis. A variant methylation locus, cg20469139, was correlated with the levels of PD-L1 and Caspase-7 and modulated tumor cell apoptosis. A novel ceRNA model was constructed based on genetic ancestries, and it could accurately evaluate patient prognosis. More importantly, although T cell dysfunction scores could determine the potential of tumor immune escape, the efficacy was obviously affected by patients’ genetic ancestries. To provide patients with more precise, personalized therapy and to further improve their quality of life and 5-year survival rate, the influence of genetic ancestry should be fully considered when selecting treatments.
Recent Advances in Understanding the Role of IKKβ in Cardiometabolic Diseases
Authors: Hernandez Rebecca , Zhou Changcheng
Published: December 2021

Cardiometabolic diseases, including cardiovascular disease, obesity, and diabetes, are the leading cause of mortality and morbidity worldwide. Cardiometabolic diseases are associated with many overlapping metabolic syndromes such as hypertension, hyperlipidemia, insulin resistance, and central adiposity. However, the underlying causes of cardiometabolic diseases and associated syndromes remain poorly understood. Within the past couple of decades, considerable progresses have been made to understand the role of inflammatory signaling in the pathogenesis of cardiometabolic diseases. The transcription factor, NF-κB, a master regulator of the innate and adaptive immune responses, is highly active in cardiometabolic diseases. IκB kinase β (IKKβ), the predominant catalytic subunit of the IKK complex, is required for canonical activation of NF-κB, and has been implicated as the critical molecular link between inflammation and cardiometabolic diseases. Recent studies have revealed that IKKβ has diverse and unexpected roles in mediating adiposity, insulin sensitivity, glucose homeostasis, vascular function, and atherogenesis through complex mechanisms. IKKβ has been demonstrated as a critical player in the development of cardiometabolic diseases and is implicated as a promising therapeutic target. This review summarizes current knowledge of the functions of IKKβ in mediating the development and progression of cardiometabolic diseases.
m6A Regulators in Human Adipose Tissue - Depot-Specificity and Correlation With Obesity
Authors: Rønningen Torunn , Dahl Mai Britt , Valderhaug Tone Gretland , Cayir Akin , Keller Maria , Tönjes Anke , Blüher Matthias , Böttcher Yvonne
Published: December 2021

Background

N6-methyladenosine (m6A) is one of the most abundant post-transcriptional modifications on mRNA influencing mRNA metabolism. There is emerging evidence for its implication in metabolic disease. No comprehensive analyses on gene expression of m6A regulators in human adipose tissue, especially in paired adipose tissue depots, and its correlation with clinical variables were reported so far. We hypothesized that inter-depot specific gene expression of m6A regulators may differentially correlate with clinical variables related to obesity and fat distribution.

Methods

We extracted intra-individually paired gene expression data (omental visceral adipose tissue (OVAT) N=48; subcutaneous adipose tissue (SAT) N=56) of m6A regulators from an existing microarray dataset. We also measured gene expression in another sample set of paired OVAT and SAT (N=46) using RT-qPCR. Finally, we extracted existing gene expression data from peripheral mononuclear blood cells (PBMCs) and single nucleotide polymorphisms (SNPs) in METTL3 and YTHDF3 from genome wide data from the Sorbs population (N=1049). The data were analysed for differential gene expression between OVAT and SAT; and for association with obesity and clinical variables. We further tested for association of SNP markers with gene expression and clinical traits.

Results

In adipose tissue we observed that several m6A regulators (WTAP, VIRMA, YTHDC1 and ALKBH5) correlate with obesity and clinical variables. Moreover, we found adipose tissue depot specific gene expression for METTL3, WTAP, VIRMA, FTO and YTHDC1. In PBMCs, we identified ALKBH5 and YTHDF3 correlated with obesity. Genetic markers in METTL3 associate with BMI whilst SNPs in YTHDF3 are associated with its gene expression.

Conclusions

Our data show that expression of m6A regulators correlates with obesity, is adipose tissue depot-specific and related to clinical traits. Genetic variation in m6A regulators adds an additional layer of variability to the functional consequences.
High Fasting Blood Glucose Level With Unknown Prior History of Diabetes Is Associated With High Risk of Severe Adverse COVID-19 Outcome
Authors: Wang Wenjun , Chai Zhonglin , Cooper Mark E. , Zimmet Paul Z. , Guo Hua , Ding Junyu , Yang Feifei , Chen Xu , Lin Xixiang , Zhang Kai , Zhong Qin , Li Zongren , Zhang Peifang , Wu Zhenzhou , Guan Xizhou , Zhang Lei , He Kunlun
Published: December 2021

Background

We aimed to understand how glycaemic levels among COVID-19 patients impact their disease progression and clinical complications.

Methods

We enrolled 2,366 COVID-19 patients from Huoshenshan hospital in Wuhan. We stratified the COVID-19 patients into four subgroups by current fasting blood glucose (FBG) levels and their awareness of prior diabetic status, including patients with FBG<6.1mmol/L with no history of diabetes (group 1), patients with FBG<6.1mmol/L with a history of diabetes diagnosed (group 2), patients with FBG≥6.1mmol/L with no history of diabetes (group 3) and patients with FBG≥6.1mmol/L with a history of diabetes diagnosed (group 4). A multivariate cause-specific Cox proportional hazard model was used to assess the associations between FBG levels or prior diabetic status and clinical adversities in COVID-19 patients.

Results

COVID-19 patients with higher FBG and unknown diabetes in the past (group 3) are more likely to progress to the severe or critical stage than patients in other groups (severe: 38.46% vs 23.46%-30.70%; critical 7.69% vs 0.61%-3.96%). These patients also have the highest abnormal level of inflammatory parameters, complications, and clinical adversities among all four groups (all p<0.05). On day 21 of hospitalisation, group 3 had a significantly higher risk of ICU admission [14.1% (9.6%-18.6%)] than group 4 [7.0% (3.7%-10.3%)], group 2 [4.0% (0.2%-7.8%)] and group 1 [2.1% (1.4%-2.8%)], (P<0.001). Compared with group 1 who had low FBG, group 3 demonstrated 5 times higher risk of ICU admission events during hospitalisation (HR=5.38, 3.46-8.35, P<0.001), while group 4, where the patients had high FBG and prior diabetes diagnosed, also showed a significantly higher risk (HR=1.99, 1.12-3.52, P=0.019), but to a much lesser extent than in group 3.

Conclusion

Our study shows that COVID-19 patients with current high FBG levels but unaware of pre-existing diabetes, or possibly new onset diabetes as a result of COVID-19 infection, have a higher risk of more severe adverse outcomes than those aware of prior diagnosis of diabetes and those with low current FBG levels.
Implications of Membrane Binding by the Fe-S Cluster-Containing N-Terminal Domain in the Drosophila Mitochondrial Replicative DNA Helicase
Authors: So Minyoung , Stiban Johnny , Ciesielski Grzegorz L. , Hovde Stacy L. , Kaguni Laurie S.
Published: December 2021

Recent evidence suggests that iron-sulfur clusters (ISCs) in DNA replicative proteins sense DNA-mediated charge transfer to modulate nuclear DNA replication. In the mitochondrial DNA replisome, only the replicative DNA helicase (mtDNA helicase) from Drosophila melanogaster (Dm) has been shown to contain an ISC in its N-terminal, primase-like domain (NTD). In this report, we confirm the presence of the ISC and demonstrate the importance of a metal cofactor in the structural stability of the Dm mtDNA helicase. Further, we show that the NTD also serves a role in membrane binding. We demonstrate that the NTD binds to asolectin liposomes, which mimic phospholipid membranes, through electrostatic interactions. Notably, membrane binding is more specific with increasing cardiolipin content, which is characteristically high in the mitochondrial inner membrane (MIM). We suggest that the N-terminal domain of the mtDNA helicase interacts with the MIM to recruit mtDNA and initiate mtDNA replication. Furthermore, Dm NUBPL, the known ISC donor for respiratory complex I and a putative donor for Dm mtDNA helicase, was identified as a peripheral membrane protein that is likely to execute membrane-mediated ISC delivery to its target proteins.
The Chemokine Receptor CCR5 Links Memory CD4+ T Cell Metabolism to T Cell Antigen Receptor Nanoclustering
Authors: Blanco Raquel , Gómez de Cedrón Marta , Gámez-Reche Laura , Martín-Leal Ana , González-Martín Alicia , Lacalle Rosa A. , Ramírez de Molina Ana , Mañes Santos
Published: December 2021

The inhibition of anabolic pathways, such as aerobic glycolysis, is a metabolic cornerstone of memory T cell differentiation and function. However, the signals that hamper these anabolic pathways are not completely known. Recent evidence pinpoints the chemokine receptor CCR5 as an important player in CD4+T cell memory responses by regulating T cell antigen receptor (TCR) nanoclustering in an antigen-independent manner. This paper reports that CCR5 specifically restrains aerobic glycolysis in memory-like CD4+T cells, but not in effector CD4+T cells. CCR5-deficient memory CD4+T cells thus show an abnormally high glycolytic/oxidative metabolism ratio. No CCR5-dependent change in glucose uptake nor in the expression of the main glucose transporters was detected in any of the examined cell types, although CCR5-deficient memory cells did show increased expression of the hexokinase 2 and pyruvate kinase M2 isoforms, plus the concomitant downregulation of Bcl-6, a transcriptional repressor of these key glycolytic enzymes. Further, the TCR nanoclustering defects observed in CCR5-deficient antigen-experienced CD4+T cells were partially reversed by incubation with 2-deoxyglucose (2-DG), suggesting a link between inhibition of the glycolytic pathway and TCR nanoscopic organization. Indeed, the treatment of CCR5-deficient lymphoblasts with 2-DG enhanced IL-2 production after antigen re-stimulation. These results identify CCR5 as an important regulator of the metabolic fitness of memory CD4+T cells, and reveal an unexpected link between T cell metabolism and TCR organization with potential influence on the response of memory T cells upon antigen re-encounter.
Imiquimod Boosts Interferon Response, and Decreases ACE2 and Pro-Inflammatory Response of Human Bronchial Epithelium in Asthma
Authors: Nieto-Fontarigo Juan José , Tillgren Sofia , Cerps Samuel , Sverrild Asger , Hvidtfeldt Morten , Ramu Sangeetha , Menzel Mandy , Sander Adam Frederik , Porsbjerg Celeste , Uller Lena
Published: December 2021

Background

Both anti-viral and anti-inflammatory bronchial effects are warranted to treat viral infections in asthma. We sought to investigate if imiquimod, a TLR7 agonist, exhibits such dual actions in ex vivo cultured human bronchial epithelial cells (HBECs), targets for SARS-CoV-2 infectivity.

Objective

To investigate bronchial epithelial effects of imiquimod of potential importance for anti-viral treatment in asthmatic patients.

Methods

Effects of imiquimod alone were examined in HBECs from healthy (N=4) and asthmatic (N=18) donors. Mimicking SARS-CoV-2 infection, HBECs were stimulated with poly(I:C), a dsRNA analogue, or SARS-CoV-2 spike-protein 1 (SP1; receptor binding) with and without imiquimod treatment. Expression of SARS-CoV-2 receptor (ACE2), pro-inflammatory and anti-viral cytokines were analyzed by RT-qPCR, multiplex ELISA, western blot, and Nanostring and proteomic analyses.

Results

Imiquimod reduced ACE2 expression at baseline and after poly(I:C) stimulation. Imiquimod also reduced poly(I:C)-induced pro-inflammatory cytokines including IL-1β, IL-6, IL-8, and IL-33. Furthermore, imiquimod increased IFN-β expression, an effect potentiated in presence of poly(I:C) or SP1. Multiplex mRNA analysis verified enrichment in type-I IFN signaling concomitant with suppression of cytokine signaling pathways induced by imiquimod in presence of poly(I:C). Exploratory proteomic analyses revealed potentially protective effects of imiquimod on infections.

Conclusion

Imiquimod triggers viral resistance mechanisms in HBECs by decreasing ACE2 and increasing IFN-β expression. Additionally, imiquimod improves viral infection tolerance by reducing viral stimulus-induced epithelial cytokines involved in severe COVID-19 infection. Our imiquimod data highlight feasibility of producing pluripotent drugs potentially suited for anti-viral treatment in asthmatic subjects.
Chimeric Fusion (F) and Attachment (G) Glycoprotein Antigen Delivery by mRNA as a Candidate Nipah Vaccine
Authors: Loomis Rebecca J. , DiPiazza Anthony T. , Falcone Samantha , Ruckwardt Tracy J. , Morabito Kaitlyn M. , Abiona Olubukola M. , Chang Lauren A. , Caringal Ria T. , Presnyak Vladimir , Narayanan Elisabeth , Tsybovsky Yaroslav , Nair Deepika , Hutchinson Geoffrey B. , Stewart-Jones Guillaume B. E. , Kueltzo Lisa A. , Himansu Sunny , Mascola John R. , Carfi Andrea , Graham Barney S.
Published: December 2021

Nipah virus (NiV) represents a significant pandemic threat with zoonotic transmission from bats-to-humans with almost annual regional outbreaks characterized by documented human-to-human transmission and high fatality rates. Currently, no vaccine against NiV has been approved. Structure-based design and protein engineering principles were applied to stabilize the fusion (F) protein in its prefusion trimeric conformation (pre-F) to improve expression and increase immunogenicity. We covalently linked the stabilized pre-F through trimerization domains at the C-terminus to three attachment protein (G) monomers, forming a chimeric design. These studies detailed here focus on mRNA delivery of NiV immunogens in mice, assessment of mRNA immunogen-specific design elements and their effects on humoral and cellular immunogenicity. The pre-F/G chimera elicited a strong neutralizing antibody response and a superior NiV-specific Tfh and other effector T cell response compared to G alone across both the mRNA and protein platforms. These findings enabled final candidate selection of pre-F/G Fd for clinical development.
IL1β Promotes TMPRSS2 Expression and SARS-CoV-2 Cell Entry Through the p38 MAPK-GATA2 Axis
Authors: Cioccarelli Chiara , Sánchez-Rodríguez Ricardo , Angioni Roberta , Venegas Francisca C. , Bertoldi Nicole , Munari Fabio , Cattelan Annamaria , Molon Barbara , Viola Antonella
Published: December 2021

After the outburst of the SARS-CoV-2 pandemic, a worldwide research effort has led to the uncovering of many aspects of the COVID-19, among which we can count the outstanding role played by inflammatory cytokine milieu in the disease progression. Despite that, molecular mechanisms that regulate SARS-CoV-2 pathogenesis are still almost unidentified. In this study, we investigated whether the pro-inflammatory milieu of the host affects the susceptibility of SARS-CoV-2 infection by modulating ACE2 and TMPRSS2 expression. Our results indicated that the host inflammatory milieu favors SARS-CoV-2 infection by directly increasing TMPRSS2 expression. We unveiled the molecular mechanism that regulates this process and that can be therapeutically advantageously targeted.
Qigong for Muscle Strength and Static Postural Control in Middle-Aged and Older Postmenopausal Women: A Randomized Controlled Trial
Authors: Carcelén-Fraile María del Carmen , Aibar-Almazán Agustín , Martínez-Amat Antonio , Brandão-Loureiro Vânia , Jiménez-García José Daniel , Castellote-Caballero Yolanda , Hita-Contreras Fidel
Published: December 2021

In the present study, we aimed to determine the effects of a Qigong exercise program on the muscle strength and postural control in middle-aged and older postmenopausal women. This is a randomized clinical trial (https://clinicaltrials.gov/ct2/show/NCT03989453) conducted on 125 women who were initially assigned to either an experimental group (n = 63) that performed a Qigong exercise program for 12 weeks or to a control group (n = 62) that did not receive any intervention. Muscle strength (dynamometer) and postural control (stabilometric platform) were evaluated before and immediately after an intervention period. The main findings of this study suggest that the women in the experimental group had improvements in muscle strength, mean velocity of the displacement of the center of pressure (CoP) with both eyes open and closed, and the surface sway area covered by the CoP, as well as the mediolateral and anteroposterior oscillations of the CoP, only with eyes open. The results of the present study determined that a 12 week Qigong exercise program has beneficial effects on muscle strength and postural control of middle-aged and older postmenopausal Spanish women.
Production of SARS-CoV-2 N Protein-Specific Monoclonal Antibody and Its Application in an ELISA-Based Detection System and Targeting the Interaction Between the Spike C-Terminal Domain and N Protein
Authors: Kim Dongbum , Kim Jinsoo , Park Sangkyu , Kim Minyoung , Baek Kyeongbin , Kang Mijeong , Choi Jun-Kyu , Maharjan Sony , Akauliya Madhav , Lee Younghee , Kwon Hyung-Joo
Published: December 2021

SARS-CoV-2 infections continue to spread quickly by human-to-human transmission around the world. Therefore, developing methods to rapidly detect SARS-CoV-2 with high sensitivity are still urgently needed. We produced a monoclonal antibody that specifically detects the N protein of SARS-CoV-2 and recognizes N protein in cell lysates of SARS-CoV-2–infected Vero cells but not in cell lysates of MERS-CoV- or HCoV-OC43-infected Vero cells. This antibody recognized N protein in SARS-CoV-2 clades S, GR, and GH and recognized N protein in all the SARS-CoV-2 clades to ∼300 pfu. Previously, we reported that the coronavirus N protein interacts with the C-terminal domain of the spike protein (Spike CD). In this study, we developed an ELISA-based “bait and prey” system to confirm the interaction between SARS-CoV-2 Spike CD and N protein using recombinant fusion proteins. Furthermore, this system can be modified to quantitatively detect SARS-CoV-2 in culture media of infected cells by monitoring the interaction between the recombinant Spike CD fusion protein and the viral N protein, which is captured by the N protein–specific antibody. Therefore, we conclude that our N protein–specific monoclonal antibody and our ELISA-based bait and prey system could be used to diagnose SARS-CoV-2 infections.
Co-circulation of a Novel Dromedary Camel Parainfluenza Virus 3 and Middle East Respiratory Syndrome Coronavirus in a Dromedary Herd With Respiratory Tract Infections
Authors: Teng Jade Lee Lee , Wernery Ulrich , Lee Hwei Huih , Fung Joshua , Joseph Sunitha , Li Kenneth Sze Ming , Elizabeth Shyna Korah , Fong Jordan Yik Hei , Chan Kwok-Hung , Chen Honglin , Lau Susanna Kar Pui , Woo Patrick Chiu Yat
Published: December 2021

Since the emergence of Middle East Respiratory Syndrome (MERS) in 2012, there have been a surge in the discovery and evolutionary studies of viruses in dromedaries. Here, we investigated a herd of nine dromedary calves from Umm Al Quwain, the United Arab Emirates that developed respiratory signs. Viral culture of the nasal swabs from the nine calves on Vero cells showed two different types of cytopathic effects (CPEs), suggesting the presence of two different viruses. Three samples showed typical CPEs of Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) in Vero cells, which was confirmed by partial RdRp gene sequencing. Complete genome sequencing of the three MERS-CoV strains showed that they belonged to clade B3, most closely related to another dromedary MERS-CoV isolate previously detected in Dubai. They also showed evidence of recombination between lineages B4 and B5 in ORF1ab. Another three samples showed non-typical CPEs of MERS-CoV with cell rounding, progressive degeneration, and detachment. Electron microscopy revealed spherical viral particles with peplomers and diameter of about 170nm. High-throughput sequencing and metagenomic analysis showed that the genome organization (3'-N-P-M-F-HN-L-5') was typical of paramyxovirus. They possessed typical genome features similar to other viruses of the genus Respirovirus, including a conserved motif 323FAPGNYALSYAM336 in the N protein, RNA editing sites 5'-717AAAAAAGGG725-3', and 5'-1038AGAAGAAAGAAAGG1051-3' (mRNA sense) in the P gene with multiple polypeptides coding capacity, a nuclear localization signal sequence 245KVGRMYSVEYCKQKIEK261 in the M protein, a conserved sialic acid binding motif 252NRKSCS257 in the HN protein, conserved lengths of the leader (55nt) and trailer (51nt) sequences, total coding percentages (92.6–93.4%), gene-start (AGGANNAAAG), gene-end (NANNANNAAAAA), and trinucleotide intergenic sequences (CTT, mRNA sense). Phylogenetic analysis of their complete genomes showed that they were most closely related to bovine parainfluenza virus 3 (PIV3) genotype C strains. In the phylogenetic tree constructed using the complete L protein, the branch length between dromedary camel PIV3 (DcPIV3) and the nearest node is 0.04, which is >0.03, the definition used for species demarcation in the family Paramyxoviridae. Therefore, we show that DcPIV3 is a novel species of the genus Respirovirus that co-circulated with MERS-CoV in a dromedary herd in the Middle East.
Whole-Genome Sequencing of Gram-Negative Bacteria Isolated From Bovine Mastitis and Raw Milk: The First Emergence of Colistin mcr-10 and Fosfomycin fosA5 Resistance Genes in Klebsiella pneumoniae in Middle East
Authors: Tartor Yasmine H. , Abd El-Aziz Norhan K. , Gharieb Rasha M. A. , El Damaty Hend M. , Enany Shymaa , Soliman Enas A. , Abdellatif Samah S. , Attia Amira S. A. , Bahnass Mosa M. , El-Shazly Yousry A. , Elbediwi Mohammed , Ramadan Hazem
Published: December 2021

Antimicrobial resistance is a major concern in the dairy industry. This study investigated the prevalence, antimicrobial resistance phenotypes, and genome sequencing of Gram-negative bacteria isolated from clinical (n = 350) and subclinical (n = 95) bovine mastitis, and raw unpasteurized milk (n = 125). Klebsiella pneumoniae, Aeromonas hydrophila, Enterobacter cloacae (100% each), Escherichia coli (87.78%), and Proteus mirabilis (69.7%) were the most prevalent multidrug-resistant (MDR) species. Extensive drug-resistance (XDR) phenotype was found in P. mirabilis (30.30%) and E. coli (3.33%) isolates. Ten isolates (four E. coli, three Klebsiella species and three P. mirabilis) that displayed the highest multiple antibiotic resistance (MAR) indices (0.54–0.83), were exposed to whole-genome sequencing (WGS). Two multilocus sequence types (MLST): ST2165 and ST7624 were identified among the sequenced E. coli isolates. Three E. coli isolates (two from clinical mastitis and one from raw milk) belonging to ST2165 showed similar profile of plasmid replicon types: IncFIA, IncFIB, IncFII, and IncQ1 with an exception to an isolate that contained IncR, whereas E. coli ST7624 showed a different plasmid profile including IncHI2, IncHI2A, IncI1α, and IncFII replicon types. ResFinder findings revealed the presence of plasmid-mediated colistin mcr-10 and fosfomycin fosA5 resistance genes in a K. pneumoniae (K1) isolate from bovine milk. Sequence analysis of the reconstructed mcr-10 plasmid from WGS of K1 isolate, showed that mcr-10 gene was bracketed by xerC and insertion sequence IS26 on an IncFIB plasmid. Phylogenetic analysis revealed that K1 isolate existed in a clade including mcr-10-harboring isolates from human and environment with different STs and countries [United Kingdom (ST788), Australia (ST323), Malawi (ST2144), Myanmar (ST705), and Laos (ST2355)]. This study reports the first emergence of K. pneumoniae co-harboring mcr-10 and fosA5 genes from bovine milk in the Middle East, which constitutes a public health threat and heralds the penetration of the last-resort antibiotics. Hence, prudent use of antibiotics in both humans and animals and antimicrobial surveillance plans are urgently required.
Autochthonous Probiotics Alleviate the Adverse Effects of Dietary Histamine in Juvenile Grouper (Epinephelus coioides)
Authors: Liu Zi-Yan , Yang Hong-Ling , Hu Ling-Hao , Yang Wei , Ai Chun-Xiang , Sun Yun-Zhang
Published: December 2021

High dose (0.3%) of dietary histamine can cause adverse effects on growth performance, innate immunity, and gut health in juvenile grouper (Epinephelus coioides). In the present study, three autochthonous probiotics (Bacillus pumilus SE5, Psychrobacter sp. SE6, and Bacillus clausii DE5) were supplemented separately to diets containing 0.3% of histamine and their effects on growth performance, innate immunity, and gut health of grouper (E. coioides) were evaluated in a 56-day feeding trial. The results showed considerable increase in weight gain, specific growth rate, hepatosomatic index, and decreased feed conversion rate in groupers fed with probiotic-supplemented diets. Supplementation of autochthonous probiotics has improved antioxidant capacity and innate immunity of E. coioides by measuring correlative parameters, such as total antioxidant capacity, superoxide dismutase activity, malondialdehyde content, and so on. Additionally, dietary probiotics have significantly reduced the levels of serum interleukin-1β (at days 28 and 56), fatty acid-binding protein 2, and intestinal trefoil factor (at day 28), and promoted intestinal integrity following remarkably increased muscle thickness and mucosal fold height at day 56, especially in grouper fed with B. pumilus SE5 containing diet (P < 0.05). On day 56, the gut microbial composition of E. coioides was positively shaped by autochthonous probiotics, the relative abundance of potentially pathogenic Photobacterium decreased while beneficial Lactobacillus increased in fish fed with probiotic strains, especially with B. pumilus SE5 and B. clausii DE5. These results suggest that among the three autochthonous probiotic strains tested, B. pumilus SE5 is showing better efficiency in alleviating the adverse effects of (high levels) dietary histamine by decreasing the expression of inflammatory markers and by improving the growth, innate immunity, and gut health of juvenile grouper E. coioides.
Effects of Ellagic Acid Supplementation on Jejunal Morphology, Digestive Enzyme Activities, Antioxidant Capacity, and Microbiota in Mice
Authors: Xu Qiuying , Shen Mingkang , Han Yuxin , Diao Hui
Published: December 2021

Ellagic acid (EA), a plant polyphenol mainly found in nuts and fruits, exhibits various biological effects. However, the effects of EA on intestinal health remain poorly understood. Hence, the present study aimed to assess the effects of EA supplementation on jejunal morphology, digestive enzyme activities, antioxidant capacity, and microbiota in C57BL/6J mice. A total of 144 mice were randomly assigned to three treatments groups: the control (CON) group received a standard pellet diet, the 0.1% EA group received a standard pellet diet plus 0.1% EA, and the 0.3% EA group received a standard pellet diet plus 0.3% EA. The mice were killed at the end of the experimental period, and jejunal samples were collected. The results revealed that the mice in the 0.3% EA group had higher (P < 0.05) average daily gain and greater (P < 0.05) jejunal villus height than those in the CON group. In addition, the jejunal lactase and sucrase activities were higher (P < 0.05) in the 0.1% EA and 0.3% EA groups, and the alkaline phosphatase activity was higher (P < 0.05) in the 0.3% EA group than in the CON group. Compared with the CON group, the administration of EA increased (P < 0.05) the superoxide dismutase and catalase activities but decreased (P < 0.05) the malonaldehyde content in the jejunum. Moreover, the jejunal messenger RNA expression levels of nuclear factor-E2-related factor 2 (Nrf2) and haem oxygenase-1 (HO-1) were higher (P < 0.05) in the 0.3% EA group than in the CON group. Furthermore, compared with the CON group, the count of Escherichia coli decreased (P < 0.05), and that of Lactobacillus species increased (P < 0.05) in the 0.3% EA group. In general, our findings indicate that the administration of EA can enhance the growth of mice, promote intestinal development, increase the antioxidant capacity, and regulate the intestinal microbiota.
A Mathematical Model to Characterize the Role of Light Adaptation in Mammalian Circadian Clock
Authors: Shi Yuzeng , Liu Yu , Yang Ling , Yan Jie
Published: December 2021

In response to a light stimulus, the mammalian circadian clock first dramatically increases the expression of Per1 mRNA, and then drops to a baseline even when light persists. This phenomenon is known as light adaptation, which has been experimentally proven to be related to the CRTC1-SIK1 pathway in suprachiasmatic nucleus (SCN). However, the role of this light adaptation in the circadian rhythm remains to be elucidated. To reveal the in-depth function of light adaptation and the underlying dynamics, we proposed a mathematical model for the CRTC1-SIK1 network and coupled it to a mammalian circadian model. The simulation result proved that the light adaptation is achieved by the self-inhibition of the CRTC1/CREB complex. Also, consistently with experimental observations, this adaptation mechanism can limit the phase response to short-term light stimulus, and it also restricts the rate of the phase shift in a jet lag protocol to avoid overly rapid re-entrainment. More importantly, this light adaptation is predicted to prevent the singularity behavior in the cell population, which represents the abolishment of circadian rhythmicity due to desynchronization of oscillating cells. Furthermore, it has been shown to provide refractoriness to successive stimuli with short gap. Therefore, we concluded that the light adaptation generated by the CRTC1-SIK1 pathway in the SCN provides a robust mechanism, allowing the circadian system to maintain homeostasis in the presence of light perturbations. These results not only give new insights into the dynamics of light adaptation from a computational perspective but also lead us to formulate hypotheses about the related physiological significance.
Economic Costs of Delayed Diagnosis of Functional Motor Disorders: Preliminary Results From a Cohort of Patients of a Specialized Clinic
Authors: Tinazzi Michele , Gandolfi Marialuisa , Landi Stefano , Leardini Chiara
Published: December 2021

Background: Functional motor disorders (FMDs) are prevalent and highly disabling conditions in young adults that can result in reduced independence. Despite advances in diagnosis and treatment, the economic burden of FMDs is largely unknown.

Objective: This pilot retrospective study provides a real-world overview of the economic costs related to delayed diagnosis of FMDs from a cohort of patients of a specialized clinic in Italy, based on Italian healthcare costs.

Methods: Sociodemographic data, clinical history, healthcare service utilization, and associated direct costs were collected for a period of up to 5 years before a definite diagnosis of FMDs in 40 patients.

Results: The mean time lag between the onset of FMDs symptoms and diagnosis was 6.63 years (±8.57). The mean annual use of recourses per patient was three specialist visits (95% CI 2.4–3.4) and three diagnostic examinations (95% CI 2.2–3.6) that made up a total of six investigations and over seven (95% CI 5.5–9.7) rehabilitation contacts per year per patient were used before a diagnosis of FMDs was established. In more than 50% of the cases, patients had been hospitalized or made an ER visit at least once before receiving the correct diagnosis. The average annual costs for delayed diagnosis, taking into account only direct healthcare costs (without medications), was about €2,302 (CI 95% €1,570–2,830) per patient [€1,524 covered by the NHS (CI 95% €1,214–1,834) and € 778 by the patient (CI 95% €606–960)]. Hospitalization accounted for €916 (CI 95% €670–1,160) per patient per year, followed by rehabilitation €493 (CI 95% €345–641) and diagnostic tests € 387 (CI 95% €314–460).

Conclusion: These preliminary results shed some light on the high healthcare services volume and direct healthcare costs from clinic to clinic for visits, unnecessary tests, and prescribed treatments in a real-world overview from a cohort of patients of a specialized clinic in Italy. It may represent a starting point for future studies to statistically test and quantify cost reduction after implementing appropriate healthcare pathways.