bluuebunny/crossref_metadata_2025 huggingface dataset:
Deciphering Local Adaptation Of Native Indian Cattle (Bos Indicus) Breeds Using Landscape Genomics And In-Silico Prediction Of Deleterious SNP Effects On Protein Structure And Function
Authors: Bhardwaj Shivam , Singh Sanjeev , Ganguly Indrajit , Bhatia Avnish Kumar , Dixit S. P.
Published: June 2021

Present study aimed to explore genomic basis of adaptation of Indian native cattle and to predict the impact of key SNPs on amino acid changes that affect protein function. Four native cattle breeds belonging to contrasting landscape and climatic conditions were genotyped using Illumina 777 K BovineHD BeadChip: Siri & Ladakhi from cold hilly areas, and Kankrej and Hallikar from hot arid and semi-arid regions, respectively. The R.SamBada package in R was used to perform the genotype-environment association analysis. A total of 1,12,780 significant (q < 0.05), models with 30,350 unique SNPs were obtained. Significantly associated SNPs had impact on 4,435 genes and 141 pathways. Only ten SNP variants had a SIFT score of < 0.05 (deleterious), and only two of them, each lying in the genes CRYBA1 and USP18, were predicted to be deleterious with high confidence.. RaptorX predicted the tertiary structures of proteins encoded by wild and mutant variants of these genes. The quality of the models was determined using Ramachandran plots and RaptorX parameters, indicating that they are accurate. RaptorX and I-Mutant 2.0 softwares revealed significant differences among wild and mutant proteins. Identified adaptive alleles might be responsible for the local adaptation of these cattle breeds.
The Economic Value of the Ecosystem Services of the Papenkuils Wetland – a Wetland in a Dryland
Authors: Horn Annabel Marian , Law Matthew , Lorentz Simon , Day Liz , Dalgliesh Christopher , Reuther Sue , Kloppers Wilna
Published: June 2021

The Wetlands in Drylands presented in this study focussed on the Papenkuils Wetland, which is in the Western Cape of South Africa, north of the Brandvlei Dam, and south west of Worcester, downstream of the confluence of the Breede (or Bree) and Smalblaar Rivers. This study sets out to establish the shadow price of the environmental services of this wetland, and to understand how this value changes with the possible future diversion of water to an agricultural dam before the Wetland, water provision to the wetlands. The study strongly recommends that the functionality of this wetland, as the largest in the Breede (Afrikaans word meaning wide) Catchment and with biodiversity that is recognised as an important remnant of habitats in the region, be maintained through management and sufficient inundation of water. This would be accompanied by a programme of abstraction for irrigation at a pumping station below the Papenkuils Wetland, as opposed to further abstraction of winter water above the wetland, as is currently proposed.
Nanomolar EP4 Receptor Potency and Expression of Eicosanoid- Related Enzymes in Normal Appearing Colonic Mucosa From Patients with Colorectal Neoplasia
Authors: Feddersen Ulrike Ries , Hendel Sebastian Kjærgaard , Berner-Hansen Mark Alexander , Jepps Thomas Andrew , Bindslev Niels , Berner-Hansen Mark
Published: June 2021

BackgroundAberrations in cyclooxygenase and lipoxygenase (LOX) pathways in non-neoplastic, normal appearing mucosa from patients with colorectal neoplasia (CRN), could hypothetically qualify as predisposing CRN-markers. To test this hypothesis, biopsies were obtained during colonoscopy from macroscopically normal colonic mucosa from patients with and without CRN. Prostaglandin E2 (PGE2) receptors, EP1-4, were examined in Ussing-chambers by exposing biopsies to selective EP receptor agonists, antagonists and PGE2. Furthermore, mRNA expression of EP receptors, prostanoid synthases and LOX enzymes were evaluated using qPCR technology.Results Data suggest that PGE2 binds to high and low affinity EP receptors. In particular, PGE2 demonstrated EP4 receptor potency in the low nanomolar range. Similar results were detected using EP2 and EP4 agonists. In CRN patients, mRNA-levels were higher for EP1 and EP2 receptors and for enzymes prostaglandin-I synthase, 5-LOX, 12-LOX and 15-LOX. ConclusionIn conclusion, normal appearing colonic mucosa from CRN patients demonstrates deviating expression in eicosanoid pathways, indicating a likely predisposition for early CRN development. Moreover, PGE2 potency activates high affinity EP4 receptor subtypes, supporting relevance of testing EP4 antagonists in colorectal cancer management.
Underrecognized Sleep Disorders Across Rare Diseases: Real-world Insights From a Patient and Caregiver Summit
Authors: Picone Maria , Naujokas Marisa F. , Gorman Casey , Jesteadt Lindsay , Kelly Erica , Kelly Jeremy , King Rebecca , Maier Steve , O’Shaughnessy Sharon , Pullen Lara C. , Rivard Paige , Strong Theresa V , Pfalzer Anna C , Bichell Terry Jo
Published: June 2021

Background: Disorders of sleep-wake stability have a negative impact on patient and caregiver quality of life. There is evidence that sleep disorders and their sequelae may be an underrecognized burden for people living with rare diseases. Given that the sleep-wake cycle is regulated via the hypothalamus, people with neurological disorders may be particularly affected. To collect real-world insights into the impact of sleep disturbances and excessive daytime sleepiness (EDS) on people with rare disorders, Harmony Biosciences organized a Summit on Sleep Disruption. The attendees were from seven patient advocacy groups, each representing a rare neurological disorder reporting sleep disturbances, specifically EDS: Angelman syndrome, idiopathic hypersomnia, Kleine-Levin syndrome, myotonic dystrophy, narcolepsy, Prader-Willi syndrome, and Smith-Magenis syndrome. One person represented COMBINEDBrain, a patient advocacy consortium representing 25 rare, genetic neurological disorders. Results: The overwhelming response was that disordered sleep, particularly EDS, is a major health problem within their populations that they feel is not adequately diagnosed or treated. Participants felt that burdens associated with sleep disturbances were underrecognized as a treatable medical issue and were not effectively addressed by health care providers. Participants noted the following unmet needs: patient and physician education on sleep disturbance, effective medications approved for these disease populations, and medically acceptable patient-centered devices to measure sleep parameters. Participants described impacts of disordered sleep and EDS on behavior and school performance, describing impaired wakefulness as an interference with normal daytime functioning. Participants also revealed tremendous burdens on the caregivers and family members who live with people experiencing sleep-wake instability. Conclusions: These results provide real-world insights that disordered sleep including EDS and subsequent impaired daytime functioning are major burdens in these rare disease communities. Furthermore, these burdens are underrecognized for caregivers and, for some rare diseases, among the patients themselves. Participants identified gaps in knowledge and treatment of sleep disorders and resolved to continue the dialog to find ways to raise awareness of disordered sleep and reduce burdens in these patient populations.
Evaluation of A Simultaneous Adsorption Device For Cytokines And Neutrophil-Platelet Complexes In Vitro And In A Lung-Protective Ventilated Rabbit Acute Lung Injury Model
Authors: Sekiya Yumiko , Shimada Kaoru , Takahashi Hiroshi , Kuga Chisa , Komachi Shunsuke , Miwa Keishi , Kotani Toru
Published: June 2021

Background: Neutrophil-platelet complexes (NPCs) readily migrate into tissues and induce tissue damage via cytokine or other pathogenic factors release. These actions are involved in onset and progression of acute respiratory distress syndrome (ARDS). Thus, simultaneous removal of cytokines and activated neutrophils that includes NPCs by blood purification may prevent development of ARDS and enhance drug effects. The goal of this study was to examine the effect of a newly developed adsorption column (NOA-001) that eliminates cytokines and activated neutrophils in a lung injury model.Results: Adsorption of cytokines such as IL-8, IL-6 and HMGB-1, and NPCs was first measured in vitro. Lung injury was induced by HCl and lipopolysaccharide intratracheal infusion in rabbits ventilated at a low tidal volume (7-8 mL/kg) and PEEP (2.5 cmH2O) for lung protection. Arterial blood gas, hematologic values, plasma IL-8, blood pressure and heart rate were measured, and lung damage was evaluated histopathologically in animals treated with 8-hour direct hemoperfusion with or without use of NOA-001. The in vitro adsorption rates for IL-8, IL-6, HMGB-1, activated granulocytes and NPCs were 99.4 ± 0.0164%, 63.6 ± 0.367%, 59.0 ± 1.58%, 7.05 ± 9.63% and 55.7 ± 12.7%, respectively. Absorption of NPCs onto fibers was confirmed microscopically. These adsorption effects were associated with several improvements in the rabbit model. In respiratory function, the PaO2/FIO2 ratios at 8 h were 314 ± 55.3 mmHg in the NOA-001 group and 134 ± 40.8 mmHg in the sham group. The oxygenation index and PaCO2 also differed significantly between the two groups (p<0.05). Acidosis was observed in the sham group, whereas blood pH was maintained within the normal range in the NOA-001 group (p<0.05). In lung histopathology, fewer hyaline membrane and inflammatory cells were observed in the NOA-001 group.Conclusion: A column for simultaneous removal of cytokines and NPCs showed efficacy for improvement of pulmonary function in an animal model. This column may be effective in support of treatment of ARDS.
Multicenter Observational Study on Detection of Atrial Fibrillation Using Insertable Cardiac Monitors in Patients With Cryptogenic Stroke in Japan : LOOK Registry - Study Design and Characteristics
Authors: Suda Satoshi , Katano Takehiro , Kitagawa Kazuo , Iguchi Yasuyuki , Fujimoto Shigeru , Ono Kenjiro , Kano Osamu , Takekawa Hidehiro , Koga Masatoshi , Ihara Masafumi , Morimoto Masafumi , Yamagami Hiroshi , Terasaki Tadashi , Yamaguchi Keiji , Okubo Seiji , Ueno Yuji , Ohara Nobuyuki , Kamiya Yuki , Takeuchi Masataka , Yazawa Yukako , Terasawa Yuka , Doijiri Ryosuke , Tsuboi Yoshifumi , Sonoda Kazutaka , Nomura Koichi , Shimoyama Takashi , Kutsuna Akihito , Kimura Kazumi
Published: June 2021

The authors have requested that this preprint be removed from Research Square.
Chronic Exposure to Perfluorohexane Sulfonate Leads to a Reproduction Deficit by Suppressing Hypothalamic Kisspeptin Expression in Mice
Authors: Yin Xiaorui , Di Tingting , Cao Xinyuan , Liu Zhengnan , Xie Jingyan , Zhang Suyun
Published: June 2021

BackgroundPerfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid found as an environmental contaminant. This study aims to investigate the effects of PFHxS exposure on female reproduction and the underlying mechanism in mice. MethodsEight-week-old ICR mice were divided randomly into four groups: corn oil (vehicle) and PFHxS at doses of 0.5, 5, and 50 mg/kg/day for 42 days by intragastric administration. Body weight, ovarian weight, estrous cycle, follicle counts, and serum sex hormone levels were evaluated. Expression of kisspeptin and gonadotropin releasing hormone (GnRH) in the hypothalamus was also detected. ResultsCompared to vehicle exposure, 5 mg/kg/day PFHxS prolonged the estrous cycle, especially the duration of diestrus, after 42 days of treatment. The numbers of antral follicles and corpus lutea were significantly reduced in PFHxS-treated mice. Moreover, compared with the control group, PFHxS-treated mice showed decreases in serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (E2), and reduced GnRH mRNA levels, along with the lack of an LH surge. Furthermore, PFHxS-treated mice had lower levels of kisspeptin immunoreactivity and kiss-1 mRNA in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV). After intraventricular administration of kisspeptin-10, the numbers of antral follicles and corpus lutea recovered, along with the levels of GnRH mRNA, FSH, and LH in mice treated with 5 mg/kg/day PFHxS. Conclusion﻿These results indicate that chronic exposure of mice to 5 mg/kg/day PFHxS affects reproductive functions by inhibiting kisspeptin expression in the ARC and AVPV regions, leading to the deficit of follicular development and ovulation.
Children’s Screen Time At Home: A Study of Parents’ Knowledge, Attitude and Practice
Authors: Arippin Nur Fatin-Aqilah , Mahmud Mardiah Haji , Rahman Hanif Abdul , Aliy-Yuin Kolinmo-Yumni A. , Lai Swee Ching Linda , Abdul-Mumin Khadizah H.
Published: June 2021

Background

The present study investigated the parent’s knowledge, attitude, practice and experience of the screen time spent by their children at home aged below five years old, identify the common screen-based devices use, content type and level of screen time spent by the children and identify the association between sociodemographic variables and parent’s knowledge, attitude and practice on screen time.
Methods

We assessed target population of parents having children aged zero to four years old attending the Maternal and Child Health Care Clinics in four districts in Brunei Darussalam.
Results

Parents’ attitude and practice of screen time spent by their children are generally positive, however, the health knowledge level is poor with scores of < 50%. Children studied (< 2 years old and 3 to 4 years old) found to spent more time watching television. Interactive form of screen time content was mostly spent by the children (50%). Statistically significant association observed between children of both aged group with time spent on tablet device (p = 0.037) and (p = < 0.001). Also, significant association between parent’s knowledge, attitude and practice with gender of the parents, household income and total number of children was reported.
Conclusion

The children in our study exceeds the recommended guidelines on screen time behavior and the parent’s health knowledge with regards to screen time was poor which emphasized the need for improvement and further study.
Spreading Dynamics Analysis of a Novel SEAIRS Epidemic Model with Protection and Hospital Quarantine under Government Pre-warning
Authors: Xue Bingchuan , Li Tao , Cheng Xinming , Li Yumiao , Wu Yuanyuan , Shi Gaojun
Published: June 2021

To study the impact of protection and hospital quarantine measure, government pre-warning mechanism and heterogeneity of underlying networks on epidemic spreading, a novel SEAIRS epidemic model is proposed on scale-free networks. The spreading dynamics of the model is studied by means of the mean-field theory. Two equilibriums and the basic reproductive number R0 of the model is analyzed in detail. The global asymptotic stability of the disease-free equilibrium, the permanence of the epidemic spreading and the global attractivity of the endemic equilibrium are proved. Sensitivity analysis shows that the basic reproductive number R0 is dependent on the coverage rate of home quarantine (ωQ,ηA ,ηS ), hospitalization rate η1 and government pre-warning intensity δ . Finally, the theoretical analysis results are confirmed by means of numerical simulations.
Pleistocene-Holocene Monogenetic Volcanism at Malko-Petropavlovsk Zone of Transverse Dislocations on Kamchatka: Geological Setting, Spatial, Geochemical Paticular Features and Potential Volcanic Hazards
Authors: Bergal-Kuvikas Olga , Bindeman Ilya , Chugaev Andrey , Larionova Yulia , Perepelov Alexander , Khubaeva Olga
Published: June 2021

Based on government statistical data ~80% of the local Kamchatkan population (~250 ka people) live in the major cities on the coastal line of Avacha Gulf . It is the main transport seaway to Kamchatka , and and important Asia - North America air transport corridor. The Avacha Gulf is located in the Malko-Petropavlovsk zone of transverse dislocations (MPZ) on the extension of deep transform fault on the boundary between various ly aged slabs. Most of monogenetic cinder cones chaotic distributed in relation to the trench and belong to the long-living rupture zones of MPZ. Some of the monogenetic volcanoes are parasitic cones on the slopes of Koryaksky and Avachinsky stratovolcanoes and related with their magma plumbing systems. We here present new results of the geochemical and isotopic stud ies of monogenetic volcanism in MPZ. Based on whole rock and trace element geochemistry, Sr-Nd-Pb isotopic ratios of monogenetic volcanism, ­­ magmas were shown to sample the enriched mantle source with dominance decompression melting without significant inputs of the slab`s components. Calculations of the P, T conditions suggest magma residence of monogenetic cinder cones on the Moho boundary. That correlates with the geophysical observation of crustal discontinuity under the MPZ. Monogenetic cinder cones have an active magma plumbing system because during the Holocene time were several periods of activations. Presented results show necessary install continuous monitoring of environment changing around the Avacha Gulf and more serious attention from government and science. A more detailed investigation of MPZ will help degrease potential risks of eruptions from monogenetic volcanoes for human and infrastructures.
Evaluation Method of Node Importance in Temporal Satellite Networks Based on Time Slot Correlation
Authors: Xu Rui , Di Xiaoqiang , He Xiongwen , Qi Hui
Published: June 2021

Temporal satellite networks can accurately describe the dynamic process of satellite networks by considering the interaction relationship and interaction sequence between satellite nodes. In addition, the measurement of node importance in satellite networks plays a crucial role in understanding the structure and function of the network. The classical supra-adjacency matrix (SAM) temporal model identifies the key nodes in the temporal network to some extent, which ignores the differences of inter-layer connectivity relationships leading to the inability to reflect the dynamic variations of satellite nodes. Therefore, the evaluation method based on time slot correlation is proposed to measure the importance of satellite nodes in this paper. Firstly, the correlation coefficient of time slot nodes is defined to measure the coupling relationship of adjacent time slots. Secondly, the dynamic supra-adjacency matrix (DSAM) temporal network model is proposed considering the correlation between adjacent time slots and the characteristics of link time. Finally, the node importance ranking results in each time slot and a global perspective are obtained by utilizing the eigenvector centrality. Through experimental simulations of the Iridium and Orbcomm constellations, it is demonstrated that the DSAM method has a more accurate recognition rate and is more stable than the SAM method.
Dye Anionic Removal From Water by Green Synthesized Nannochloropsis Sp.- Cetyltrimethylammonium Bromide Surfactant: Kinetics, Adsorption Isotherm and Adsorbent Regeneration
Authors: . Buhani , Miftahza Nurul , . Suharso , Permatasari Desy , . Sumadi
Published: June 2021

The authors have requested that this preprint be removed from Research Square.
Dynamic Handgrip Exercise: Feasibility and Physiologic Stress Response of a Needle-Free Cmr Stress Test
Authors: Ochs Andreas , Nippes Michael , Salatzki Janek , Weberling Lukas D , Riffel Johannes , Müller-Hennessen Matthias , Giannitsis Evangelos , Osman Nael , Stehning Christian , André Florian , Katus Hugo A , Frey Norbert , Friedrich Matthias G , Ochs Marco M
Published: June 2021

Purpose: CMR pharmacological stress-testing is well-established to detect myocardial ischemia. Despite stressor and contrast agents appear rather save, contraindications and side effects have to be considered. Substantial costs are further limiting its applicability. Dynamic handgrip exercise(DHE) may have the potential to address these shortcomings as a physiological stressor. We therefore evaluated the feasibility and physiologic stress response of DHE in relation to pharmacological dobutamine-stimulation by cardiac magnetic resonance(CMR).Methods: Two subgroups were prospectively enrolled: (i)volunteers without relevant disease and (ii)patients with known CAD referred for stress-testing. A both-handed, metronome-guided DHE was performed over 2 minutes continuously with 80 contractions/minute by all participants, whereas dobutamine stress-testing was only performed in group(ii). Short axis strain by fast-Strain-ENCoded imaging was acquired at rest, immediately after DHE and during dobutamine infusion. Results: Eighty middle-aged individuals(age 56±17years, 48males) were enrolled. DHE triggered significant positive chronotropic(HRrest:68±10bpm, HRDHE:91±13bpm, p<0.001) and inotropic stress response(GLSrest:-19.4±1.9%, GLSDHE:-20.6±2.1%, p<0.001). Exercise-induced increase of longitudinal strain was present in healthy volunteers and CAD patients to the same extent, but in general pronounced from basal to apical layers(p<0.01). DHE was aborted by a minor portion(7%) due to peripheral fatigue. The inotropic effect of DHE appears to be non-inferior to intermediate dobutamine-stimulation(GLSDHE=-19.5±2.3%, GLSDob=-19.1±3.1%, p=n.s.), whereas its chronotropic effect was superior (HRDHE=89±14bpm, HRDOB=78±15bpm, p<0.001). Conclusions: DHE causes positive ino- and chronotropic effects superior to intermediate dobutamine-stimulation, suggesting a relevant increase of myocardial oxygen demand. DHE appears safe and timesaving with broad applicability. The data encourages further studies to determine its potential to detect obstructive CAD.
Risk Factors Associated with Self-Removal of Shoulder Braces After Rotator Cuff Repair
Authors: Won Yoo-Sun , Lee Jae Sung , Jung Hyoung-Seok , Jang Ye-Hoon , Jung Chan-Woo , Kim Jae Yoon
Published: June 2021

Background: Rotator cuff repair is a widely performed surgery, with the re-tear rate reportedly above 20%. To protect the repair site, patients are instructed to wear braces for 4-6 weeks, but the compliance is known to be poor. This study aimed to identify the risk factors for poor compliance and to determine whether poor compliance leads to complications such as re-tears. Additionally, we planned to determine the patients’ subjective factors for self-removal of the brace.Method: This study included 101 patients who underwent rotator cuff repair between June 2019 and August 2020. The patients could select from two types of braces, namely, the sling-type and hard-type abduction brace. They were then instructed to wear the brace for 6 weeks postoperatively. During the follow-up, ultrasonography was performed to evaluate the repair site, and a questionnaire was administered to evaluate the compliance. Result: The participants were categorized into three groups (Groups A, B, and C) according to the degree of self-removal. Compliance was found to be poor, and only 35 patients met the standard of Group A. There were no statistically significant patient factors affecting the compliance. Re-tears were noted in 4 patients. Only the surgery type (open versus arthroscopic surgery) was a statistically significant factor for re-tears. Among the subjective factors, discomfort while sleeping was the most common complaint and the most common reason for the actual removal of the brace.Conclusion: Although the risk factors for self-removal of the braces could not be identified clearly and statistically, catastrophic re-tears requiring re-operation were observed in patients with poor compliance. For better compliance, the postoperative guidelines and education of the patients should be reviewed. Furthermore, the braces need to be modified to a more comfortable design.
Encapsulated Allogeneic Synovial Membrane Mesenchymal Stem Cells Provide Better Outcomes of Chondral Lesions in Horses
Authors: Santos Vitor Hugo , Pfeifer João Pedro Hübbe , Stievani Fernanda de Castro , Rosa Gustavo Santos , Apolonio Emanuel Vitor Pereira , Rossi Mariana Correa , Constantino Leonel Vinicius , de Melo Thadeu Rodrigues , Fonseca-Alves Carlos Eduardo , Alves Ana Liz Garcia
Published: June 2021

BackgroundOsteoarthritis is the main cause of equine lameness and its treatment remains ineffective. Synovial membrane mesenchymal stem cells (SMMSC) provide satisfactory outcomes in joint injuries, mainly due to their immunomodulatory and reparative properties. This study aimed to evaluate the effect of MSMSC, either encapsulated in alginate hydrogel or free, in chondral lesions of horses.MethodsChondral lesions were surgically induced in medial trochlea of talus of fifteen horses. Animals were treated with PBS, 1x107 free SMMSC or 1x107 encapsulated SMMSC. Physical evaluations, lameness scores and synovial fluid analysis were determined (cytological analysis and dosage of IL-1, IL-10, IL-6, INF-Ɣ, TNF 𝛼, P Substance, Serum Amyloid A, TGF-β, IGF and PGE2) initially and followed for up to two weeks. Cartilage biopsies were performed 150 days after the induction for histological analysis and immunohistochemistry staining.ResultsAll groups presented inflammation initially. Although free SMMSC showed moderate tissue repair, encapsulated SMMSC modulated inflammation and had the lower grade of inflammation with superior tissue macro and microscopic aspects at the end, while the control group showed fibrosis and poor cartilage appearance. This study suggests better stem cell effectiveness in chondral defects when encapsulated MSCs are used.ConclusionsWhile the absence of treatment perpetuates cartilage degradation, encapsulated SMMSC responded better to the initial inflammation, interacting and modulating the environment through the release of anti-inflammatory cytokines. Better outcomes observed in encapsulated MSCs were related to the immuno and physical barrier provided by the alginate hydrogel, allowing a longer period of permanence and interaction between MSCs and the environment.
Comparison of Blood Test Data Between Patients With COVID-19 and Influenza: a Retrospective Cross-sectional Survey in a Japanese University Hospital
Authors: Fukui Sayato , Inui Akihiro , Saita Mizue , Kobayashi Daiki , Naito Toshio
Published: June 2021

Background: Characteristics features, including blood test data, of COVID-19 compared to those of influenza have not been defined.Purpose: We aimed to compare clinical parameters, including blood test data, between COVID-19 and influenza.Methods: This retrospective cross-sectional survey was conducted at Juntendo University Nerima Hospital, Tokyo, Japan. We recruited patients diagnosed with COVID-19 between January 1 and December 31, 2020, and all patients underwent blood tests. For comparison, we recruited patients diagnosed with influenza. The number of patients with influenza and those with COVID-19 was the same. All patients with influenza underwent blood tests and the period was dated back from December 31, 2020 until the period that was the same number of COVID-19.Results: During the study period, 228 patients (male:female, 123 [54.0%]:105 [46.0%], age [mean±standard deviation], 54.68±18.98 years) were diagnosed with COVID-19. We recruited the same number of influenza patients (228 patients; male:female, 129 [56.6%]:99 [43.4%], age [mean±standard deviation], 69.6±21.25). Age 15–70 years (vs. 71 years), difficulty in breathing, malaise, and percentage of lymphocytes >20% were significantly more frequent in COVID-19. However, nausea, body temperature >38.1°C, and white blood cell count >9000/μL were more frequent in influenza.Conclusion: Our results are useful for differentiating COVID-19 from influenza.
Safety Monitoring Experience of Single-low Dose Primaquine Co-administered With Artemether-lumefantrine Among Providers and Patients in Routine Healthcare Practice: a Qualitative Study in Eastern Tanzania
Authors: Mosha Dominic , Kakolwa Mwaka A , Mahende Muhidin K , Masanja Honorati , Abdulla Salim , Drakeley Chris , Gosling Roland , Wamoyi Joyce
Published: June 2021

Background: Primaquine is a gametocytocidal drug recommended by the WHO in a single-low dose combined with artemisinin-based combination therapy (ACT) for the treatment and prevention of Plasmodium falciparum malaria transmission. Safety monitoring concern and the lack of universal validated and approved primaquine pharmacovigilance tool is a challenge for a national rollout in many countries. This study aimed explored acceptance, reliability and perceived effectiveness of the primaquine roll out monitoring pharmacovigilance tool (PROMPT). Methods: This study was conducted in three dispensaries in the Coastal region of Eastern Tanzania. The study held six in-depth interviews with healthcare providers and six participatory focus group discussions with malaria patients (3) and parents/guardians of sick children (3). Participants were purposively sampled. Thematic analysis was conducted with the aid of NVivo qualitative analysis software.Results: The respondents’ general acceptance and perceived effectiveness of the single-low dose primaquine and PROMPT was good. Screening procedure for treatment eligibility and explaining to patients about the possible adverse events was considered very useful for safety reasons. Crushing and dissolving of primaquine tablet to get the appropriate dose, particularly in children, was reported by all providers to be challenging. Transport cost and poor access to the health facility were the main reasons for a patient failing to return to the clinic for a scheduled follow-up visit. Treatment was perceived to be safe by both providers and patients and reported no case of a severe adverse event. Some providers were concern with the haemoglobin drop observed on day seven. Conclusion: Single-low dose primaquine was perceived to be safe and acceptable among providers and patients. PROMPT demonstrated to be a reliable and user-friendly tool among providers. Further validation of the tool by involving the National Malaria Control Program is pivotal to address key challenges and facilitate the adoption of primaquine in the national policy.
Polypharmacy and Falls Risk-increasing Drugs: Their Relation to Fall Recurrence
Authors: Akın Sibel , Şentürk Nurdan Durmuş , Soysal Tuba , Özer Firuzan Fırat , Gokcekuyu Bilge Müge , Zararsız Gözde Ertürk
Published: June 2021

Background: Polypharmacy and adverse drug side effects are among the high-risk causes for falls in older adults.Objective: To assess the association between polypharmacy and the risk of recurrent falls and different pharmacological groups of drugs with falls.Setting: University hospital in community-dwelling older adults in Turkey.Method: Falls risk-increasing drugs were identified as Cardiovascular drugs, Analgesics, Central Nervous System (CNS) drugs, Endocrine drugs, and others. Falls were evaluated as to whether absent or present during the past 12 months. Two or more falls were recorded as a recurrent faller.Main outcome measure: Low hand grip strength (HGS) increased the risk of fall approximately 1.7 times (Odds Ratio (OR) 1.69 95% CI 1.11-2.58). Older age and using angiotensin-converting enzyme inhibitors (ACE-I) increased the risk of recurrent falls (OR 1.05: 95% CI 1.00-1.09 and OR 4.04: 95% CI 1.70-9.60, respectively).Results: Patients' mean (SD) age was 71.9 (7.5)  years, and 71.0% of them were female. While 87 (51.4%) participants fall once, 82 (48.5%) of participants reported recurrent falls. Two hundred and eighty-eight (55.6%) participants had four or more prescribed medications. The percentage of patients who used at least one PIM on admission, as defined by the Beers criteria, was 155 (29.9%). Conclusion: Although the polypharmacy rate of the participants was high, there was no significant relationship between polypharmacy and falling. But low HGS, one of the components of sarcopenia, was a risk factor for fall, and older age and use of ACE-I were risk factors for recurrent fall.
The 3D Organisation of Mitochondria in Primate Photoreceptors
Authors: Hayes Matthew J , Tracey-White Dhani , Kam Jaimie Hoh , Powner Michael B , Jeffery Glen
Published: June 2021

Vertebrate photoreceptors contain large numbers of closely-packed mitochondria which sustain the high metabolic demands of these cells. These mitochondria populations are dynamic and undergo fusion and fission events. This activity serves to maintain the population in a healthy state. In the event of mitochondrial damage, sub-domains, or indeed whole mitochondria, can be degraded and population homeostasis achieved. If this process is overwhelmed cell death may result. Death of photoreceptors contributes to loss of vision in aging individuals and is associated with many eye diseases. In this study we used serial block face scanning electron microscopy of adult (Macaca fascicularis) retinae to examine the 3D structure of mitochondria in rod and cone photoreceptors. Healthy-looking photoreceptors contain mitochondria with a range of shapes which are associated with different regions of the cell. In some photoreceptors we observe mitochondrial swelling and other changes we associate with stress or degeneration of the cell. In both rods and cones we identify elongated domains of mitochondria with densely-packed normal cristae associated with photoreceptor ciliary rootlet bundles. We observe mitochondrial fission and mitochondrion fragments localised to these domains. Swollen mitochondria with few intact cristae are located towards the periphery of the photoreceptor inner-segment in rods, whilst they are found throughout the cell in cones. Swollen mitochondria exhibit sites on the mitochondrial inner membrane which have undergone complex invagination resulting in membranous, electron-dense aggregates. Membrane contact occurs between the mitochondrion and the photoreceptor plasma membrane in the vicinity of these aggregates, and a series of subsequent membrane fusions results in expulsion of the mitochondrial aggregate from the photoreceptor. These events are primarily associated with rods, likely reflecting the ageing mechanism in primates where many rods die but cones do not. Possible consequences of this atypical mitochondrial degradation are discussed.
DPYSL2 is a Potential Diagnostic and Prognostic Biomarker Linked to Immune Infiltration in Lung Adenocarcinoma
Authors: Wu Yangjie , Nai Aitao , He Guicheng , Xiao Fei , Li Zhimin , Tang Sanyuan , Liu Yanping , Ai Xiaohong
Published: June 2021

Background: Dihydropyrimidinase Like 2 (DPYSL2) has been linked to tumor metastasis. However, the function of DPSY2L in lung adenocarcinoma (LUAD) is yet to be explored.Methods: Herein, we assessed DPYSL2 expression in various tumor types via online databases such as Oncomine and Tumor Immune Estimation Resource (TIMER). Further, we verified the low protein and mRNA expressions of DPYSL2 in LUAD via the ULCAN, The TCGA and GEPIA databases. We applied the ROC curve to examine the role of DPYSL2 in diagnosis. The prognostic significance of DPYSL2 was established through the Kaplan-Meier plotter and the Cox analyses (univariate and multivariate). TIMER was used to explore DPYSL2 expression and its connection to immune infiltrated cells. Through Gene Set Enrichment Analysis, the possible mechanism of DPYSL2 in LUAD was investigated. Results: In this study, database analysis revealed lower DPYSL2 expression in LUAD than in normal tissues. The ROC curve suggested that expression of DPYSL2 had high diagnostic efficiency in LUAD. The DPYSL2 expression had an association with the survival time of LUAD patients in the Kaplan-Meier plotter and the Cox analyses. The results from TIMER depicted a markedly positive correlation of DPYSL2 expression with immune cells infiltrated in LUAD, such as macrophages, dendritic cell, CD4+ T cells, and neutrophils. Additionally, many gene markers for the immune system had similar positive correlations in the TIMER analysis. In Gene Set Enrichment Analysis, six immune-related signaling pathways were associated with DPYSL2.Conclusions: In summary, DPYSL2 is a novel biomarker with diagnostic and prognostic potential for LUAD as well as an immunotherapy target.
Understanding Pathogen-host Interplay by Expression Profiles of LncRNA and mRNA in the Liver of Echinococcus Multilocularis-infected Mice
Authors: Nian Xiaofeng , Li Li , Ma Xusheng , Li Xiurong , Li Wenhui , Zhang Nianzhang , Ohiolei John Asekhaen , Li Le , Dai Guodong , Yan Hongbin , Fu Baoquan , Xiao Sa , Jia Wanzhong
Published: June 2021

Background: Echinococcus multilocularis (Em) infection and the growth and proliferation of its metacestode within the internal organs of hosts are related to complex host–parasite interactions at the molecular level. Previous studies reported the profiles of long non-coding RNAs (lncRNAs) and mRNAs in Echinococcus granulosus-infected mice or cells, suggesting the potential role of lncRNAs in regulating host-parasite interplay. However, the profiles of lncRNAs and mRNAs of mice in response to Em are poorly understood. Methods: Numerous differentially expressed lncRNAs (DELs) and mRNAs (DEMs) in the mouse liver at eight time points after Em infection were identified by microarray. Functional Annotation of dysregulated DEMs was conducted by gene ontology (GO) classification and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The potential function of DELs was predicted by constructing lncRNA-mRNA co-expression network and Transcription factor (TF)-lncRNA-mRNA Ternary Network. Additionally, qRT-PCR and western blotting were used to validate the upregulated DEMs at 30 days post-infection (dpi), which were enriched in Toll-like and RIG-I-like receptor signaling pathways. Cytokines and chemokines involved in these two pathways were determined by ELISA.Results: Thirty-one DEMs and 68 DELs were found continuously dysregulated. These DEMs were notably enriched in the “antigen processing and presentation,” “Th1 and Th2 cell differentiation” and “Th17 cell differentiation” pathways. The potential function prediction of DELs revealed that most DELs might influence the differentiation of Th17 cell and TGF-β/Smad pathway through trans regulating the SMAD3, STAT1, and early growth response (EGR) genes. Additionally, the validated results by qRT-PCR and western blotting showed that the mRNA expression levels of these genes increased while the corresponding protein expression levels were unaltered except c-Jun amino-terminal kinase (JNK). Regardless, phospho-nuclear factor Kappa B (p-NF-κB) downstream of these two pathways was induced at 15 and 30 dpi, which led to the elevated levels of IL-1 beta and IL-6 in the serum. Conclusion: Our data provide novel clues in understanding the roles of lncRNAs in the host–Em interplay and the influence of Em infection on host innate immunity.
Development and Evaluation of a Multiplex SARS-CoV-2 RT-ddPCR, Applicable to Respiratory and Wastewater Samples
Authors: Poelvoorde Laura A. E. Van , Gand Mathieu , Fraiture Marie-Alice , De Keersmaecker Sigrid C. J. , Verhaegen Bavo , Hoorde Koenraad Van , Cay Ann Brigitte , Balmelle Nadège , Herman Philippe , Roosens Nancy
Published: June 2021

The worldwide emergence and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since 2019 has highlighted the importance of rapid and reliable diagnostic testing to prevent and control the viral transmission. The monitoring of the viral spread can be performed using individual diagnostics in clinical samples and global detection of SARS-CoV-2 in wastewater samples. Reverse-transcription droplet digital PCR (RT-ddPCR) offers an attractive platform for absolute RNA quantification in comparison to the gold standard reverse transcription quantitative PCR (RT-qPCR) that only yields relative quantification results. To avoid inaccurate results due to false negatives caused by polymorphisms or point mutations that can possibly compromise the accuracy of the diagnostic tests, a multiplex RT-ddPCR method was developed by combining previously published SARS-CoV-2 detection RT-qPCR assays targeting well-conserved ORF1a and RdRp genes. These assays were successfully evaluated in silico for their inclusivity using GISAID sequences from the beginning of November 2020 to the end of February 2021. The sensitivity and specificity of the new RT-ddPCR method was evaluated and its applicability on both clinical and wastewater samples was illustrated. In conclusion, a reliable and sensitive multiplex one-step RT-ddPCR assay for reliable quantification of SARS-CoV-2 RNA in clinical and wastewater samples was developed and assessed, providing a key tool for the current health crisis.
Cell Surface and Functional Features of Cortical Bone Stem Cells
Authors: Sasaki Norihiko , Itakura Yoko , Mohsin Sadia , Ishigami Tomoaki , Kubo Hajime , Chiba Yumi
Published: June 2021

Background: The newly established mouse cortical bone–derived stem cells (mCBSCs) are unique stem cells compared with mouse mesenchymal stem cells (mMSCs), and can improve cardiac function after myocardial infarction. However, the mCBSCs’ characterizations including their stem cell features, non-cardiac therapeutic potential, and cell surface features have not been fully understood. In this study, we examined stem cell features, cell surface glycan profiles, and cell functional features in mCBSCs compared to the bone marrow-derived mMSCs. Methods: The stem cell features were compared between mCBSCs and mMSCs by immunoblotting of stem cell markers, self-renewal assay, and multilineage differentiation. The cell surface glycan profiles were examined by lectin array analysis and fluorescence-activated cell sorting analysis using lectins. The production of transforming growth factor (TGF)-β1 from mCBSCs were examined by ELISA. The effects of TGF-β1 released from mCBSCs on self-migration and on activation of fibroblast were examined by migration assay and immunocytostaining, respectively. Results: The stem cell feature, including the self-renewing ability in mCBSCs was higher than that in mMSCs. In contrast, the differentiation ability of mCBSCs was limited to the chondrogenic lineage among three types of cells (adipocyte, osteoblast, chondrocyte). The cell surface glycan profiles revealed that α2-6sialic acid is expressed at very low levels on the cell surface of mCBSCs compared with that on mMSCs. Additionally, the lactosamine (Galβ1-4GlcNAc)-structure, poly lactosamine- or poly N-acetylglucosamine-structure, and α2-3sialic acid on both N- and O-glycans are more highly expressed in mCBSCs compared with mMSCs. Furthermore, these highly expressed glycans were increased with cellular aging of mCBSCs. We found that TGF-β1 was released from mCBSCs and the released TGF-β1 contributed to the self-migration of mCBSCs and activation of fibroblasts. Conclusions: These results reveal the differences between mCBSCs and mMSCs, and it is proposed that there is the potential use of mCBSCs for infarct healing and wound healing.
Triptolide Inhibits the Activation of NLRP3 Inflammasome by Inhibiting NF-κB Pathway and Improves Myocardial Fibrosis
Authors: Shen Jianyao , Ma Hailiang , Wang Chaoquan
Published: June 2021

ObjectiveTriptolide (TPL) is identified to be involved in the treatment for myocardial fibrosis (MF). This study investigated the mechanism of TPL in MF in rats and observed its effect on NLRP3 inflammasome signaling pathway.Materials and MethodsThe MF rat model was established by subcutaneous injection of isoproterenol (ISO), and treated by subcutaneous injection of TPL. After modeling for 1 week, the cardiac function of rats was evaluated, including LVEF, LVFS, LVES, LVED LVIDs and LVPWs. The HMI and LVMI were measured. The expressions of ANP, BNP, inflammatory related factors (IL-1β, IL-18, TNF-α, MCP-1, VCAM-1), and NLRP3 inflammasome factors (NLRP3, ASC, caspase-1) in rats were detected. HE staining and Masson staining were used to observe myocardial cell inflammation and fibrosis of rats.ResultsLVED, LVES, LVIDs and LVPWs of MF group were significantly upregulated, LVEF and LVFS were significantly downregulated, HMI and LVMI were upregulated, while TPL treatment reversed these trends; TPL treatment downregulated the tissue injury and improved the pathological damage of MF rats. TPL treatment downregulated the levels of inflammatory factors and fibrosis factors, and inhibited the activation of NLRP3 inflammasome. Activation of NLRP3 inflammasome or NF-κB pathway reversed the effect of TPL on MF.ConclusionsTPL inhibited the activation of NLRP3 inflammasome by inhibiting NF-κB pathway, and improved the degree of MF in MF rats.
Zinc Systematics Quantify Crustal Thickness Control on Fractionating Assemblages of Arc Magmas
Authors: Chiaradia M.
Published: June 2021

Understanding the processes leading to the broad chemical variability of arc magmas is an essential, yet not fully elucidated, issue in Earth Sciences. Here, I show that Zn-MgO-SiO2 systematics of magmatic arc rocks correlate significantly with arc thickness. Because Zn-MgO-SiO2 systematics are mostly controlled by fractionation of different mineral phases this suggests a systematic change in the proportions of fractionating mineral assemblages depending on arc thickness. Using a mass balance model with a Monte Carlo approach, I show that Zn-MgO-SiO2 systematics can be quantitatively explained by a continuous transition from plagioclase-dominated fractionating assemblages in thin arcs to amphibole-garnet-magnetite-dominated assemblages in increasingly thicker arcs. Such a systematic change results from the increase of average depth of magma differentiation that is ultimately controlled by arc thickness. Results presented have implications on the causes of different geochemical trends in arcs, the role of arcs as H2O filters, and their association with major porphyry deposits.
Dexmedetomidine reduces isoflurane-induced neuroapoptosis through regulating BDNF and proBDNF
Authors: Ding Xudong , Zhang Hui , Sun Shiwei , Ma Chenguang , ZHENG NINGNING , Liu Hongtao
Published: June 2021

Background: It is well-acknowledged that Isoflurane induces neuroapoptosis in neonatal rats. Dexmedetomidine, as an α2-adrenergic agonist, was previously demonstrated to provide neuroprotection when administered during isoflurane anesthesia. Our study aims to investigate the mechanisms concerning the neuroprotective effect of dexmedetomidine from the alterations of BDNF,ERK, and JNK signals in the hippocampal region. Methods: Neonatal Sprague-Dawley rats at postnatal day 7 were assigned into Control group, Isoflurane group, Dexmedetomidine group and Inhibitor group. After exposed to 2% isoflurane in 40% of oxygen mixed with nitrogen for 4h, the hippocampus tissues were separated and critical signal pathway proteins of BDNF, proBDNF, JNK, ERK, and caspase 3 were detected. Results: Neuroapoptosis was triggered by Isoflurane with the increased expression of caspase 3 and TUNEL-positive cells. This effect was reversed by dexmedetomidine accompanying with up-regulation of BDNF and phospho-ERK and down-regulation of proBDNF and phospho-JNK. Conclusions: This study revealed that dexmedetomidine pretreatment can attenuate neurotoxicity caused by isoflurane in neonatal rats by regulating BDNF, proBDcNF, ERK, and JNK, which would provide a new target for neuroprotection.